1,2,3-Triazole-containing hybrids as potential anticancer agents: Current developments, action mechanisms and structure-activity relationships

European Journal of Medicinal Chemistry 183 (2019) 111700

Contents lists available at ScienceDirect

European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech

Review article

1,2,3-Triazole-containing hybrids as potential anticancer agents: Current developments, action mechanisms and structure-activity relationships Zhi Xu a, *, 1, Shi-Jia Zhao b, 1, Yi Liu b, ** a b

Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, PR China Wuhan University of Science and Technology, Wuhan, PR China

a r t i c l e i n f o

a b s t r a c t

Article history: Received 25 July 2019 Received in revised form 8 September 2019 Accepted 12 September 2019 Available online 16 September 2019

Anticancer agents are critical for the cancer treatment, but side effects and the drug resistance associated with the currently used anticancer agents create an urgent need to explore novel drugs with low side effects and high efficacy. 1,2,3-Triazole is privileged building block in the discovery of new anticancer agents, and some of its derivatives have already been applied in clinics or under clinical trials for fighting against cancers. Hybrid molecules occupy an important position in cancer control, and hybridization of 1,2,3-triazole framework with other anticancer pharmacophores may provide valuable therapeutic intervention for the treatment of cancer, especially drug-resistant cancer. This review emphasizes the recent advances in 1,2,3-triazole-containing hybrids with anticancer potential, covering articles published between 2015 and 2019, and the structure-activity relationships, together with mechanisms of action are also discussed. © 2019 Elsevier Masson SAS. All rights reserved.

Keywords: 1,2,3-Triazole Hybrid molecules Anticancer Action mechanism Structure-activity relationship

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 1,2,3-Triazole hybridizes with other anticancer pharmacophores (type I) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2.1. 1,2,3-Triazole-artemisinin hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2.2. 1,2,3-Triazole-azole hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.2.1. 1,2,3-Triazole-triazole hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 2.2.2. 1,2,3-Triazole-imidazole hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 2.2.3. 1,2,3-Triazole-ox(adi)azole/isoxazole hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 2.2.4. 1,2,3-Triazole-pyrazole hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 2.2.5. 1,2,3-Triazole-thiazole hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 2.3. 1,2,3-Triazole-chalcone hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 2.4. 1,2,3-Triazole-coumarin/flavone hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 2.5. 1,2,3-Triazole-indole/isatin hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 2.6. 1,2,3-Triazole-pyridine hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 2.7. 1,2,3-Triazole-pyrimidine hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 2.8. 1,2,3-Triazole-quinazoline hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 2.9. 1,2,3-Triazole-quinoline/quinolone hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 2.10. 1,2,3-Triazole-quinone hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 2.11. 1,2,3-Triazole-steroid hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

* Corresponding author. ** Corresponding author. E-mail addresses: [email protected] (Z. Xu), [email protected] (Y. Liu). 1 These authors contributed equally. https://doi.org/10.1016/j.ejmech.2019.111700 0223-5234/© 2019 Elsevier Masson SAS. All rights reserved.

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2.12. 1,2,3-Triazole-sugar hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 2.13. Miscellaneous 1,2,3-triazole hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 1,2,3-Triazole as a linker (type II) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 3.1. 1,2,3-Triazole tethered artemisinin hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 3.2. 1,2,3-Triazole tethered chalcone/coumarin hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 3.3. 1,2,3-Triazole tethered indole/isatin hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 3.4. Miscellaneous 1,2,3-triazole tethered hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

1. Introduction Cancer is one of the leading causes of death and results in around 9 million deaths annually [1,2]. Anticancer agents are indispensable for cancer treatment, and up to date, more than 100 drugs have been approved for this purpose [3,4]. However, the rapid development of drug resistance and the acute side effects of clinical used anticancer drugs are still the major obstacles to efective chemotherapy [5e7], making an urgent need to explore new drugs with low side effects and high efficacy. (see Figs. 4e29) 1,2,3-Triazoles, one of the most important classes of nitrogen containing heterocycles, have the ability to form various noncovalent interactions such as hydrophobic interactions, hydrogen bonds, van der Waals forces and dipole-dipole bonds with different biological targets, so 1,2,3-triazole derivatives possess diverse pharmaceutical properties such as antibacterial [8,9], antimalarial [10,11], antifungal [12,13], antiviral [14,15], antitubercular [16,17] and anticancer [18,19] activities. Moreover, some of 1,2,3-triazolecontaining compounds such as Cefatrizine and Carboxyamidotriazole (Fig. 1) have already been used in clinics or under clinical evaluation for cancer treatment, revealing their potential as putative anticancer drugs. Hybrid molecules have the potential to reduce side effects and overcome the drug resistance since hybrids with two or more different pharmacophores may also own multiple action mechanisms [20,21]. It is worth to notice that several hybrid molecules are under different phase clinical trials for the treatment of various diseases including those caused by drug-resistant organisms, revealing hybridization is a useful strategy to develop novel drugs [22,23]. Obviously, it is conceivable that hybridization of 1,2,3triazole framework with other anticancer pharmacophores has the potential to provide novel anticancer candidates with low toxicity and high efficacy against drug-resistant cancers. There are two major types of 1,2,3-triazole-containing hybrids (Fig. 2): 1. Type I, 1,2,3-triazole hybridizes with other anticancer pharmacophores through different linkers; 2. Type II, 1,2,3-triazole acts as a linker to tether the two anticancer pharmacophores. The review emphasizes 1,2,3-triazole-containing hybrids (Type I and Type II) with potential anticancer activity, covering articles published between 2015 and 2019. The structure-activity relationships (SARs) together with mechanisms of action are also discussed to

Fig. 1. Chemical structures of 1,2,3-triazole-containing anticancer agents Cefatrizine and Carboxyamidotriazole.

provide an insight for rational design of more effective 1,2,3triazole hybrids. 2. 1,2,3-Triazole hybridizes with other anticancer pharmacophores (type I) In recent years, many pharmacophores such as Artemisinin, azole, chalcone, coumarin/flavone, indole/isatin, pyridine, pyrimidine, quinazoline, quinoline/quinolone, quinone, steroid, and sugar were found to possess potential anticancer activity. Attachment of these anticancer pharmacophores with 1,2,3-triazole backbone is a promising strategy to develop novel anticancer candidates which are highly effective against both drug-sensitive and drug-resistant cancers due to their individual action mechanisms. 2.1. 1,2,3-Triazole-artemisinin hybrids Artemisinin and its derivatives like Dihydroartemisinin, Arteether and Artesunate with peroxide-containing sesquiterpene lactone structure are mainstays of chemotherapy against malaria [24e26]. Beyond their outstanding antimalarial activity, Artemisinin derivatives also possess high specificity toward cancer cells and broad-spectrum effects against different types of cancer even drugresistant cancers due to their ability to form cytotoxic reactive oxygen species (ROS), which induce cancer cell damage [27e29]. Thus, hybridization of 1,2,3-triazole with Artemisinin moiety may provide novel anticancer candidates with high selectivity and favorable efficacy against a series of cancers. The 1,2,3-triazole-artemisinin hybrids 1 (Fig. 3 IC50: 2.5e175.9 mM, MTT assay) and their regio-isomers 2 (IC50: 5.7e108.1 mM) possess broad spectrum in vitro anticancer activity against four cancer cell lines including MCF-7, LU-1, HL-60 and P388 cells, and a significant part of them were more active than the reference Dihydroartemisinin (IC50: 39.9e84.3 mM) [30]. The endoperoxide-induced cell death, which was mediated by heme or a heme-containing protein, could be of main responsibility for the action mechanism. Most of hybrids 1 were more potent than the corresponding meta-position analogs 2, suggesting the position of the amide has great influence on the activity. Piperidyl especially 4methylpiperidyl and 2-methylpiperidyl at R position enhanced the activity remarkably, while pyrrolidyl was detrimental to the activity. The representative hybrid 1g (IC50: 2.5e4.7 mM) was comparable to Ellipticine (IC50: 1.7e3.5 mM), and 10.5e21.6 folds more potent than Dihydroartemisinin against the all tested cancer cell lines. Thus, this hybrid can be considered as an excellent anticancer candidate which could be a useful starting point in drug development of anticancer agents. The 1,2,3-triazole-artemisinin hybrids 3 and their derivatives 4 (IC50: 4.06e89.85 mM, MTT assay) exhibited promising activity against K562, PC-3, A431, MDAMB-231, COLO-205, and A549 cancer cell lines [31]. The anticancer activity of hybrids 3 was higher than

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Fig. 2. The two major classes of 1,2,3-triazole-containing hybrids.

Fig. 3. Chemical structures of 1,2,3-triazole-artemisinin hybrids 1e8.

that of the corresponding derivatives 4, implying the endoperoxide framework was essential for the high activity. Among them, conjugate 3a (IC50: 4.06e36.65 mM) was highly active against the tested six cancer cell lines, demonstrating attachment of hydrogen bond donor was beneficial to the activity. Conjugate 3a was comparable to Doxorubicin (IC50: 1.43e11.99 mM), and superior to Dihydroartemisinin (IC50: 42.44e52.63 mM) and Artemisinin (IC50: 39.03e68.82 mM) against all cancer cell lines. Moreover, conjugate 3a was non-toxic on human erythrocyte and towards normal HEK293 cells, suggesting its excellent safety profile. Further

investigation revealed that hybrid 3a which was able to induce the ROS formation in tested cell lines showed significant cell cycle arrest at G2/M phase and apoptosis in skin and lung cancer cells. The in vitro anticancer SAR of 1,2,3-triazole-artemisinin hybrids 5e7 against CME, HeLa and HEMC-1 cancer cell lines revealed that hybrids 7 (IC50: 2.7e40 mM, MTT assay) were generally more potent than hybrids 5 (IC50: 20->250 mM) and 6 (IC50: 10e62 mM), implying the ester linker between 1,2,3-triazole and Artemisinin moieties was more favorable than the ether linker [32]. Compound 5a (IC50: 20e35 mM) was more active than the regio-isomer 5b

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Fig. 4. Chemical structures of 1,2,3-triazole-triazole hybrids 9e18.

(IC50: 127->250 mM), while attachment of both electron-donating and electron-withdrawing groups (5c-e, IC50: 30e175 mM) onto the phenyl ring could improve the activity. For hybrids 6, introduction of halogen atoms into the phenyl ring could boost up the activity as evidenced by the conjugate 6b (IC50: 20e35 mM) showed the strongest activity in this series. For hybrids 7, replacement of substituted phenyl with indole could not enhance the activity, and compound 7a (IC50: 2.7e34 mM) was highly active against all tested

cancer cell lines. Further study indicated that replacement of Artemisinin by aza-artemisinin motif (8, IC50: 0.92e155 mM) was also tolerated, and the highest activity was found for compound 8d with IC50 values of 0.92 and 1.2 mM against CEM and HeLa cells, respectively. Moreover, this hybrid proved to be 30-fold more active in tumor versus endothelial cells, pointing to a potential cancerselective mechanism of action [32].

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Fig. 5. Chemical structures of 1,2,3-triazole-imidazole hybrids 19e23.

Fig. 6. Chemical structures of 1,2,3-triazole-ox(adi)azole/isoxazole hybrids 24e28.

2.2. 1,2,3-Triazole-azole hybrids Azoles, the nitrogen-containing five-membered heterocycles,

are presented in a huge number of biological active compounds such as anticancer agents Anastrozole, Cefatrizine, Carboxyamidotriazole, Letrozole and Tazobactam [33,34]. Thus, hybridization of

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Fig. 7. Chemical structures of 1,2,3-triazole-pyrazole hybrids 29e32.

Fig. 8. Chemical structures of 1,2,3-triazole-thiazole hybrids 33e36.

1,2,3-triazole with azoles is probably an attractive strategy to develop novel anticancer candidates. 2.2.1. 1,2,3-Triazole-triazole hybrids Triazole, the bioisostere of ester and amide, can be divided into 1,2,3-triazole and 1,2,4-triazole, and it has the potential to improve pharmacological, pharmacokinetic, and physicochemical profiles of molecules [35,36]. Thus, 1,2,3-triazole-triazole hybrids are potential prototypes for the discovery of novel anticancer candidates. The binaphthylamino tethered 1,2,3-triazole dimer 9a (IC50: 5.53 and 9.13 mM, MTT assay) showed promising activity against HeLa and A549 cancer cell lines, and it was non-toxic towards

normal mouse myoblast C2C12 cells (IC50:
40 mM) [37]. The anticancer activity of dimer 9a was higher than that of the analog 9b (IC50: 7.24 and 15.13 mM), suggesting the 1,2,3-triazole moiety could improve the anticancer activity. This dimer could bind the c-MYC Gquadruplex with higher affinity, and down-regulated the c-MYC expression in transcriptional and translational level. Moreover, dimer 9a was able to inhibit cancer cell growth by inducing Sub G1 phase cell cycle arrest and apoptosis. The pyridine tethered 1,2,3triazole dimer 10a (IC50: 1.7 and 1.3 mM, MTT assay) and its regioisomer 10b (IC50: 14.4 and 15.1 mM) as well as 1,2,3-triazole trimers 11a,b (IC50: 7.1e13.4 mM, MTT assay) also displayed considerable activity against MCF-7 and HCT-116 cancer cell lines, and

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Fig. 9. Chemical structures of 1,2,3-triazole-chalcone hybrids 37e41.

compounds 10a, 11a were more potent than the regio-isomers 10b, 11b, suggesting the 1,2,3-triazole and amide moieties at meta-position of phenyl ring was better than para-position [38e40]. All the four compounds were non-toxic towards C2C12 cells (IC50: >40 mM), indicating the favorable safety profile. Interestingly, cellular studies revealed that dimer 10a down-regulated BCL-2 gene expression, while 10b up-regulated BCL-2 gene expression in cancer cells [38]. Moreover, dimer 10a could trigger apoptosis via activation of caspases 3 and 7, whereas 10b reduced the level of active caspases 3/7 and decreases the percentage of apoptotic cancer cells. The pyrazoline-containing dimers 12 (IC50: >100 mg/mL, MTT assay) without amide was devoid of activity against HCT116, and HepG2 cancer cell lines, but they (IC50: 32.26e66.79 mg/mL) were comparable to 5-Fluorouracil (IC50: 30.00 mg/mL) against MCF7 cells [41]. The anticancer activity of dimers 12b,c (IC50: 32.26 and 43.50 mg/mL) bearing N-thioamide moiety against MCF-7 was higher than that of the acetyl analog 12a (IC50: 66.79 mg/mL), demonstrating thioamide could enhance the activity. Dimer 13 (IC50: 30.3 and 38.2 mM, MTT assay) was 37.3 and 16.3 times more potent Temozolomide (IC50: 1132 and 624.8 mM) against highly drug-resistant human glioblastoma (GBM) GBM02 and GBM95 cancer cell lines [42]. The SAR indicated that substitution of aldehyde with imine led to loss of activity. The dimer 13 was not only effective against highly drug-resistant cancer cell lines, but also not toxic to astrocytes. Moreover, the ADMET properties of this compound in the in silico analysis met the criteria for central nervous system (CNS)-acting drugs. These results demonstrated that dimer 13 might be a potent CNS-acting drug candidate. The majority of 1,4-dihydropyridine tethered 1,2,3-triazole dimers 14 were inactive against MDA-MB-231 and MCF-7 cancer cell lines, and similar results were also observed for carnosic acid and carnosol tethered 1,2,3-triazole dimers 15 and 16 [43,44]. However, the amide tethered dimers 17a,b (IC50: 7e45.63 mM, MTT assay) displayed considerable anticancer activity, and both of them (IC50: 7 and 12 mM) were comparable to Tamoxifen (IC50: 11.2 mM) against MDA-MB-231 cancer cell line, and they were non-toxic (IC50: >50 mM) in normal human embryonic kidney (HEK-293) cells [45]. These results proved that the linker between the two 1,2,3-triazole

moieties influenced the anticancer of dimers significantly. Besides the 1,2,3-triazole-triazole hybrids mentioned above, the benzotriazole-1,2,3-triazole hybrids [46,47] and 1,2,3-triazole1,2,4-triazole hybrids [48] also exhibited potential anticancer activity. Among them, 1,2,3-triazole-1,2,4-triazole hybrids 18 (IC50: 0.31e0.60 mM, CCK-8 assay) was highly active against ABC-DLBCL cell line, and the SAR revealed that the 2-chloroacetylamide moiety was indispensable for the high activity [48]. 2.2.2. 1,2,3-Triazole-imidazole hybrids Imidazole derivatives such as Pretomanid (PA-824) and Delamanid possess great potency against multidrug-resistant organisms, so 1,2,3-triazole-imidazole hybrids are reasonable choice for the discovery of novel anticancer candidates which may be active against both drug-sensitive and drug-resistant cancers [49,50]. The majority of 1,2,3-triazole-benzimidazole hybrids 19e21 (IC50: 0.05e62.14 mM, MTT assay) exhibited considerable activity against A549, HeLa, CFPAC-1 (ductal pancreatic adenocarcinoma), and SW620 (metastatic colorectal adenocarcinoma) cells, which could be attributed to the induction of apoptosis and primary necrosis [51,52]. The SAR revealed that amidines on the C-5 position of benzimidazole were closely related with the activity, and the order was imidazoline > amidine > N-isopropylamidine. Trifluoromethyl at R position was favorable to all cancer cell lines, while chlorine and iodine atoms gave extremely potent effect on A549 cells and SW620 cells. The representative hybrid 19e (IC50: 0.32e2.09 mM) was comparable to or better than 5-Fluorouracil (IC50: 0.08e8.81 mM) against the tested cancer cells, but it was also toxic towards normal human lung fibroblasts (WI38, IC50: 0.52 mM). The anticancer SAR of hybrids 22 (IC50: 0.788e63.09 mM, MTT assay) against a panel of four human cancer cell lines HeLa, DU-145, MCF-7 and HepG2 indicated that electron-donating group at R1 and R2 positions was beneficial to the activity, while electronwithdrawing group was detrimental to the activity [53]. The most active hybrids 22a,b (IC50: 0.788e6.456 mM) were no inferior to Doxorubicin (IC50: 1.428e2.594 mM) against all tested cancer cells. The flow cytometric analysis revealed that these two conjugates could cause cell cycle arrest at G2/M phase, effectively inhibit

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Fig. 10. Chemical structures of 1,2,3-triazole-coumarin hybrids 42e52.

microtubule assembly and disrupt the microtubule organization in the lung cancer cells. The conjugates 23 (IC50: 0.51e47.64 mM, MTT assay) displayed predominately activity against A549, DU-145, HCT-116 and MDAMB 231 cancer cell lines [54,55]. The SAR revealed that introduction of either electron-donating methoxy or electron-withdrawing chloro at R1 position decreased the activity when compared with the unsubstituted analogs, while halogen atom at R2 position had positive effect on the activity. Mechanism study demonstrated that these hybrids arrested the cell cycle at G2/M phase in A549 cells, inhibited tubulin, and induced cell death by apoptosis. Hybrids 22a,b (IC50: 0.51e3.98 mM) were found to be most active against the tested cancer cell lines, and the activity was comparable to that of Nocodazole (IC50: 1.38e1.65 mM). The two hybrids (IC50: 63.53 and 91.25 mM) also showed low cytotoxicity towards human embryonic kidney cells HEK 293, so they can potentially serve as lead molecules for the development of novel anticancer chemotherapeutic agents. 2.2.3. 1,2,3-Triazole-ox(adi)azole/isoxazole hybrids Ox(adi)azole/isoxazole rings, containing nitrogen and oxygen atoms in the five-membered aromatic ring, are ubiquitous and privileged scaffolds in drug design. A huge number of ox(adi)azole/

isoxazole compounds exhibit wide spectrum of pharmacological profiles, and some of them have been frequently employed as clinical drugs for the treatment of various types of diseases [56,57]. The anticancer SAR of 1,2,3-triazole-oxazole hybrids 24 (IC50: 3.1e88 mM, MTT assay) against the human solid cancer cell lines A549, HBL-100 (breast), HeLa, SW1573 (non-small cell lung), T-47D (breast) and WiDr (colon) revealed that oxazole moiety was crucial for the high activity, and replacement of oxazole by thiazole resulted in loss of activity [58]. The substituents at R1 position were crucial for the activity, and the relative contribution order was allyl > eCH2Bn > i-Pr > n-Pr. Hybrids with alkyl substituent at R2 position showed higher activity than the unsubstituted analogs, and the branched alkyl was better than the linear alkyl group. Among them, hybrid 24j (IC50: 3.1e6.6 mM) was found to be most active against all tested human solid cancer cell lines, and it was at least comparable to 5-Fluorouracil (IC50: 4.3e49 mM). Moreover, hybrid 24j (IC50: 53 mM) also displayed lower cytotoxicity than 5Fluorouracil (IC50: 5.5 mM) towards normal BJ-hTert cells. These results suggested a potential anticancer activity vested in this new class of 1,2,3-triazole-oxazole scaffolds. The 1,2,3-triazole-benzoxazole hybrid 25 (IC50: 6.8, 7.1, and 11.2 mg/mL, MTT assay) exhibited potential activity against HeLa, SKBr3, and HepG2 cancer cells [59]. The dose dependent

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Fig. 11. Chemical structures of 1,2,3-triazole-flavone/flavanone hybrids 53e57.

Fig. 12. Chemical structures of 1,2,3-triazole-indole hybrids 58e65.

cytotoxicity analysis indicated that increasing the concentration from 5 to 30 mg/mL led to decrease in the percent viability of the three cancer cell lines, implying the potential applicability of this compound as a cancer therapeutic agent. The majority of 1,2,3-triazole-isoxazole hybrids 26 (GI50: >100 mg/mL, SRB assay) were devoid of activity against breast cancer cell lines, and only hybrids 26a,b (GI50: 85.7 and 27.7 mg/mL) showed moderate activity against MCF-7 and T47D cells, but the activity was lower than that of Etoposide (GI50: 7.5 and 7.9 mg/mL)

[60]. 1,2,3-Triazole-benzisoxazole hybrids 27 exhibited potential inhibitory activity against various human acute myeloid leukemia cell lines (MOLM13, MOLM14 and MV4-11 cells), and compound 27f (IC50: 2 mM, MTT assay) which was found to be the most potent against MV4-11 cells could induce cytotoxicity by increasing apoptosis of AML cells (MOLM13, MOLM14 and MV4-11 cells) as well as sub-G1 cell population and apoptotic cells at submicromolar concentrations [61]. The 1,2,3-triazole-1,3,4-oxadiazole-2-one hybrids 28 (GI50:

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Fig. 13. Chemical structures of 1,2,3-triazole-isatin hybrids 66e70.

0.82e10.22 mM, SRB assay) possessed broad spectrum anticancer activity against HeLa, MDA-MB-231, DU-145, and HEPG2 cells, and the SAR revealed that hydrogen and methyl at R1 position increased the activity, while halogen atoms chloro and bromo reduced the activity [62]. Substituents at R2 position also had great influence on the activity, and 4-methoxy and 4-nitro were harmful to the activity, while 2-fluoro improved the activity when compared with the unsubstituted analogs. Three hybrids 28a-c (GI50: 0.82e2.39 mM) demonstrated the highest activity against the tested four cancer cell lines, but all of them were far less potent than the references Paclitaxel (GI50: <0.016e0.05 mM) and Nocodazole (GI50: <0.011e0.034 mM).

2.2.4. 1,2,3-Triazole-pyrazole hybrids Pyrazole is a 5-membered ring of three carbon atoms and two adjacent nitrogen atoms, and its derivatives are potent medicinal scaffolds and exhibit a full spectrum of biological activities [63,64]. Pyrazole derivatives can act as the inhibitors of cyclin dependent kinase (CDK), aurora kinase, break point cluster region-Abelson (BCR-ABL) tyrosine kinase, heat shock protein (HSP 90), polo-like kinase, cyclo-oxygenase (COX), lypo-oxygenase (LOX), EGFR, and reticular activating system-neuro endocrine tumor (Ras-Net) ETSlike transcription factor (Elk-3) pathway, and some anticancer agents such as Tozasertib contain pyrazole moiety [65,66]. Obviously, pyrazole derivatives occupy an important position in the discovery of novel anticancer candidates. Most of 1,2,3-triazole-pyrazole hybrids 29 (IC50: <10 mM, MTT assay) showed promising activity against four human cancer cell lines A549, HT-29 (colon), PC3 (prostate), and U87MG (brain) [67]. The SAR indicated that electron-withdrawing groups at R1 position could improve the activity, whereas electron-donating groups especially 3,4-dimethoxy at R2 position were favorable to the activity, and electron-withdrawing groups like fluoro, chloro, trifuromethyl at R2 position resulted in dramatically loss of potency.

Among them, three hybrids 29a-c (IC50: 0.86e3.71 mM) were superior to 5-Flurouracil (IC50: 2.42e3.61 mM) against the tested four cancer cell lines. The action mechanism study proved that these hybrids could inhibit cancer cell migration and induce cell cycle arrest at G1 phase. Moreover, these hybrids induced apoptosis in U87MG cells by causing collapse of DJm, elevation of ROS production, inducing DNA breaks and changes in Bax/Bcl-2 gene expression profiles. Further investigation indicated that hybrids 29d,e (GI50: 0.13e0.73 mM, SRB assay) were highly active against HeLa, MCF-7 and MIAPaCa-2 (pancreatic) cancer cells, and both of them were more potent than Nocodazole (GI50: 0.81e0.95 mM, SRB assay) [68,69]. Treatment of MCF-7 cells with the two hybrids resulted in G2/M cell cycle arrest and down-regulation of CDK1 expression in MCF-7 cells. Moreover, both hybrids were able to induce apoptosis through depolarization of mitochondrial membrane potential and increment of ROS production. The anticancer activity of 1,2,3-triazole-pyrazole hybrids 30 (IC50: 6.8e27.6 mM, MTT assay) was comparable to that of Toremifene (IC50: 7.0 and 13.0 mM) against MCF-7 and MDA-MB-231 cancer cell lines, and three of them 30a-c (IC50: 21.9e25.3 mM) were also active against MCF-10A, while Toremifene (IC50: >100 mM) was devoid of activity [70]. The presence of electronwithdrawing groups like fluoro, chloro, nitro and trifluoromethyl in phenyl ring at R2 position could boost up the activity against MCF-7 and MDA-MB-231 cancer cells when compared with the unsubstituted phenyl and heterocyclic ring analogs. Further study revealed that these hybrids showed minimum binding energies and good affinities towards the active pockets of EGFR kinase and human estrogen receptor respectively, which were comparable with those of the standard drug Toremifene. The anticancer SAR of hybrids 31 against A549, HCT-116, MCF-7 and HT-29 cancer cell lines revealed that hybrids with electrondonating groups at R1 position were more potent than the analogs with electron-withdrawing groups [71]. For R2 position,

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Fig. 14. Chemical structures of 1,2,3-triazole-pyridine hybrids 71e81.

electron-withdrawing groups were favorable to the activity, and 4nitro was the best. Hybrids 31a,b (IC50: 1.764e9.463 mM, MTT assay) showed promising growth inhibition against the tested four cancer cell lines, but both of them were less active than Camptothecin (IC50: 0.030e0.800 mM). Further investigation ascertained the role of apoptosis induction as the mechanism of action of these hybrids. The eleven 1,2,3-triazole-pyrazole hybrids 32 (GI50: 1.8e9.7 mM, SRB assay) showed considerable activity against HeLa, HepG2, MCF7 and IMR-32 cancer cells, but none of them were superior to Paclitaxel (GI50: <0.01e0.04 mM) and Nocodazole (GI50: <0.01e0.02 mM) [72]. Replacement of 1,2,3-triazole moiety by isoxazole led to loss of activity, and aromatic ring was tolerated at R1 position when compared with the unsubstituted analogs. Halogen atom at R2 position and nitro at R3 position were beneficial to the activity, and hybrid 32i (GI50: 1.8e3.8 mM) which was found to be most active against all tested cancer cell lines could act as a platform for the further exploration. 2.2.5. 1,2,3-Triazole-thiazole hybrids Thiazole, which contains both sulfur and nitrogen atoms, exhibits a variety of pharmacological properties including anticancer activity [73]. Some thiazole-containing drugs such as Tiazofurin and Bleomycin have already been used in clinics for cancer

treatment, so hybridization of 1,2,3-triazole with thiazole may provide novel anticancer candidates. The 1,2,3-triazole-benzothiazole hybrids 33 (IC50: 33e154 mM, MTT assay) were active against T47D, MCF7, HCT116 and Caco2 cancer cells, and the SAR indicated that replacement of alkylhydroxyl group by ester could not improve the activity apparently [74]. For alcohol side chain, prolongation of carbon spacer or introduction of phenyl enhanced the activity to some extent. Hybrid 33b with IC50 values of 33e48 mM was found to be the most active against the four cancer cell lines, but it was still less active than Doxorubicin (IC50: 1e10 mM). The 1,2,3-triazole-benzothiazole hybrids 34 (IC50: 2.12e6.02 mM, MTT assay) bearing pyrimidine moiety showed great potency against MCF-7, A549 and A375 (skin cancer) cells, and the SAR suggested that the aromatic ring was better than cycloalkyl at R position [75]. The activity of hybrids 34 was as high as that of Paclitaxel (IC50: 2.58e8.0 mM, MTT assay) against all three cancer cell lines, and it was superior to Doxorubicin (IC50: 4.9 and 8.0 mM) against A549 and A375. These hybrids were able to affect the expression of key proteins such as ERK1/2, NF-kB and Survivin that cause abnormal cell proliferation, but they did not cause significant cytotoxicity in normal breast cells, demonstrating their potential for the development of novel anticancer candidates. The anticancer SAR of 1,2,3-triazole-benzo[d]imidazo[2,1-b]

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Fig. 15. Chemical structures of 1,2,3-triazole-pyrimidine hybrids 82e87.

Fig. 16. Chemical structures of 1,2,3-triazole-quinazoline hybrids 88e93.

thiazole hybrids 35 (IC50: 0.607e35.77 mM, MTT assay) against human cancer cell lines DU-145, HeLa, MCF-7, HepG2 and A549 cells revealed that the nature of substituents at both R1 and R2

positions were closely related with the activity, and electrondonating group at R1 position as well as electron-withdrawing group at R2 position could enhance the activity [76]. Among

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Fig. 17. Chemical structures of 1,2,3-triazole-quinoline/quinolone hybrids 94e102.

Fig. 18. Chemical structures of 1,2,3-triazole-quinone hybrids 103e109.

them, hybrids 35a (IC50: 0.607e7.413 mM) and 35b (IC50: 0.781e6.606 mM) exhibited significant antiproliferative effect. These conjugates accumulated more tubulin in the soluble fraction

corroborated well with the tubulin polymerization inhibition, and caused cell cycle arrest at G2/M phase. Furthermore, the two hybrids could effectively inhibit microtubule assembly and disrupt

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Fig. 19. Chemical structures of 1,2,3-triazole-steroid hybrids 110e114.

Fig. 20. Chemical structures of 1,2,3-triazole-sugar hybrids 115 and 116.

the microtubule organization in the breast cancer cells, implying they are useful in the development of new agents for breast cancer chemotherapy. The electron-donating groups were favorable to the anticancer activity of 1,2,3-triazole-benzo[d]thiazol-2(3H)-one hybrids 36 (IC50: 12.15->200 mM, MTT assay) against MCF-7 and HeLa cancer cells, while electron-withdrawing group diminished the activity [77]. Hybrid 36a (IC50: 17.54 and 12.15 mM) was found to be most active against the two cancer cell lines, but it was slightly less potent than the reference Cisplatin (IC50: 11.44 and 5.92 mM). 2.3. 1,2,3-Triazole-chalcone hybrids Chalcone is ubiquitous in nature, and its derivatives possess diverse biological properties including anticancer activity via regulating more than 400 genes involved in inflammation, cell survival, cell proliferation, invasion, angiogenesis, and metastasis [78,79]. Thus, hybridization of chalcone with 1,2,3-triazole may provide valuable therapeutic intervention in the cancer control. The 1,2,3-triazole-chalcone hybrids 37 (GI50: 1.3e186.2 mM, SRB assay) exhibited potential inhibitory activity against A549, HeLa, DU145 and HepG2 cancer cell lines, but the activity was lower than

that of trimethoxy chalcone (GI50: 0.06e0.08 mM) [80]. The SAR implied that replacement of a,b-unsaturated ketone fragment by pyrazoline moiety resulted in loss of activity. Substituent at paraposition could improve the activity, and fluoro, amino and methoxy were preferred. The most active hybrids 37a,b (GI50: 1.3e8.2 mM) could cause accumulation of cells in G2/M phase, inhibit tubulin polymerization, and trigger apoptosis which was apparent from their ability to reduce mitochondrial membrane potential and activate caspases 3 and 9. The majority of hybrids 38 were devoid of activity against human cancer cell lines IMR32 (neuroblastoma), HepG2, MCF-7, DU-145, and A549, while conjugate 38a (IC50: 17.11e69.90 mM, MTT assay) was active against all tested cancer cells, and it was comparable to or better than Doxorubicin (IC50: 17.69e69.33 mM) against IMR-32, DU-145, and A549 cells [81]. The 1,2,3-triazole-chalcone hybrids 39 (6%e70% growth inhibition at 10 mM, MTT assay) showed considerable inhibitory activity against MCF-7, MIA-Pa-Ca-2, A549, and HepG2 cancer cell lines, and the SAR revealed that substituents at R1 and R2 positions influenced the activity remarkably. Attachment of methoxy at R1 position was favorable to the activity, while incorporation of fluoro and bromo at R2 position decreased the activity [82]. In particular, conjugate 39a was found to be most active against all the tested

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Fig. 21. Chemical structures of 1,2,3-triazole hybrids 117e125.

cancer cell lines with IC50 values in the range of 4e11 mM (MTT assay) and showed better or comparable activity to the reference drug PI-103 (IC50: 3e8 mM). This hybrid could induce apoptosis and G2/S arrest in MIA-Pa-Ca-2 cells and triggered mitochondrial potential loss in MIA-Pa-Ca-2 cells. Furthermore, conjugate 39a also triggered caspase-3 and PARP-1 cleavage, which increased in dose dependent manner. Most of ether and amine tethered 1,2,3-triazole-chalcone hybrids 40 (IC50: 6.44e50.57 mM, MTT assay) and 41 (IC50: 1.53e42.38 mM, MTT assay) were active against MGC-803 (gastric), SK-N-SH (neuroendocrine) and HepG2 cancer cell lines, and amine linked hybrids were generally more potent than the corresponding ether tethered analogs [83e86]. Among them, hybrids 40a (IC50: 6.44e11.56 mM) and 41a (IC50: 1.53e2.73 mM) were found to be the most active compound in each series, and compound 41a was 2.6e6.7 folds more potent than 5-Fluorouracil (IC50: 7.22e10.32 mM) against all tested cancer cells. The mechanism studies revealed that compound 41a inhibited the proliferation of SK-N-SH cancer cells by inducing apoptosis and arresting the cell cycle at G1 phase. Based on the aforementioned findings, this

hybrid could act as a promising therapeutic agent candidate for further study. 2.4. 1,2,3-Triazole-coumarin/flavone hybrids Coumarin and flavone are privileged natural products that display a fascinating array of pharmacological properties, and their derivatives can trigger such as cell cycle arrest, kinase inhibition, monocarboxylate and aromatase inhibition on different cancer cell lines including drug-resistant cells [87e89]. Some coumarin/ flavone-containing compounds such as Irosustat and Luteolin are under clinical trials for the treatment of various cancers [90,91], demonstrating the potential of coumarin/flavone derivatives in the discovery of anticancer agents. The 1,2,3-triazole-coumarin hybrids 42 (IC50: 0.90->100 mM, MTT assay) showed weak to moderate activity against A549, HepG2, CFPAC-1, HeLa and SW620 cancer cell lines, but some of them displayed great potency against drug-resistant bacteria [92]. The strong correlation between lipophilicity of hybrids and their anticancer potency was observed, and introduction of lipophilic

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Fig. 22. Chemical structures of 1,2,3-triazole hybrids 126e136.

Fig. 23. Chemical structures of 1,2,3-triazole hybrids 137e140.

Fig. 24. Click Chemistry to form 1,2,3-triazole ring between two pharmacophores.

substituents at R1 position was favorable to the activity. Compared with hybrids with methyl at R2 position, the corresponding hydroxyl analogs showed low toxicity towards normal fibroblasts WI38 and 3T3 cells. Among them, hybrid 42a (IC50: 8.73e9.16 mM) displayed promising activity against A549, HepG2, and HeLa cancer

cell lines, but it was also toxic against normal fibroblasts WI38 (IC50: 13.96 mM). Further study indicated that the substituents on the C-6 and/or C-7 position of coumarin moiety have great influence on the anticancer activity, and hydroxyl was better than methoxy [93]. The number and position of hydroxyl group were

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Fig. 25. Chemical structures of 1,2,3-triazole tethered artemisinin hybrids 141e145.

Fig. 26. Chemical structures of 1,2,3-triazole tethered chalcone/coumarin hybrids 146e151.

also closely related with the activity, and the relative contribution order was 6,7-dihydroxyl > 6-hydroxyl > 7-hydroxyl. Introduction of methyl at the para-position of phenyl ring (R2 position) could improve the selective effect on K562 cells when compared with the

unsubstituted analog. Four hybrids 43a-d (IC50: 9.7e81.9 mM, MTT assay) not only possessed broad spectrum activity against HeLa, CaCo-2, and K562 cancer cells, but also showed high cytotoxicity against normal kidney MDCK1 cells (IC50: 36.7e46.0 mM).

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Fig. 27. Chemical structures of 1,2,3-triazole tethered indole hybrids 152e157.

The anticancer SAR of ether tethered 1,2,3-triazole-coumarin hybrids 44 (IC50: 0.03e91.61 mM, MTT assay) against MDA-MB231 cells indicated that attachment of substituents at para-position of phenyl could enhance the activity, and hybrids with 3,4-disubstituents possessed the highest activity [94]. The representative compound 44a (IC50: 0.03 and 1.34 mM under hypoxic and normoxic conditions, respectively) was 20e156 times more potent than the references Doxorubicin (IC50: 0.60 mM) and Cisplatin (IC50: 4.68 mM) against MDA-MB-231 cells under hypoxia. The hybrids 45a-c (IC50: 0.13e6.25 mM, MTT assay) exhibited great potency against PC3 (prostate), MGC803 (gastric) and HepG2 cancer cell lines, and two hybrids 45b,c (IC50: 0.13e1.74 mM) were more active than Colchicine (IC50: 0.27e4.6 mM) [95]. The SAR indicated that the linkage pattern influenced the activity remarkably, and hybrids 45b,c tethered via C-7 position were more potent than the C-4 linked hybrid 45a (IC50: 3.66e6.25 mM). Compared with unsubstituted compound 45b, hybrid 45c with methyl at C-4 position of coumarin moiety displayed higher activity against PC3 and MGC803 cancer cell lines. Replacement of coumarin by other heterocycles such as indole, thiazole, oxazole, tetrazole, thiadiazole, and unsym-triazine led to great loss of activity, implying coumarin motif was critical for the high activity. Hybrid 45c with IC50 of 0.43, 0.13 and 1.74 mM against PC3, MGC803 and HepG2 cancer cells respectively could induce G2/M phase arrest, inhibit MGC803 cells apoptosis, colony formation, and tubulin polymerization, so it could act as a promising therapeutic agent candidate for further investigation. The majority of hybrids 46 (PC50: >100 mM, EB/AO assay) were inactive against PANC-1 cells, while compound 46a (PC50: 8.5e29 mM) was active against PANC-1, MIA PaCa-2, and Capan-1 cancer cell lines [96]. The position of trifluoromethyl had a substantial effect on activity, and movement of trifluoromethyl from meta-position to para-position led to loss of activity. The activity of

hybrid 47 (IC50: 4.96e36.84 mM, MTT assay) against MGC-803, MCF-7 and PC-3 cancer cell lines was comparable to or higher than that of 5-Fluorouracil (IC50: 7.01e27.07 mM), making it a promising lead in drug development to combat various types of cancers [97]. The 1,2,3-triazole-coumarin hybrids 48 and their regio-isomers 49 (IC50: 9.83e26.21 mM, MTT assay) showed considerable activity against MCF-7 and HeLa cancer cell lines, and the activity was as high as that of Cisplatin (IC50: 18 and 10 mM), but lower than that of Doxorubicin (IC50: 5.2 and 3.83 mM) [98]. The SAR revealed that incorporation of halogen atoms at R position was favorable to the activity, while electron-donating groups hydroxyl, methoxy and alkyl led to loss of activity. The anticancer SAR of hybrids 50 (IC50: 7.5->100 mM, MTT assay) against AGS cancer cells indicated that hybrids with phenyl ring were more potent than the corresponding benzyl analogs [99]. Introduction of electron-withdrawing group into phenyl ring could enhance the activity, while electron-donating group resulted in loss of activity, and the relative contribution order was eCF3 > Cl > eF > eCH3 > eOCH3. Among them, hybrids 50a,b (IC50: 8.2 and 7.5 mM) were 3.6- and 3.9-fold more potent than 5-Fluorouracil (IC50: 29.6 mM) against AGS cancer cells. Moreover, the two hybrids (IC50: >100 mM) were non-toxic towards L02 normal cell line. Cell cycle analysis revealed that compound 50b inhibited cell growth via the induction of S/G2 phase arrest in AGS cells. Some other coumarin-1,2,3-triazoles such as cyclic 1,2,3triazole-coumarin hybrids 51 and 52 were also active against cancer cell lines [100e104]. In spite of most of them were less potent than the references, the SAR was enriched. Most of 1,2,3-triazole-flavone hybrids 53 (GI50: <0.01e92.1 mM, SRB assay) were active against HeLa, MDA-MB-231, MIA PaCa (pancreatic), and IMR 32 (neuroblastoma) cancer cell lines, but far less potent than Doxorubicin (GI50: 0.023e0.097 mM) and Paclitaxel (GI50: 0.025e0.091 mM) [105]. The substituents at 1,2,3-triazole

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Fig. 28. Chemical structures of 1,2,3-triazole tethered isatin hybrids 158e165.

moiety (R position) affected the activity greatly, and benzyl > phenyl > alkyl. Similar trends were also observed for hybrids 54 (IC50: 10e40 mM against three human ovarian cancer cell lines, OVCAR-3, Caov-3, and SKOV3, MTT assay), and introduction of benzimidazole moiety into the hybrids (55, IC50: 14.2e99.7 mM against MCF-7, SRB assay) could not increase the activity apparently [106e108]. Among them, hybrid 53a (GI50: 0.11e1.0 mM) showed the strongest activity against MDA-MB-231, MIA PaCa, and IMR 32 cancer cell lines, while compound 54a (IC50: 10e20 mM) was most active against OVCAR-3, Caov-3, and SKOV3 cells. Hybrid 54a could induce apoptosis in SKOV3 cancer cells via the accretion of ROS and reduction in mitochondrial membrane potential, and it also modulated the expression of B-cell lymphoma 2 (Bcl-2) and Bcl-2associated X protein. The 1,2,3-triazole-flavanone hybrids 56 (IC50: 12.721e102.754 mM, SRB assay) showed weak to moderate activity against HeLa, CaSki (cervical) and SK-OV-3 (ovarian) cancer cell lines [109]. However, hybrids 57 (IC50: 0.31e6.30 mM, MTT assay) were highly active against A549, taxol-resistant A549 (A549/taxol), cisplatin-resistant A549 (A549/cisplatin), HepG2, HCT-116, and U251 (glioblastoma) cancer cell lines [110]. For hybrids 57, 4-

methylpiperizin-1-yl and morpholino at R position were beneficial to the activity. The most active conjugate 57a (DDO-6318, IC50: 0.31e3.75 mM) was comparable to or better than the references DDO-6106 (IC50: 0.46e5.35 mM) and gambogic acid (IC50: 0.29e4.67 mM) against all tested cancer cell lines. In the lung cancer A549 transplanted mouse model, this hybrid displayed significant inhibitory effect on the growth of inoculated A549 in mice in a dose-dependent manner, with 30.88%, 52.21% and 71.32% inhibition in tumor growth at 5, 10 and 20 mg/kg twice daily doses by intravenous administration, respectively. This hybrid was also more potent than DDO-6101 (34.56% inhibition in tumor growth at 20 mg/kg) and 5-Fluorouracil (64.71% inhibition in tumor growth at 20 mg/kg), and no vascular irritation or weight loss was observed. This may be attributed to the increased in vitro cytotoxicity and improved druglike properties of DDO-6318, such as aqueous solubility and cell membrane permeability. 66.43% inhibition in tumor growth for DDO-6318 was observed at 50 mg/kg daily oral dose, while the inhibitory rate of DDO-6101 was 21.43%. Thus, DDO-6318 was identified as a new and orally-active natural-product-like anticancer candidate for further clinical development.

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Fig. 29. Chemical structures of 1,2,3-triazole tethered hybrids 166e172.

2.5. 1,2,3-Triazole-indole/isatin hybrids Indole including isatin can induce cell death for many cancer cell lines, and many indole-containing drugs such as Indomethacin, Melatonin, Indirubin and Sunitinib have already been applied in clinics for the treatment of various cancers. Thus, hybridization of 1,2,3-triazole with indole may afford new anticancer candidates with high efficiency for cancer treatment [111,112]. The 1,2,3-triazole-indole hybrids 58a,b showed great potency against a panel of 60 human hematological and solid cancer cell lines including leukemia, non-small cell lung, colon, CNS, melanoma, ovary, renal, prostate, and breast cancer cell lines, with the GI50 values in the low nanomolar range (mean GI50: 424 and 856 nM, SRB assay) [113]. Both of them could inhibit tubulin polymerization, and IC50 values were 18.5 and 13.5 mM. The broad spectrum and potent cytotoxicity of these hybrids, together with their inhibition of tubulin dynamics make 1,2,3-triazole-indole hybrids promising candidates for development as anticancer drugs. The anticancer SAR of 1,2,3-triazole-indole hybrids 59 (IC50: 16.10->200 mM, MTT assay) and bis-1,2,3-triazole-indole hybrids 60 (IC50: 9.08->200 mM, MTT assay) against MCF-7, HeLa, and HEH293 cancer cell lines indicated that initialization of the second 1,2,3triazole moiety into indole moiety could not enhance the activity apparently [114]. Attachment of butyl at para-position reduced the activity, while electron-withdrawing trifluoromethyl at meta-position enhanced the activity. Among them, hybrid 60f (IC50: 9.08e13.26 mM) was as potent as Cisplatin (IC50: 5.24e11.44 mM) against the three cancer cell lines. In the EAC bearing adult male swiss albino mice model, this hybrid has significant potency in terms of survival time, tumor volume, packed cell volume and viable tumor cell count at the doses of 5 mg/kg and 10 mg/kg without weight loss. On day 14, the hematological and biochemical parameters (hemoglobin level, erythrocytes count, leukocytes count, SGPT, SGOT and total protein levels) in hybrid 60f treated groups were comparable to those of Cisplatin treated groups. The majority of 1,2,3-triazole-indole hybrids 61 with IC50 > 100 mM (MTT assay) were devoid of activity against SKOV3, HeLa and DU145 cancer cell lines, while some of them were active against certain cancer cells [115,116]. The SAR revealed that introduction of tosyl group at N-1 position of indole moiety decreased

the activity when compared with the unsubstituted analogs. Among them, hybrids 61a,b demonstrated promising antiproliferative activities against DU145 cancer cell line with IC50 values of 8.17 and 8.69 mM respectively, and the activity was comparable to that of Etoposide (IC50: 9.80 mM). The hybrids 62 also showed considerable activity against A549 cancer cells, and the most active compounds 62a,b (IC50: 3.29 and 3.65 mM, MTT assay) were comparable to Doxorubicin (IC50: 3.3 mM) [117]. Conjugate 63 (MBQ-167) could inhibit breast cancer cell migration, viability, and mammosphere formation. The loss in cancer cell viability was due to MBQ-167-mediated G2-M cell-cycle arrest and the subsequent apoptosis [118]. Moreover, MBQ-167 has the potential to inhibit approximately 90% mammary tumor growth and metastasis in immune-compromised mice, so it can potentially serve as a lead for the development of novel anticancer chemotherapeutic agents. The 1,2,3-triazole-pyridazino[4,5-b]indole hybrids 64 (IC50: 0.042e38.690 mM, MTT assay) showed promising activity against MDA-MB-231, MCF-7, U-87 (glioblastoma) and IMR-32 (neuroblastoma) cancer cell lines, and the SAR indicated that the activity of hybrids bearing fluoro at R1 position was higher than that of the unsubstituted analogs [119]. Hybrids 64a,b (IC50: 0.042e0.478 mM) were highly active against MDA-MB-231, U-87 and IMR-32 cancer cell lines, which were comparable to Doxorubicin (IC50: 0.080e0.425 mM). The docking scores and the binding modes suggested that these hybrids could be potential lead pharmacophores to inhibit the overexpression of PI3 kinases, as PI3K pathway is known to be the most frequently activated pathway in human cancers. For hybrids 65, phthalimide and naphthalimide at R2 position were favorable to the activity, and only hybrids 65a,b (IC50: 3.67e26.5 mM) possessed broad spectrum activity against MCF-7, HeLa, PC-3 (prostate), HT-29 (colon), and HGC-27 (gastric carcinoma) cancer cell lines, and the activity was equal to that of Harmine (IC50: 3.52e24.45 mM) [120,121]. Molecular docking studies revealed that these hybrids could bind to DNA through minor groove binding. The anticancer SAR of 1,2,3-triazole-isatin hybrids 66 (IC50: 9.78e146.40 mM, CCK-8 assay) against TE-1, MCF-7, SW780, and MGC-803 cancer cell lines indicated that conjugate bearing ester fragment was more potent than the corresponding amide analogs

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[122]. Compound 66a (IC50: 9.78e25.21 mM) was comparable to 5Flurouracil (IC50: 6.99e17.32 mM) against all tested cancer cell lines, and it (IC50: 40.27 and 35.97 mM) was less toxic than 5-Flurouracil (IC50: 12.85 and 13.75 mM) towards normal HL-7702 and GES1 cells. Further study showed that this hybrid could cause morphological changes of MGC-803 cells and induce cell cycle arrest at G2/M phase, cellular ROS generation and migration inhibition of MGC-803 cells in a concentration-dependent manner. This hybrid induced apoptosis through the mitochondria-mediated intrinsic apoptotic pathway, the death receptor-mediated extrinsic apoptotic pathway, as well as the LSD1 inactivation. The majority of 3-benzylidene tethered 1,2,3-triazole-isatin hybrids 67 were inactive against most of the tested DU145, PC-3, MDA-MB-231, BT549, A549 and HeLa cancer cell lines, while the most potent conjugate 67a (IC50: 3.7e17.2 mM, MTT assay) was no inferior to Sunitinib (IC50: 7.4e16.3 mM) against DU145, PC-3, BT549, A549 and HeLa cells [123]. Hybrid 67a caused collapse of mitochondrial membrane potential (DJm) in DU145 cells, and it could induce cell apoptosis in DU145 cells. Replacement of 3benzylidene between 1,2,3-triazole and isatin moieties by hydrazide (68) was also tolerated, and the representative hybrid 68a (IC50: 6.22e9.94 mM, MTT assay) was active against HepG2, MDAMB-435s, MCF-7 cells overexpressing MARK4, and HEK293 cells. The cell-based assays demonstrated that this hybrid was able to inhibit cell migration, promote apoptosis and enhance ROS generation, suggesting it could be used as a novel anticancer candidate [124]. For hybrids 69, electron-donating group at C-5 position of isatin moiety was better than electron-donating group, and introduction of alkyl and benzyl could improve the activity against MCF-7, A549, HeLa and DU-145 cancer cell lines [125]. Among them, the most active conjugate 69a (IC50: 1.87e19.95 mM, MTT assay) was comparable to Doxorubicin (IC50: 1.054 and 1.986 mM) and 5-Flurouracil (IC50: 5.012 and 7.244 mM) against MCF-7 and A549 cells. The conjugate 69a treated A549 cells exhibited typical apoptotic morphological features, arrested the cells in G2/M phase of cell cycle, and led to collapse of the mitochondrial membrane potential (DJm) and increased levels of ROS. For hybrids 70, alkyl and benzyl at 1,2,3-triazole moiety were better than phenyl [126e128]. Hybrid 70a (IC50: 4.80e9.21 mM, MTT assay) showed potential activity against HeLa, MCF-7 and MDA-MB-231 cancer cell lines, but it was slightly less active than Doxorubicin (IC50: 0.55e4.63 mM). 2.6. 1,2,3-Triazole-pyridine hybrids Pyridine derivatives, privileged scaffolds with diverse biological properties, have the potential to fight against different cancers via inhibition of CDK, EGFR, PI3K, and RGGT etc. [129,130]. Some anticancer agents like Masitinib and ABT-751 (E7010) bearing a pyridine motif have already been used in clinics or under clinical trials for the treatment of cancers, indicating the potential of pyridine derivatives in the discovery of anticancer agents [131]. All 1,2,3-triazole-pyridine hybrids 71 (IC50: 0.1e19.5 mM, MTT assay) showed considerable activity against HT-29, DU-145 and A549 cancer cell lines, and most of them were no inferior to Nocodazole (IC50: 2.2e3.1 mM) and ABT-751 (IC50: 1.31e1.62 mM) [132,133]. Flow cytometric analysis revealed that these compounds arrested the cell cycle at the G2/M phase and induced cell death by apoptosis. The tubulin polymerization assay and immunofluorescence analysis showed that these hybrids effectively inhibited the microtubule assembly in DU-145 cells. It was observed that hybrids with electron-withdrawing substituents like the fluoro on the aryl ring of the 2-arylpyridine moiety (R1 position) exhibited enhanced cytotoxic activity compared to their counterparts with electrondonating substituents. In contrast, introduction of a fluoro

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substituent on the benzyl ring of 1,2,3-triazole (R2 position) was deleterious for the cytotoxic activity, while electron-donating substituents especially 3-phenoxy were favorable to the activity [132]. The position of the substituents at R1 and R2 positions also influenced the activity significantly, and the contribution order was meta- > para- and ortho- [133]. The most active conjugate 71a (IC50: 0.1e1.1 mM) was not only more potent than Nocodazole and ABT751 against all tested cancer cell lines, but also low cytotoxic towards normal human embryonic kidney (HEK-293, IC50: 59.6 mM) cells. Nicotinamide phosphoribosyltransferase (NAMPT) and histone deacetylase (HDAC), two important targets of cancer metabolism and epigenetics respectively, are attractive targets for the development of anticancer therapeutics agents [134]. A series of 1,2,3triazole-pyridine hybrids 72 were developed as dual inhibitors of NAMPT and HDAC, and all hybrids (IC50: 18e190 nM) were highly active against the two enzymes [135e137]. Some of them also displayed promising activity against HCT116, MDA-MB-231 and HepG2 cancer cell lines, and the SAR revealed that the linker (amide > without linker > carbamide) between 1,2,3-triazole and pyridine moieties as well as substituents (amide > ester) at R position were closely related with the anticancer activity. Among them, conjugate 72a possessed excellent and balanced activities against both NAMPT (IC50: 31 nM) and HDAC1 (IC50: 55 nM), and potential anticancer activity (IC50: 2.4e10 mM, MTT assay) which was better than that of SAHA (IC50: 3.1->100 mM, MTT assay) against all tested cell lines [135]. In HCT116 xenograft nude mouse model, this hybrid (administered intraperitoneally/ip at 25 mg/kg twice a day) demonstrated much higher in vivo anticancer activity (tumor growth inhibition/TGI: 69%, relative increment ratio/T/C: 31%) than the reference SAHA (TGI: 33%, T/C: 67%), and also explicitly showed an excellent antineoplastic activity. The terminal half-life, the peak concentration Cmax, plasma clearance (CL), and the volume of distribution absorption (Vss) of hybrid 72a were approximately 1.8 h, 745 ng/mL, 6173 mL/h/kg, and 6229 mL/kg, respectively, suggesting that the pharmacokinetic properties of this hybrid remain to be further improved. The anticancer SAR of 1,2,3-triazole-pyridine hybrids 73 (IC50: 0.20->100 mM, MTT assay) against HT-29 or MCF-7 cancer cell lines indicated that replacement of the amide fragment at the 2-position of pyridine with an ester sharply decreased the activity [138]. Aromatic ring at 1,2,3-triazole motif was essential for the high activity, and heterocycles were better than phenyl, while hybrids with aliphatic substituents were devoid of activity. Three hybrids 73a-c (IC50: 0.20e0.84 mM) were highly active against HT-29 or MCF-7 cancer cell lines, and the activity was 6.2e131.2 times higher than the parent Sorafenib (IC50: 5.29 and 43.30 mM). Further study indicated that these hybrids could suppress the proliferation of HT29 cancer cells by inducing apoptosis in a dose-dependent manner and almost completely inhibited colony formation at a low micromolar concentration. The hybrid 74 (BTCP) with IC50 values of 42.6, 28.2 and 42.3 mg/ mL (MTT assay) against A549, PC-3 and MDAMB-231 cells, was no inferior to Doxorubicin (IC50: 38.2, 41.9 and 53.7 mg/mL) [139,140]. Conjugate 75a (IC50: 40e82 mM, MTT assay) was more potent than unsubstituted analog 75b (IC50: >100 mM) against L1210, CEM and BAEC cancer cells, suggesting attachment of chloro at R position was favorable to the activity [141,142]. Replacement of pyridine moiety by phenyl ring could improve the activity, implying the pyridine was not indispensable for the activity. The anticancer activity of 1,2,3-triazole-pyridine organoiridium(III) complexes 77 (IC50: 0.36e5.91 mM, MTT assay) was far higher than that of their corresponding ligands 76 (IC50: 8->300 mM) against PC-3 and LNCaP (prostate) cancer cell lines, suggesting incorporation of metal ion into the 1,2,3-triazole-pyridine hybrids may be beneficial

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for the anticancer activity [143]. In particular, complex 77a (IC50: 0.85 and 0.36 mM) was 68.2 and 83.3 folds more active than Bicalutamide (IC50: 58 and 30 mM) against PC-3 and LNCaP cells. The pyrimidine tethered 1,2,3-triazole-pyridine hybrids 78 (IC50: 0.02->30 mM, MTT assay) and their regio-isomers 79 (IC50: 0.02->30 mM, MTT assay) showed considerable activity against human chronic myeloid leukemia (K562), acute myeloid leukemia (HL60), and human leukemia stem-like cells (KG1a) [144]. The SAR revealed that benzyl and piperazinyl rings were indispensable groups for the high activity against K562 and HL60 cell lines, and introduction of a trifluoromethyl group into the aromatic ring also significantly enhanced the potency against these two cell lines. The most active hybrid 78a (IC50: 0.02e1.04 mM) and its regio-isomers 79a (IC50: 0.02e1.27 mM) were 1.5e13.1 folds more potent than the reference Imatinib (IC50: 0.03e16.7 mM), so the two hybrids could act as lead molecules for further investigations. Some other 1,2,3-triazole-pyridine hybrids such as 1,2,3triazole-pyrrolo[2,3-b]pyridine hybrids 80 (IC50: 0.029e12.59 mM, MTT assay) were also active against various cancer cell lines [145e149]. Around half of hybrids 80 were comparable to or better than Foretinib (IC50: 0.26e6.25 mM) against HT-29, A549, MCF-7 and PC-3 cancer cell lines [145]. The SAR revealed that introduction of fluoro at R1 position could boost up the activity greatly when compared with the unsubstituted analogs, and trifluoromethyl at R2 position was better than methyl. Electron-withdrawing fluoro at R3 position was favorable to the activity, while incorporation of the second halogen-containing group or replacement of fluoro by electron-donating methyl resulted in great loss of activity [145]. Three hybrids 80a-c (IC50: 0.029e2.83 mM) were highly active against the tested cancer cell lines, and hybrid 80b also exhibited high inhibitory effects against c-Met (IC50: 1.68 nM), Flt-3 (IC50: 2.06 nM) and PDGFR-b (IC50: 4.57 nM), and moderate inhibitory effects against KDR, c-Kit and EGFR (IC50: 86.25, 324.58, 582.17 nM) suggesting that this hybrid was able to inhibit leukemia stem-like cells. Introduction of oxime moiety into 1,2,3-triazole-pyrrolo[2,3b]pyridine hybrids was also tolerated, and hybrids 81 (IC50: 0.12e9.3 mM, MTT assay) demonstrated potential activity against A549, HeLa and MDA-MB-231 cancer cell lines [146]. The most active hybrid 81a (IC50: 0.12e0.79 mM) could efficiently intercalate into calf thymus DNA to form 81a-DNA complex which might block DNA replication to influence their antiproliferative activity. 2.7. 1,2,3-Triazole-pyrimidine hybrids Pyrimidine is one of the privileged building blocks in drug discovery, and its derivatives are indispensable metabolites for all cells [150]. The de novo pyrimidine biosynthetic pathway is intact in most organisms including cancer cells, and the cancer cells rely on de novo pyrimidine biosynthesis to maintain its pyrimidine pools [10]. Moreover, many anticancer drugs like Ceritinib and Uramustine contain a pyrimidine moiety [129]. Thus, hybridization of 1,2,3triazole with pyrimidine may provide attractive scaffolds for development of novel cancer agents. The anticancer activity of 1,2,3-triazole-pyrimidine hybrids 82 (IC50: 0.021->1 mM, MTT assay) against a panel of cancer cell lines, including ALCL cell line KARPAS299 harboring NPM-ALK, NSCLC cell line H2228 expressing EML4-ALK, human lung adenocarcinoma (HLAC) cell line, HCC78 harboring SLC34A2-ROS1, A549 (EGFR-positive human NSCL cell line) and H460 (large cell lung cancer cell line) was comparable to that of the references Crizotinib (IC50: 0.087->1 mM) and Ceritinib (IC50: 0.026->1 mM) [151]. The SAR indicated that piperazinyl at 1,2,3-triazole motif was critical for the high activity against KARPAS299, H2228 and HCC78 cells, and hybrids 82a-c (IC50: 0.021e0.096 mM) displayed excellent anticancer activities with IC50 values in the double-digit nanomolar

range. Conjugate 82c, a promising ALK (IC50: 1.4 nM) and ROS1 (IC50: 1.1 nM) dual inhibitor, was extremely potent against the L1196M mutant (IC50: 3.1 nM) and the G1202R mutant (IC50: 8.7 nM) as well as other frequently secondary ALK mutants. The AO/ EB and western blot assays demonstrated that this hybrid induced cell apoptosis and potently inhibited cellular ALK and ROS1 activities, and it could act as a promising ALK and ROS1 dual inhibitor that could overcome crizotinib-resistant mutants. ABCB1 (also Pglycoprotein or P-gp, a main member of ATPbinding cassette (ABC) transport proteins)-mediated multidrug resistance (MDR) is a principal obstacle for successful cancer chemotherapy [152], and co-administration of ABCB1 modulators with anticancer drugs in the clinic has been deemed as a promising strategy to circumvent ABCB1-mediated MDR [153]. Almost all 1,2,3-triazole-pyrimidine hybrids 83 (IC50: 12.57->32 mM, MTT assay) were devoid of activity against sensitive SW620 cells and its Paclitaxel-resistant SW620/AD300 cells with overexpressed ABCB1, while most of them displayed moderate to great reversal potency when co-administrated with Paclitaxel [153]. The SAR indicated that chloro at R1 position increased the reversal activity, while fluoro and methyl reduced the reversal activity. The position of R2 was more important than the electronic effect of substituent, and the contribution order was meta- > ortho- > para-. For R3 position, electron-donating group improved the activity when compared with electron-withdrawing group. Among these hybrids, compound 83a displayed the most potent reversal activity, and it was about 7-fold more potent than Verapamil. Further mechanism studies revealed that this hybrid could obviously reverse Paclitaxel resistance in SW620/AD300 cells through increasing accumulation and extending maintenance of paclitaxel. The above findings revealed that these 1,2,3-triazole-pyrimidine hybrids may serve as useful lead molecules for the development of new potent and efficacious ABCB1-dependent MDR modulators. The anticancer SAR of 1,2,3-triazolo[4,5-d]pyrimidines 84 (IC50: 2.37->64 mM, MTT assay) against NCIeH1650 (human non-small cell lung cancer), MGC-803 (human gastric cancer), and PC-3 cancer cell lines revealed that benzyl at R1 and R3 positions and propargyl at R2 position were beneficial to the activity [154]. The most active hybrid 84a (IC50: 2.37e7.67 mM) was 1.9e5.2 folds more potent than the reference 5-Flurouracil (IC50: 7.86e27.61 mM). It was found that hybrid 84a could inhibit the migration of cancer cells, and induced MGC-803 apoptosis by the cascade reaction of bcl-2 family members and caspase family members. Replacement of thiosemicarbazide by imine was also tolerated, and 1,2,3-triazolo [4,5-d]pyrimidines 85 (IC50: 0.85->64 mM, MTT assay) showed considerable activity against MGC-803, MCF-7 and EC-109 cancer cell lines [155]. Benzyl with hydrophobic group at R1 position was favorable to the activity, and benzyl at R2 position was better than alkyl. For R3 position, 2-hydroxyphenyl with ether was optimal, and methyl at R4 position could enhance the activity when compared with the unsubstituted analogs. Among them, the activity of conjugate 85a (IC50: 0.85e1.77 mM) was 5.9e9.7 times higher than 5Flurouracil (IC50: 7.35e10.59 mM) against all tested cancer cell lines, and it also displayed low cytotoxicity towards normal GES1 cells (IC50: 56.17 mM). The mechanism studies demonstrated that this hybrid evidently inhibited the colony formation of MGC803 cells at 0.8 mM, and it could induce apoptosis of MGC-803 cells probably through the mitochondrial pathway accompanied with decrease of the mitochondrial membrane potential (MMP), activations of caspase-9/3, up-regulation of the expression of Bax, Bak and PUMA, as well as down-regulation of that of Bcl-2 and Mcl-1. 1,2,3-Triazole-pyrrolopyrimidine/imidazo[2,3-d]pyrimidine/ thieno[3,2-d]pyrimidine hybrids especially 86 (IC50: 0.5e30.9 mM, MTT assay) possessed considerable anticancer activity against A549, HepG2 and MCF-7 cell lines, and some of them were in the

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same level with Foretinib (IC50: 2.4e4.7 mM) [156e158]. The SAR showed that introduction of fluoro at R1 position enhanced the activity when compared with unsubstituted analogs. For substituents at R3 position, hybrids with mono-halogen atom were more potent than the corresponding di-halogen atoms analogs. Conjugate 86 (IC50: 0.5e1.0 mM, MTT assay) was 3.6e5.2 times more potent than Foretinib against the tested three cancer cell lines, and it could inhibit the c-Met selectively, with the IC50 values of 16 nM, which showed equal activity to Foretinib (IC50: 14 nM). The mechanism study claimed that this hybrid was able to induce late apoptosis of HepG2 cells by a concentration-dependent manner. The 1,2,3-triazole-pyrimidin-one hybrids were also active against various cancer cell lines, while all of them except some of 87 (IC50: 1.21->20 mM, MTT assay) were far less potent than references [159e167]. The anticancer SAR of 1,2,3-triazole-pyrimidin-one hybrids 87 against A549, OVCAR-3, SGC7901, and HepG2 cancer cell lines indicated that the linker between 1,2,3-triazole and pyrimidin-one moieties had some influence on the activity, and 4phenyl > 3-phenyl > 2-phenyl [167]. Chloro at phenyl ring (R position) could improve the activity greatly, and 4-chloro was best, while replacement of chloro by fluoro led to significant loss of activity. Three hybrids 87a-c (IC50: 1.21e2.70 mM) were highly active against A549, OVCAR-3, SGC7901, and HepG2 cancer cell lines, and they were 1.8e3.8 times more potent than Pemetrexed (IC50: 3.29e6.69 mM). Flow cytometric analysis indicated that these hybrids could inhibit A549 cells proliferation by arresting the cell cycle in the G1/S phase, and consequently induce the cell apoptosis. The western blot analysis showed that these hybrids could downregulate the cycle checkpoint proteins cyclin D1 and cyclin E to inhibit the cell cycle progression, and then induce intrinsic apoptosis by activating caspase-3, and later reduce the ratio of bcl2/bax. 2.8. 1,2,3-Triazole-quinazoline hybrids Quinazoline scaffolds represent an important class of biologically active nitrogen heterocyclic compounds with immense therapeutic potential and have played particularly important roles in the discovery of anticancer drugs since they had the potential to inhibit both wild-type and mutated EGFR, other kinases, histone deacetylase, Nox and some metabolic pathways [168e170]. Moreover, the anticancer agents Gefitinib, Erlotinib and Lapatinib are bearing a quinazoline motif, so hybridization of 1,2,3-triazole with quinazoline may generate new anticancer candidates with multiple action mechanisms. The 1,2,3-triazole-quinazoline hybrids 88 (IC50: 20.71e102.25 mM, MTT assay) showed moderate activity against HepG2, HCT116, MCF-7, and PC-3 cancer cell lines, but all of them were less active than Erlotinib (IC50: 11.57e26.87 mM) [171]. The SAR implied that chloro at the C-2 position (R2 position) and methoxy group at the 6,7 position (R1 position) of quinazoline skeleton are necessary for the activity. The most active compound 88a (IC50: 20.71e67.96 mM) with a 4-aminoquinazoline moiety as the pharmacophore, had the similar activity to that of Erlotinib and Gefitinib, but it was less potent than Erlotinib. Moreover, this hybrid showed lower toxicity than Erlotinib towards normal human epithelial kidney cell line (40.32 and 29.48 mM), human blood RBC (45.6 and 16.23 mM), and human peripheral blood mononuclear cell (37.38 and 20.46 mM, respectively). Molecular docking studies indicated that hybrid 88a could form hydrogen bond with Met 769 of the EGFR protein, which was responsible for the antiproliferative activity. This hybrid decreased the expression of EGFR and p-EGFR in MCF-7 cell lines, and it exhibited antiproliferative effects in MCF-7 cell lines via the EGFR signaling pathway. Besides, this hybrid also caused change in mitochondrial membrane

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potential and ROS-mediated apoptosis in MCF-7 cell lines. The majority of hybrids 89 (IC50: 0.04e286.75 mM, MTT assay) were more potent than Erlotinib (IC50: 13.01e99.76 mM) against HepG2, KB, and SK-Lu-1 (non-small lung cancer) cell lines, but all hybrids were less active than Ellipticine (IC50: 1.38e2.72 mM) [172]. The size of the fused dioxygenated ring was crucial for the biological activity, and hybrids containing a dioxane moiety at R1 and R2 positions were more potent than the corresponding dioxolane, dioxepine counterparts, and the analogs without oxygen substituent heterocycles. Electron-withdrawing group at R3 position could improve the activity, and ortho- > para-, meta-. The molecular docking studies showed that the most active hybrids 89a-c (IC50: 0.04e5.67 mM) displayed much stronger binding to the ATP binding site of the active and inactive conformations of EGFR than Erlotinib, and all of these three hybrids were equally potent binders to the L858R mutated EGFR, implying they could be used to treat drugresistant cancers. All 1,2,3-triazole-quinazoline hybrids 90 (IC50: 0.57e29.71 mM, MTT assay) possessed broad spectrum anticancer activity against MCF-7, MGC-803 (human gastric cancer cell line), EC-109 (human esophageal cancer cell line) and HGC-27 (human gastric cancer cell line) [173]. Electron-donating methyl at R1 position was much more beneficial than electron-withdrawing chloro, and for R2 position, substituents at para-position was more favorable than meta-position. Hybrid 90a (IC50: 0.57e7.13 mM) was more potent than 5Fluorouracil (IC50: 6.50e14.61 mM) against all tested cancer cells, indicating that it could act as lead molecule for further modification. The anticancer SAR of 1,2,3-triazole-quinazoline hybrids 91 (IC50: 2.06->30 mM, MTT assay) against SKBR3, UM159 and KG-1a cells indicated that hybrids with amine at R position showed higher activity than the alkyl analogs, and hybrids 91a-d (IC50: 2.06e7.47 mM) with IC50 values in single-digit mM level were more potent than the reference Lapatinib (IC50: 9.76e20.11 mM) [174]. In zebrafish model, the fatality rate of zebrafish treated with 91b (200 mМ for 24 h) was 0, suggesting this hybrid was devoid of acute toxicity even at high dose. The anticancer activity of most of 1,2,3-triazole-quinazolinone hybrids were far less potent than the references, whereas hybrids 92 (IC50: 5.94e30.4 mM against MCF-7, HeLa and K562 cancer cell lines, MTT assay) were comparable to Luotonin A (IC50: 5.94e28.8 mM), and hybrid 93a (IC50: 12.05e98.01 mM against MDA-MB-231, MCF-7, T-47D, A549, and PC3 cancer cell lines, MTT assay) was no inferior to Etoposide (IC50: 16.77e62.69 mM) [175e177]. 2.9. 1,2,3-Triazole-quinoline/quinolone hybrids Quinoline and quinolone derivatives possess significant cytotoxic activity against cancer cell lines, and several quinoline/quinolone agents which are exemplified by Cabozantinib, Voreloxin, and Quarfloxin have already been used in clinics or under clinical trials for the treatment of various cancers, making quinoline/quinolone derivatives promising candidates for cancer treatment [6,178,179]. Thus, it is possible to develop novel anticancer agents by hybridization of the pharmacophore moiety of quinoline/quinolone with 1,2,3-triazole. 1,2,3-Triazole-quinine hybrids 94 (IC50: 0.53e14.6 mM, MTT assay) showed promising activity against HT-29, MCF-7, A549, DU145, MCF-10 A (epithelial mammary gland) and MV-4-11 (leukemia) cancer cell lines [180]. Movement of 1,2,3-triazole from C-2 position to C-6 position of quinine skeleton had little influence on the activity, while incorporation of the second quinoline moiety led to loss of activity. Conjugate 94b (IC50: 0.53e6.4 mM) was comparable to or better than Cisplatin (IC50: 5.5e18.9 mM) against all

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tested cancer cell lines, and it could act as a platform for the further exploration. The majority of 7-choroquinoline-1,2,3-traizole hybrids 95 (IC50: 5.8e34 mM, MTT assay) were more active than the parent Chloroquinoline (IC50: 52e76 mM) against H460, HCC827 (lung) and BxPC3 (pancreatic) cancer cells [181]. Phenyl and benzyl at 1,2,3triazole motif (R position) were generally more favorable than heterocycles and alkyl, and introduction of a second 1,2,3-triazole moiety was also found to be detrimental to inhibitory activity. Among them, compound 95a (EAD1, IC50: 5.8e11 mM) could inhibit autophagy, as judged by the cellular accumulation of the autophagy-related autophagosome proteins LC3-II and p62 and induced apoptosis. Thus, EAD1 is a promising lead for evaluation of the anticancer activity of autophagy inhibitors in vivo. The linkage pattern also had great influence on the activity, and hybrid 96 (QTCA-1, IC50: 19.91 and 31.7 mM against MDA-MB-231 and MCF-7 cancer cell lines, MTT assay) induced cytotoxicity on independenthormonal adenocarcinoma breast cancer cells and this effect was contributed to high apoptosis induction but no cell-cycle arrest [182]. Moreover, molecular docking showed a high affinity of QTCA1 to PARP-1, Scr and PI3 K/mTOR targets, indicating selectivity of this hybrid for triple negative breast cancer cells. Movement of the chloro from C-7 position to C-2 position or removal of chloro from quinoline also influenced the anticancer activity remarkably, and some of them such as hybrid 97 with GI50 values ranging from <10 to 503 nM (SRB assay) against a panel of 59 human cancer cell lines demonstrated great anticancer potential [183e187]. The anticancer SAR of 1,2,3-traizole-quinoline hybrids 98 (IC50: 0.03e6.14 mM, MTT assay) against HT-29, H460, A549 and MKN-45 cancer cell lines revealed that substituents at R1 position had little influence on the activity, while electron-withdrawing group at R2 position was more favorable than electron-donating group, and hybrids with mono-substituent showed higher activity than the bis-substituents analogs [188]. The representative compound 98a (IC50: 0.03e0.18 mM) was highly active against all tested cancer cells, and it was 1.1e1.9 times more potent than Foretinib (IC50: 0.032e0.21 mM). This hybrid not only exhibited high inhibitory effects against c-kit, Flt-3 and c-Met kinase (IC50: 2.27e9.36 nM), but also showed inhibitory effects against VEGFR-2, Ron, and EGFR (IC50: 96.68e529.4 nM), suggesting it is a promising multitarget inhibitor of tyrosine kinases. The 1,2,3-triazole-benzofuroquinoline hybrids 99 (IC50: 0.02e43.09 mM, MTT assay) were active against most of the tested cell lines such as A549, Raji (lymphoma) and CA46 (lymphoma) cancer cell lines [189]. Three hybrids 99a-c (IC50: 0.02e5.53 mM, MTT assay) could arrest Raji cell cycle in G0/G1 phase, and remarkably inhibit A549 cell proliferation without the influence of normal primary cultured mouse mesangial cells. Further cellular and in vivo investigations indicated that these hybrids showed inhibitory activity on the proliferation of cancer cells, presumably through the down-regulation of transcription of c-myc gene. Some of 1,2,3-triazole-(tetrahydro)isoquinoline hybrids also demonstrated certain anticancer activity, but the activity was far less potent than references [190e192]. However, hybrid 100 as a potent modulator of P-gp-mediated MDR, showed high potency (EC50: 127.5 nM), low cytotoxicity (TI > 784.3), and long duration (>24 h) in reversing Doxorubicin resistance in K562/A02 cells [192]. Further study indicated that this hybrid also enhanced the effects of other MDR-related cytotoxic agents (Paclitaxel, Vinblastine, and Daunorubicin), increased the accumulation of Doxorubicin and blocked P-gp-mediated rhodamine 123 efflux function in K562/A02 MDR cells. Furthermore, hybrid 100 did not have any effect on cytochrome (CYP3A4) activity. These above results demonstrated that hybrid 100 was a relatively safe modulator of P-gp-mediated MDR that had good potential for further development.

1,2,3-Triazole-quinolone hybrids were also active against various cancer cell lines, and the most active hybrids 101 (IC50: 11.0e16.6 mM against MCF-7, T-47D and MD-MB-231 cancer cell lines, MTT assay) and 102 (IC50: 0.79 and 0.76 mM against KB and HepG2 cancer cell lines, MTT assay) were no inferior to Etoposide (IC50: 11.8e15.7 mM) and Ellipticine (IC50: 1.26 and 1.46 mM) [193e196]. Moreover, the SAR was enriched to point out the direction for further rationale design and modification of these hybrids. 2.10. 1,2,3-Triazole-quinone hybrids Quinone is an important pharmacophore in medicinal chemistry, since it is present in many bioactive or proactive molecules, such as Daunorubicin, Doxorubicin, Saintopin, Mitomycin and Mitoxantrone, which has been used in clinics for the treatment of various cancers [197,198]. The mechanisms by which quinone derivatives exert their anticancer potential are attributed to two chemical properties. One is the generation of ROS leads to DNA damage and cell death, and the other is electrophilic arylation of critical cellular nucleophiles [198]. Therefore, hybridization of 1,2,3-triazole with quinone may afford new anticancer candidates with multiple action mechanisms. The 1,2,3-triazole-naphthoquinone hybrids 103a and 103b (IC50: 14.3e99.2 mM, MTT assay) inhibited the growth of cancer cells in a concentration-dependent manner, and the two hybrids were active against HL-60, K562, K562-lucena, and PBMC cancer cell lines, whereas the reference Etoposide was only active against HL60 cells [199]. Further study indicated that both hybrids could induce cellular changes in HL-60 cells, characteristic of apoptosis, such as mitochondrial membrane depolarization, phosphatidylserine externalization, increasing sub-G1 phase, DNA fragmentation, downregulating Bcl-2 protein and upregulating Bax protein. In K562 cells, both hybrids were able to induce S-phase arrest of cell cycle, which was associated with up-regulation of p21. Moreover, the activity of the hybrids in HL-60 cells can be related to the ROS intracellular level. The 1,2,3-triazole-naphthoquinone hybrids 104 (IC50: 7.81e130.85 mM, MTT assay) showed considerable activity against MCF-7, A549, Hela, DU-145 and B-16 (mouse melanoma) cancer cell lines, and the phenyl ring at 1,2,3-triazole moiety can be replaced by benzyl, pyridinyl and esters [200]. Compared with unsubstituted analog, introduction of alkyl and halogen atom into phenyl ring could enhance the activity. The anticancer activity of the most potent hybrid 104a (IC50: 8.02e26.12 mM) was as high as Tamoxifen (IC50: 10.87e18.63 mM) against MCF-7, A549, Hela, and DU-145 cancer cell lines, and the mechanism study revealed that the anticancer activity of this hybrid could be attributed to the induction of cell cycle arrest at G0/G1 phase and apoptosis in MCF-7 cancer cell line. Among 1,2,3-triazole-naphthoquinone hybrids 105, only conjugates 105a,b (IC50: 6.8e31.7 mM, MTT assay) were active against all tested MCF-7, HT-29 and MOLT-4 cancer cell lines, and both of them arrested cell cycle at G0/G1 phase in MCF-7 cells [201]. Hybrid 105a (IC50: 6.8e10.4 mM) was no inferior to Cisplatin (IC50: 6.4e19.1 mM) against MCF-7, HT-29 and MOLT-4 cancer cell lines, but it was far less potent than Doxorubicin (IC50: 0.015e0.335 mM). The 1,2,3-triazole-1,4-naphthoquinone hybrids 106 and their regio-isomers 1,2,3-triazole-1,2-naphthoquinone hybrids 107 only exhibited moderate activity against MDA-MB231, Caco-2 and Calu3 human cancer cells [202,203], while their selenium-containing analogs (IC50: 0.07e8.64 mM, MTT assay) showed potential activity against HL-60, HCT-116, PC3, SF295, MDA-MB-435 and OVCAR-8 cancer cell lines [204]. Among them, hybrids 108a,b (IC50: 0.07e1.39 mM) were highly active against all tested cancer cell lines,

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and that were comparable to Doxorubicin (IC50: 0.02e0.96 mM). The mechanisms study revealed that these hybrids were intrinsically related with ROS contribution on the activity, suggesting that apoptosis was associated with ROS production. The 1,2,3-triazole1,2-naphthoquinone hybrid 109 (IC50: 0.41e1.59 mM, MTT assay) bearing an pyran fragment also showed great inhibitory potency against OBMC, PC3, HCT-116, HL-60, MDA-MB435 and SF-295 cancer cell lines, and the activity was generally no inferior to the references b-lapachone (IC50: 0.25->20.6 mM) and Doxorubicin (IC50: 0.02e0.88 mM) [205]. 2.11. 1,2,3-Triazole-steroid hybrids Steroids, naturally in animals, plants and fungi, could act as signaling molecules or as important components of cell membranes which alter membrane fluidity [206,207]. Aromasin, Galeterone and Fulvestrant are some of the anticancer agents emerged on steroidal pharmacophores [208,209], so steroids as pharmacologically significant scaffolds have been of great interest in recent years. The 1,2,3-triazole-diosgenin hybrids 110 (IC50: 5.16e31.00 mM, MTT assay) endowed with broad spectrum activity against HBL100, A-549, HT-29 and HCT-116 cancer cell lines, and some of them were more potent than the parent Diosgenin (IC50: 10.80e13.30 mM) [210]. The SAR indicated that introduction of electron-withdrawing groups nitro and cyano at ortho-position of phenyl ring had beneficial impact on the activity when compared with the unsubstituted analog. Among them, three hybrids 110a-c (IC50: 5.16e9.44 mM, MTT assay) with IC50 values in single-digit micromolar level were more potent than Diosgenin against all tested cancer cell lines. The anticancer activity of 1,2,3-triazole-estradiol 111 was lower than their corresponding diastereoisomers 112 against HeLa, MCF7, A431, A2780, T47D (expressing estrogen, progesterone and androgen receptors), MDA-MB-231 (expressing estrogen receptor and HER2) and triple-negative MDA-MB-361 cancer cell lines, and for hybrids 112, halogen-containing hybrids were less potent than their alkyl-substituted counterparts [211]. Amongst them, hybrids 112a,b (IC50: 2.4e8.3 mM, MTT assay) were highly active against all tested cancer cell lines, and they both were comparable to or better than Cisplatin (IC50: 1.3e19.1 mM). Moreover, hybrid 112a activated caspase-3 and caspase-9 without influencing caspase-8, demonstrating the induction of apoptosis via the intrinsic pathway. Betulin and betulinic acid are selective toxic to a variety of cancer cell lines, while they are typically non-toxic towards the normal cells [212,213]. 1,2,3-Triazole-betulin/betulinic acid hybrids possess broad spectrum anticancer activity, and some of them exhibited excellent potency [214e221]. Among them, hybrid 113 (IC50: 50e90 nM, MTT assay) with IC50 values in the double-digit nanomolar range against T47D, MCF-7 and SNB-19 cancer cell lines, was far more potent than the reference Cisplatin (IC50: 2.3e24.9 mM) [220]; Hybrid 114 (CBA) was 5e7 folds more potent than betulinic acid against various cancer cells, and it decreased expression of PI3K p110a, p85a, and pAKT in HL-60, depleted pGSK3b, cyclin D1 and increased expression of p21/cip, p27/Kip proteins [221]. CBA induced G0/G1 cell cycle arrest, and increased sub-G0 DNA fraction and annexin V binding of the cells besides imparting the typical surface features of cell death. The apoptotic effectors caspase 8 and caspase 9 were found to be up-regulated besides PI3K associated DNA repair enzyme PARP cleavage was observed. Thus, this hybrid could inhibit PI3K/AKT pathway with induction of subsequent cancer cell death which may be a useful therapeutic strategy against leukemias and other cancers. Some other 1,2,3-triazole-steroid hybrids also displayed potential antiproliferative activities against various human cancer cell

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lines, but they were generally far less active than references [222e227]. Therefore, they still need to be modified to improve the anticancer activity. 2.12. 1,2,3-Triazole-sugar hybrids Sugars are indispensable for cell life, and thet are involved in fundamental molecular and cell biology processes occurring in cancer [228,229]. Hybridization of 1,2,3-triazole with sugar may be beneficial for the compounds to reach the cancer cells, and consequently improve the anticancer activity [4]. The preliminary results showed that 1,2,3-triazole-ribofuranose hybrids 115 (IC50: 0.15e2.50 mM, XTT assay) were highly efficient and they were 320- to >5000-fold more active than the parent Acadesine (IC50: 800 mM) against K562 CML cancer cells [230]. The SAR revealed that ribofuranose moiety can be replaced by glucopyranose, deoxyribose, xylose, and ribose, and halide, heteroaryl or acyl groups on C-5 position of 1,2,3-triazole motif resulted in no antiproliferative efficiency, while alkynyl substituents terminated by an ester function led to high activity. The most active hybrid 115a was further evaluated for its activity against a panel of 60 cancer cell lines, and the results showed that this hybrid with GI50 values of 1.22e12.20 mM was active against all tested cancer cell lines. Notably, this hybrid (IC50: 0.34 and 0.50 mM, respectively) showed great activity against Imatinib and Azacitidin sensitive (SKM1-S) and resistant (SKM1-R) CML cancer cells. Further mechanism study suggested that this hybrid induced cell death by caspase and autophagy induction, so it could be used to circumvent resistance to apoptosis in cancer cells. In the mice xenografted with SKM1-R MDS cell line model, hybrid 115a (5 mg/kg, subcutaneously) also proved efficient as evidenced by that 115a treated mice were found to reduce the tumor volume by 50% as compared to untreated mice after 35 days. Moreover, tumor free weight was comparable in both groups of mice, demonstrating that this hybrid did not induce acute toxicity in treated mice. The 1,2,3-triazole-sugar hybrids 116 (IC50: 0.18e54.89 mM, MTT assay) showed moderate to high inhibitory activity against PC3, HT29, HepG2, A549, HL60 and U937 cancer cell lines, and most of them were more potent than 5-Fluorouracil (IC50: 8.45e69.07 mM) [231]. The SAR indicated that hybrids with (substituted) phenyl groups on the 1,2,3-triazole moiety were more active than the pyridine-3-yl analog, and introduction of either electronwithdrawing or electron-donating group into the phenyl ring could boost up the activity. The position of substituent had great influence on the activity, and para- > meta- > ortho-. Conjugate 116a (IC50: 0.54e2.66 mM), which could inhibit the proliferation of HepG2 cancer cells by inducing apoptosis (via mitochondrialmediated intrinsic pathways) and arresting the cell cycle at G1 and S phases, was 2.0e109.4 folds more potent than 5-Fluorouracil and Hederacolchiside A1 (IC50: 0.85e5.41 mM) against all tested cancer cell lines. Besides the 1,2,3-triazole-sugar hybrids mentioned above, some other analogs only exhibited weak to moderate anticancer activities, and they were less potent than references [232e237]. In spite of that, the SAR was enriched. 2.13. Miscellaneous 1,2,3-triazole hybrids 1,2,3-Triazole-benzoxazone hybrids could induce apoptosis and autophagy simultaneously. Among them, compound 117a (BTO, IC50: 8 and 10 mM, MTT assay) showed dose-dependent inhibitory effects against H460 and A549 cancer cells, and it could be potential therapeutic agent for the treatment of lung cancer [238e242]. Hybrid 117b not only showed promising in vitro activity (IC50: 21.78 and 19.46 mM against MCF-7 and HeLa cancer cells, MTT assay), but

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also exhibited in vivo potency in EAC-bearing mice model as compared with the reference drug Cisplatin in terms of increased the MST, decreased the tumor volume, packed cell volume and viable cell count in 5 mg/kg and 10 mg/kg [242]. Some 1,2,3-triazole-macrocycles also exhibited considerable anticancer activity, and 1,2,3-triazole-macrolide 118 (IC50: 0.69 and 0.99 mM against MCF-7 and A549 cells, MTT assay) and 1,2,3triazole-rapamycin 119 (IC50: 6.05e25.88 mM against MGC-803, H1299, Caski, and H460 cancer cell lines, MTT assay) were superior to the references SAHA (IC50: 3.27 and 5.00 mM against MCF-7 and A549, respectively) and rapamycin (IC50: 18.74e35.13 mM) respectively [243e248]. Mechanism study revealed that 1,2,3triazole-rapamycin 119 was able to cause cell morphological changes and induce apoptosis in the Caski cell line [248]. Most importantly, this hybrid could decrease the phosphorylation of mTOR and its downstream key proteins, S6 and P70S6K1, suggesting that it can effectively inhibit the mTOR signaling pathway. Thus, 1,2,3-triazole-rapamycin 119 may have the potential to become a new mTOR inhibitor against various cancers. All 1,2,3-triazole-podophyllotoxin hybrids 120 (IC50: 21.1e124.2 nM, MTT assay) were highly active against A549, PC-3 and MCF-7 cancer cell lines, and the majority of them were in the same level with the parent Podophyllotoxin (IC50: 24.1e34.4 nM) [249]. The SAR indicated that electron-withdrawing group at R position could improve the activity, while electron-donating group was generally detrimental to the activity. Further study indicated that the substituted phenyl ring can be replaced by heterocycles such as pyridine and thiophene, and the ester linker between 1,2,3triazole and Podophyllotoxin moiety can be replaced by amide (121) without affecting the activity [250e252]. For hybrids 121, compounds with phenyl ring (n ¼ 0) at 1,2,3-triazole framework showed higher activity than the corresponding benzyl (n ¼ 1) analogs, and attachment of electron-withdrawing group at the phenyl enhanced the activity [252]. The most active conjugate 120a also showed great potency against K562, HCT-116, U251 (glioma), SKBR3 (breast), SMCC-7721 (hepatoma), LNCaP (prostate) and Doxorubicin-resistant K562/ADR cancer cells with IC50 values ranging from 19.6 nM to 55.3 nM [249]. Notably, the IC50 values of this hybrid in non-cancer human foreskin fibroblast (HFF) and human liver (HL7702) cell lines were 195.3 nM and 564.7 nM respectively, indicating that there was a therapeutic window to use conjugate 120a. The mechanistic studies showed that this hybrid could act on microtubule, caused cell cycle arrest at G2/M phase, and induced apoptosis in PC-3 cancer cells. Hybrid 121a (IC50: 0.70e1.21 mM, MTT assay) which was 3.8e8.5 folds more potent than Podophyllotoxin (IC50: 3.06e6.63 mM) against HeLa, MCF-7, DU-145, A549, and HepG2 cancer cell lines, showed low cytotoxicity towards normal NIH/3T3 cells (IC50: 89.04 mM). It was revealed by the mechanism study that this hybrid could arrest G2/M phase of cell cycle, induce apoptosis through depolarization of mitochondrial membrane potential and increase ROS production. The glucose tethered 1,2,3-triazole-podophyllotoxin dimers also proved promising anticancer activity, and three of them 122a-c (IC50: 0.43e30.46 mM, MTT assay) possessed broad spectrum activity against HL-60, A-549, MCF-7, SW480, and SMMC-7721 cancer cell lines [253]. The substituent at R1 position was closely correlated with the activity, and butyryl was optimal. In particular, compound 122a (IC50: 0.43e3.50 mM) was 2.8e21.3 folds more potent than Etoposide (IC50: 8.12e32.82 mM) and Cisplatin (IC50: 6.93e10.85 mM) against A-549, MCF-7, SW480, and SMMC-7721 cancer cell lines, and it was no inferior to the two reference drugs against HL-60 cells. Moreover, this hybrid also showed good selectivity (selectivity indexes/SI: 4.4e35.7) towards cancer cell lines as compared with the normal BEAS-2B cell line, demonstrating the potential application of this hybrid as a novel

anticancer agent. 1,2,3-Triazole-Gomisin B hybrids 123 (IC50: 0.24e99.5 mM, MTT assay) exhibited moderate to excellent activity against DU-145, A549, PANC1, MDA-MB-231, SIHA (cervical cancer), IMR32 (neuroblastoma) cell lines [254]. The most active hybrid 123a (IC50: 0.24e12.8 mM) was 5.0e213.3 folds more potent than Gomisin B (IC50: 51.2e66.8 mM), and it was comparable to Doxorubicin (IC50: 1.5e2.4 mM) against most of the cancer cell lines. Further study indicated that this hybrid stalled HeLa cells at G2/M phase and promoted tubulin polymerization. This was supported by the docking studies, wherein hybrid 123a showed significant binding affinity at the colchicine binding pocket of tubulin. The anticancer SAR of 1,2,3-triazole-sulfonamide hybrids 124 (IC50: 5.9e53.8 mM, MTT assay) against A549, HepG2, HeLa and DU145 cancer cell lines revealed that introduction of chloro at paraposition of phenyl ring was favorable to the activity, while incorporation of oxadiazole as linker between 1,2,3-triazole and sulfonamide moieties could not improve the activity [255e257]. Cyclization of sulfonamide also could not enhance the activity as evidenced by that hybrids 125 (IC50: 9.5e34.4 mM, MTT assay) were far less potent than 5-Fluorouracil (IC50: 1.6e1.9 mM) against C3, HeLa, MDA-B-23 and HepG2 cancer cell lines [258]. Among them, the activity of compounds 124a,b (IC50: 5.9e9.8 mM) was 3.5e9.5 times higher than that of Nimesulide (IC50: 35.21e67.81 mM), so they could be used to prepare novel and potential anticancer agents by the structure modification [255]. Almost all 1,2,3-triazole-ent-kaurene diterpenoids 126 (IC50: 3.21e13.58 mM, MTT assay) and 127 (IC50: 2.12e9.50 mM, MTT assay) exhibited strong activity against Eca109, EC9706, SMMC7721, MCF-7, PC-3 and MGC-803 cancer cell lines, and they were more active than the references Oridonin (IC50: 27.55e74.18 mM) and Jiyuan Oridonin A (IC50: 14.70e22.92 mM) [259]. The anticancer activity of hybrids 127 was higher than that of the derivatives 126, suggesting the linkage pattern had great influence on the activity. Compound 127g (IC50: 2.53e5.04 mM) was found to possess the highest antiproliferative activity, and it was 6.8e15.5 folds more potent than Oridonin. The further mechanism investigation indicated that hybrid 127g increased ROS level in cancer cells, leading to the decrease of mitochondrial membrane potential and the release of Cytochrome C into the cytoplasm, which then made Caspase-9 activate so as to induce apoptosis. Meanwhile, this hybrid halted cell cycle progression at the G2/M phase and altered the expression of cell cycle-related proteins. 1,2,3-Triazole-oridonin hybrids 128 (IC50: 1.94e9.02 mM, MTT assay) and 129 (IC50: 5.05e14.99 mM, MTT assay) also showed potential activity against HCT116, MCF-7 and Bel7402 cancer cell lines, and all of them were more potent than 5-Fluorouracil (IC50: 16.28e24.80 mM) [260]. Moreover, all hybrids 128 were also more active than the parent Oridonin (IC50: 6.84e17.56 mM), implying their potential for the development of novel anticancer agents. 1,2,3-Triazole-terpene hybrids such as 1,2,3-triazole-myrrhanone C hybrids 130 (IC50: 6.16e63.09 mM, MTT assay) and 131 (IC50: 9.33e158.48 mM, MTT assay) displayed weak to moderate activity against A549, HeLa, MCF-7, DU-145 and HepG2 cancer cell lines, and oxime-containing hybrids 130 were more potent than the derivatives 131, suggesting the oxime fragment could increase the activity [261e264]. For hybrids 130, introduction of either electronwithdrawing or electron-donating group led to loss of activity. The activity of conjugate 130a (IC50: 6.16e9.59 mM) was higher than that of the parent Myrrhanone C (IC50: 12.02e26.61 mM), but in the same level with that of Doxorubicin (IC50: 1.13e3.01 mM). Flowcytometric analysis revealed that this hybrid arrested the cell cycle at G2/M phase and induced apoptosis. 1,2,3-Triazole-melampomagnolide B hybrids 132 (GI50: 0.02e23.4 mM, SRB assay) showed great potency against a panel of

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60 human cancer cell lines derived from nine cancer cell lines and grouped into disease sub-panels that represent leukemia, lung, colon, CNS, melanoma, renal, ovary, breast, and prostate cancer cells [265e267]. In particular, compound 132a (GI50: 0.02e1.86 mM) was highly active against all tested cancer cell lines, and it reduced DNA binding activity of NF-kB via inhibition of IKK-b mediated p65 phosphorylation and caused elevation of basal IkBa levels through inhibition of constitutive IkBa turnover and NF-kB activation in TMD-231 breast cancer cells. Thus, this hybrid could act as an ideal candidate for potential clinical application. The anticancer activity of 1,2,3-triazole-phenothiazine hybrids 133 (IC50: 1.2e20.2 mM, MTT assay) was no inferior to that of 5Fluorouracil (IC50: 6.9e19.4 mM) against three gastric cancer cell lines (MKN28, MGC-803 and MKN45) [268,269]. Conjugate 133a (IC50: 1.2e3.5 mM) was superior to 5-Fluorouracil against all three gastric cancer cell lines, and it could not only inhibit migration by regulating the expression level of N-cadherin, E-cadherin, Vimentin, and actived-MMP2, but also regulate wnt/b-catenin signaling pathway on MGC-803 cells in a concentration-dependent manner by decreasing the expression level of Wnt5a, b-catenin and TCF4. Hybrid 133a was a novel tubulin polymerization inhibitor and could effectively inhibit MGC-803 xenograft tumor growth in vivo (oral administration) without obvious side effects. Overall, hybrid 133a might be an orally active anticancer candidate for clinical treatment of gastric cancer. Further study indicated that replacement of phenyl at N-1 position of 1,2,3-triazole moiety by benzyl (134) was also tolerated, and 1,2,3-triazole was essential for the high anticancer activity [270]. Attachment of trifluoromethyl at phenothiazine motif (R1 position) was detrimental to the activity when compared with hydrogen, while electron-donating group at R2 position was favorable to the activity. Compound 134a (IC50: 0.8e1.7 mM, MTT assay) was 6.2e15.8 times more potent than 5-Fluorouracil (IC50: 7.5e12.7 mM) against MDA-MB-231, MDA-MB-468 and MCF-7 cancer cell lines, and it could induce apoptosis against MCF7 cells by regulating apoptosis-related proteins (Bcl-2, Bax, Bad, Parp, and DR5). Thus, this potent 1,2,3-triazole-phenothiazine hybrid could be a novel apoptosis inducer and potential anticancer candidate. 1,2,3-Triazole-salinomycin hybrid 135 (IC50: 0.25e2.07 mM, MTT assay) was 8.3e64.1 folds more potent than Cisplatin against 4T1, HL-60, A549, HeLa, MCF-7, SW480 and SMMC-7721 cancer cell lines, while introduction of ester linker between 1,2,3-triazole and Salinomycin moieties (136, IC50: 1.21e4.68 mM, MTT assay) could not enhance the anticancer activity [271,272]. The 1,2,3-triazole-hydroxamic acid hybrid 137a (IC50: 40.6e64.3 mM, MTT assay) was comparable to 5-Fluorouracil (IC50: 20.7e116.8 mM) against PLC, K562, A549, ES-2, PC-3 and H7402 cancer cell lines, and it was non-toxic towards normal HUVEC (IC50: >2000 mM) [273]. It was worth to notice that this hybrid exhibited synergistic antiproliferation effect against all tested cancer cell lines when combined with 5-Fluorouracil. The in vivo anticancer evaluation showed that application of hybrid 137a alone or combined application of hybrid 137a with 5-Fluorouracil could effectively inhibit tumor growth without significant toxic signs in a mouse heptoma H22 tumor transplant model, indicating that it could act as a lead compound for further investigations. The dihydropyridin-2-one tethered 1,2,3-triazole-hydroxamic acid hybrids 138 (IC50: 0.6e25.4 mM, MTT assay) displayed significant antiproliferative effect on PC-3, MDA-MB-231, BGC-3, A549, and HepG2 cancer cell lines, and they were non-toxic towards normal RWPE-a and VERO cells [274]. The SAR revealed that the length of the alkyl linker had great influence on the activity, and longer linker was preferred. Besides the 1,2,3-triazole hybrids mentioned above, other 1,2,3-

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triazone hybrids such as 1,2,3-triazole-curcumin [275,276], 1,2,3triazole-bavachinin [277], 1,2,3-triazole-benzodiazepine [278], 1,2,3-triazole-benzodiazepinone [279], 1,2,3-triazole-benzopyran [280], 1,2,3-triazole-benzoxepine [281], 1,2,3-triazole-camptothecin [282], 1,2,3-triazole-honokiol [283], 1,2,3-triazole-ketorolac [284], 1,2,3-triazole-lamiridosin A [285], 1,2,3-triazole-maleimide [286], 1,2,3-triazole-meiogynin A [287], 1,2,3-triazole-phenanthrene [288], 1,2,3-triazole-sapinofuranone [289], 1,2,3-trizoletamibarotene [290], 1,2,3-triazole-thiomorpholine [291,292], 1,2,3triazole-vanillin [293], and 1,2,3-triazole-thiocarbamate [294e296] hybrids also showed certain anticancer activity, but the majority of them were no superior to the references. The representative 1,2,3triazole-thiocarbamate 139 (DYC-279) could induce G2/M arrest and apoptosis in a dose-dependent manner, and DYC-279-induced G2/M arrest effect was correlated with the inhibition of cyclindependent kinase 1 activity, including a concomitant downregulation of cyclinD1 and cdc2 and up-regulation of cyclinB1 in HepG2 cells [296]. DYC-279 also significantly increased the ratio of Bax/Bcl-2, stimulated the released of cytochrome c into cytosol and also activated caspase-9 and caspase-3, demonstrating DYC-279 induced apoptosis via mitochondrial apoptotic pathway. 1,2,3Triazole-curcumin hybrid 140 (CT-1) was able to selectively and significantly inhibit the breast cancer cell lines, retard cells cycle progression at S phase and induce mitochondrial-mediated cell apoptosis [276]. CT-1 selectively binds to minor groove of DNA and induces DNA damage, leading to the increase in p53 along with the decrease in its ubiquitination. Most interestingly, oral administration of CT-1 induced significant inhibition of tumor growth in LA-7 syngeneic orthotropic rat mammary tumor model. CT-1 treated mammary tumor showed enhancement in DNA damage, p53 upregulation, and apoptosis. Thus, CT-1 exhibited potent anticancer effect both in vitro and in vivo and could serve as a safe orally active lead for anti-cancer drug development. 3. 1,2,3-Triazole as a linker (type II) 1,2,3-Triazole is able to mimic different functional groups, and has already been utilized as carboxylic acid, amide and ester amide bioisostere in multiple therapeutic contexts [297,298]. Moreover, 1,2,3-triazole framework, which can be readily achieved by Cupromoted azide-alkyne cycloaddition reaction (“Click Chemistry”), has also frequently been used as a linker to connect the two pharmacophores to diverse molecular architectures [299,300]. 3.1. 1,2,3-Triazole tethered artemisinin hybrids The activity of 1,2,3-triazole tethered artemisinin-coumarin hybrids 141 (IC50: 0.05e120.72 mM, MTT assay) was comparable to that of their regio-isomers 142 (IC50: 0.35e125.40 mM, MTT assay) against HCT-116 (did not express CA IX in response to anoxia), MDA-MB-231 (CA IX negative), and HT-29 (overexpressed high amounts of CA IX) cancer cell lines [301]. The SAR revealed that introduction of halogen atom (chloro or fluoro) and methyl at C-3 and C-4 position respectively could enhance the activity. Extension of the carbon spacers between 1,2,3-triazole and artemisinin as well as between 1,2,3-triazole and coumarin moieties was generally detrimental to the activity. However, for hybrids 143 (IC50: 0.01e95.74 mM, MTT assay), prolongation of the length of alkyl linker between 1,2,3-triazole and artemisinin was preferred [301,302]. Replacement of coumarin by quinoline moiety could not improve the anticancer activity as evidenced by that the activity of conjugate 144 (IC50: 5.7e19.5 mM against MCF-7, LU-1, HL-60 and P388 cancer cells, MTT assay) was in the same level with the coumarin analog [30]. Among them, conjugate 143 (IC50: 0.01 and 1.03 mM, under hypoxia condition) was 5.7e1825 folds more potent

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than Doxorubicin (IC50: 0.25 and 5.98 mM) and Artemisinin (IC50: 18.52 and 5.64 mM) against MDA-MB-231 and HT-29 cancer cells [302]. Further study indicated that these hybrids obviously inhibited proliferation of HT-29 cells, arrested G0/G1 phase of HT29 cells, suppressed the migration of tumor cells, and induced a great decrease in mitochondrial membrane potential, leading to apoptosis of cancer cells. The anticancer SAR of 1,2,3-triazole tethered artemisininazidothymidine hybrids 145 (IC50: 16.5->178 mM, MTT assay) against KB and HepG2 cancer cell lines indicated that azidothymidine was not indispensable for the activity, and the ester linked hybrids were more potent than the corresponding amide analogs [303]. The alkyl linker between 1,2,3-triazole and artemisinin motifs had great influence on the activity, and liner alkyl was more favorable than branched and cyclo alkyl linkers, and shorter carbon spacer was preferred. Among them, hybrid 145a (IC50: 16.5 and 44.3 mM) was more active than the references Dihydroartemisinin (IC50: 95.3 and 63.7 mM) and Artesunate (IC50: 78.5 and 59.4 mM), but it was far less potent than Elipticine (IC50: 0.81 and 0.93 mM).

3.2. 1,2,3-Triazole tethered chalcone/coumarin hybrids The 1,2,3-triazole tethered chalcone-azole hybrids 146 (IC50: 1.52e63.84 mM, MTT assay) showed potential activity against MGC803, SK-N-SH and HepG2 cancer cell lines, and the SAR revealed that replacement of phenyl ring by heterocycles such as pyridine and thiophene was detrimental to the activity [304,305]. Among them, hybrids 146a-c (IC50: 1.52e10.42 mM) bearing 3,4,5trimethoxy group on the phenyl ring displayedhighest potency, and they were no inferior to 5-Fluorouracil (IC50: 7.14e10.30 mM) against all tested cancer cells. Further mechanism studies revealed that hybrid 146b could induce morphological changes of SK-N-SH cancer cells possibly by inducing apoptosis. Chalcone-1,2,3-triazole-azazerumbone hybrids 147 (IC50: 0.61e2.85 mM, MTT assay) and chalcone-1,2,3-triazole-matrine 148 (IC50: 6.06e88.02 mM, MTT assay) possessed broad spectrum activity against LU, A549, HepG2, MCF-7, P338, SW480 and Bel-7402 cancer cell lines, and all of them were more potent than azazerumbone (IC50: 6.25e34.58 mM), Zerumbone (IC50: 2.63e13.34 mM), and Matrine (IC50: >50 mM [306,307]. For chalcone-1,2,3-triazoleazazerumbone hybrids 147, the analogs without 1,2,3-triazole moiety also exhibited excellent activity, while for hybrids 148, compounds without 1,2,3-triazole moiety were devoid of activity. In particular, the anticancer activity of conjugate 147a (IC50: 0.61e1.12 mM) was as high as that of Ellipticine (IC50: 0.38e0.63 mM) against all tested cancer cells. The 1,2,3-triazole-tethered ferrocenylchalcone-uracil hybrids 149, 1,2,3-triazole linked chalcone dimer 150a, tetramer 150b (IC50: 11.37e51.56 mg/mL, MTT assay) and 1,2,3-triazole tethered coumarin hybrids such as sulfonamides 151 (IC50: 0.4e6.0 mg/mL, MTT assay) also exhibited certain anticancer activity [308e314]. In particular, the activity of compound 151a (IC50: 0.4e3.5 mg/mL) was higher than that of 5-Fluorouracil (IC50: 6.9e26.3 mM) against MGC803, BGC-823 and SGC-7901 cancer cell lines. Cellular mechanism studies indicated that conjugate 151a has the ability to induce apoptosis by down-expression level of Bcl-2 and Parp and upexpression level of BAX, inhibit the epithelial-mesenchymal transition process by up-regulating E-cadherin and down-regulating Ncadherin [314]. Moreover, this hybrid showed potential tubulin polymerization inhibitory activity, and IC50 was 2.4 mM. In vivo anticancer assay elucidated that hybrid 151a (inhibitory rate: 64.18% at 60 mg/kg) could effectively inhibit MGC-803 xenograft tumor growth without causing significant loss of body weight.

3.3. 1,2,3-Triazole tethered indole/isatin hybrids The majority of 1,2,3-triazole tethered indolehydroxycinnamamide hybrids 152 (IC50: 3.57e24.4 mM, MTT assay) were active against HCT-116, K562, MCF-7, HepG2, and Lovo (human colon carcinoma cells), and the SAR showed that the electron-donating methoxy at R1 and R2 positions was favorable to the activity [315]. The shorter carbon spacer between 1,2,3-triazole and indole moieties was favorable to the activity, whereas the longer side chain between 1,2,3-triazole and hydroxycinnamamide motifs was preferred. The most active conjugate 152a (IC50: 3.57e6.21 mM) was more potent than SAHA (IC50: 4.95e7.11 mM) against all tested cancer cell lines, and it also exhibited much better selectivity for HDAC1 over HDAC6 and HDAC8 than SAHA. Moreover, this hybrid could dose-dependently induce cancer cell cycling arrest at G0/G1 phase and promote the expression of the acetylation for histone H3 and tubulin. The indole-1,2,3-triazole-dehydrocostus-lactones 153 (GI50: 0.16e58.5 mM, SRB assay) and -parthenolide hybrids 154 (GI50: 0.12e31.6 mM, SRB assay) showed considerable activity against SIHA, PANC1, MDA-MB-231, IMR-32, DU-145, and A549 cancer cell lines, but they were far less potent than Doxorubicin (GI50: <0.01 mM) [316]. Most of indole/oxindole-1,2,3-triazole-glucose hybrids 155e157 (GI50: 9.3e165.2 mM, SRB assay) were active against DU145, HeLa, A549 and MCF-7 cell lines, and the most active conjugates 155a (GI50: 14.4e33.0 mM) and 156a (GI50: 9.3e85.6 mM) displayed a cell cycle arrest at the sub-G1 phase in DU145 cells [317,318]. Further study specified that these two hybrids had capability to induce apoptosis in cells through an intrinsic pathway and led to subsequent cell death. Moreover, they could also act against protein kinase B (Akt/PKB) pathway to inhibit proliferation of cancer cells. The majority of isatin-1,2,3-triazole-nitroimidazole hybrids 158 (IC50: 16.06->100 mM, MTT assay) were devoid of activity against MCF-7 and MDA-MB-231 cancer cell lines, but some of them such as 158a (IC50: 20.76 and 16.06) displayed potential activity [319]. The SAR indicated that extension of the alkyl side chain between isatin and 1,2,3-triazole moieties as well as attachment of halogen atom such as fluoro and chloro could boost up the activity, while introduction of thiosemicarbazone at C-3 position instead of ketone was detrimental to activity. All of 1,2,3-triazole tethered indole-hydroxycinnamamide hybrids 159 (IC50: 1.14e24.28 mM, MTT assay) with either electronwithdrawing or electron-donating group at C-5 position were more potent than the unsubstituted analog (IC50: >30 mM) against SW620, PC3, AsPC-1, and NCIeH23 cancer cell lines, and methoxy was optimal [320]. However, 1,2,3-triazole was not critical for the activity as evidenced by that the activity of hybrids without 1,2,3triazole moiety was in the same level with that of the corresponding 1,2,3-triazole analogs. Further study revealed that phenyl ring can be replaced by alkyl, and propylene (n ¼ 1) was the best [321]. Among them, conjugate 159a (IC50: 1.14e2.62 mM) and 160a (IC50: 0.49e0.76 mM) were more potent than SAHA (IC50: 3.20e3.75 mM) against all tested cancer cells, demonstrating their potential as novel anticancer candidates. The anticancer SAR of isatin-1,2,3-triazole-curcumin hybrids 161 (IC50: 1.12e14.05 mM, MTT assay) against THP-1, COLO-205, HCT-116 and PC-3 cancer cell lines implied that introduction of chloro or bromo at C-5 position of isatin moiety or replacement of phenyl ring by heterocycles led to great loss of activity [322]. Electron-donating group at phenyl ring (R2 position) was favorable to the activity, and tri-substituted hybrids were more potent than di-substituted and mono-substituted analogs. Replacement of curcumin by coumarin moiety (162, IC50: 0.73e12.99 mM, MTT assay) could enhance the anticancer activity to some extent, and

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the activity decreased significantly with the prolongation of the length of carbon-bridge [323]. For hybrids 162, initialization of either electron-withdrawing or electron-donating group at C-5 position of isatin fragment was detrimental to the activity, and the order was eH > eF > -Cl > -Br > eI > eNO2 > eOCH3. Conjugates 161a (IC50: 1.12e5.67 mM) and 162a (IC50: 0.73e3.75 mM) were found to be most active in each series, and it could significantly inhibit the tubulin polymerization (IC50: 1.2 and 1.06 mM, respectively). Preliminary SAR study of isatin-1,2,3-triazole-coumarin hybrids 163 (IC50: 15.46->50 mM, SRB assay) indicated that the length of the linker between isatin and 1,2,3-triazole moieties as well as substituents at both C-3 and C-5 positions of isatin motif had significantly influence on the anticancer activity against HepG2, HeLa, A549, DU145, SKOV3, MCF-7, and drug-resistant MCF-7/DOX (doxorubicin-resistant MCF-7) cancer cell lines [324,325]. The diethylene glycol (n ¼ 1) tethered hybrids were more potent than the corresponding tetraethylene glycol linked analogs (n ¼ 3), and similar results were also observed for 1,2,3-triazole tethered homonuclear and heteronuclear isatin dimers 164 (IC50: 0.18->50 mM, SRB assay) [326,327]. For hybrids 163, hydrogen-bond donor oxime at C-3 position of isatin skeleton could enhance the activity, while methyloxime was optimal for hybrids 164. For C-5 position of hybrids 163, electron-donating methyl could enhance the activity, while for hybrids 164, introduction of either electron-withdrawing or electron-donating group at this position was detrimental to the activity. Notably, the resistance index (RI: IC50(MCF-7/DOX)/IC50(MCF-7)) of all hybrids was less than 1, suggesting that these hybrids may have novel mechanism of action. Among them, compounds 163a (IC50: 15.46e31.50 mM) and 164a (IC50: 0.18e9.92 mM) were found to possess broad spectrum anticancer activity against all tested cell lines, and conjugate 164a with RI of 0.32 was > 1.55 folds more potent than Etoposide (IC50: 6.94-
50 mM) against all tested cancer cell lines. Thus, this hybrid could act as a lead for further optimization. The anticancer SAR of isatin-1,2,3-triazole-steroidal hybrids 165 (IC50: 4.06->128 mM, MTT assay) against MCF-7, U87, SH-SY5Y, MGC-803 and EC109 cancer cell lines demonstrated that attachment of chloro at C-4 position of isatin moiety was beneficial to the activity, and incorporation of the second halogen atom could further increase the activity [328]. The representative compound 165a (IC50: 4.06e32.25 mM) was slightly less active than 5Fluorouracil (IC50: 1.25e7.61 mM), but it could arrest cell cycle at G2/M phase, induce apoptosis, accompany the decrease of mitochondrial membrane potential, and inhibit LSD1 potently (IC50: 3.18 mM).

and the contribution order was vinylene > cycloalkyl > branched alkyl > liner alkyl. Hybrid 168a with IC50 values of 0.3 and 1.3 mM against KB and HepG2 cancer cells was slightly more potent than Ellipticine (IC50: 1.3 and 1.5 mM), but far more active than Azidothymidine (IC50: >400 mM). The 1,2,3-triazole tethered steroid dimers also displayed excellent anticancer activity. Among them, hybrids 169a,b (IC50: 0.49e31.44 mM, MTT assay) were active against most of the tested A549, HCT116, HeLa, CCRF-CEM (childhood T acute lymphoblastic leukemia), CEM-DNR (CCRF-CEM Daunorubicin resistant), K562 (chronic myelogenous), K562-Tax (K562 Paclitaxel resistant), HCT116p53/ (null p53 gene), and U2OS (osteosarcoma) cancer cell lines, and they both could act at the cytoskeletal level by inhibiting tubulin polymerization [341,342]. The 1,2,3-triazole tethered quinolone/quinoline hybrids possess broad spectrum anticancer activity, and the most emblematic examples were hybrids 170 and 171 [343e349]. The anticancer activity of conjugate 170 (IC50: 1.6e3.00 mM, MTT assay) against three different MDR cancer cell lines and their sensitive counterparts (non-small cell lung carcinoma NCIeH460/R/NCIeH460, colorectal carcinoma DLD1-TxR/DLD1 and glioblastoma U87-TxR/U87) was in the same level, implying this hybrid was not the substrate for Pglycoprotein which was indicated as a major mechanism of MDR in used cell lines [348]. Moreover, this hybrid could increase ROS production and induce mitochondrial damage in MDR cancer cells, and it could act as inhibitor of autophagy. Notably, simultaneous treatment of this hybrid with Paclitaxel increased sensitivity of MDR cancer cells to Paclitaxel. Hybrids 171a,b with GI50 values of 0.189e2.17 mM and 1.51e14.50 mM (SRB assay) were active against a panel of 60 cancer (leukemia, melanoma, cancers of lung, colon, kidney, ovary, breast, prostate, and CNS) cell lines, and both of them could induce apoptosis [349]. Interestingly, the two hybrids caused activation of caspase 8, while compound 171b also caused activation of caspase 9. The 1,2,3-triazole linked quinazoline hybrids 172a,b (IC50: 0.51e8.76 mM, MTT assay) also exhibited considerable activity against A549, BT-474, A431, SK-BR-3 and NCIeH1975 cancer cell lines, and both of them were comparable to Lapatinib (IC50: 0.06e7.25 mM) and Vorinostat (IC50: 1.90e2.67 mM) [350e352]. Conjugate 172b also exhibited highest inhibitory activity against wild-type EGFR, HDAC1, and HDAC6 with IC50 values ranging from 0.12 to 3.2 nM, and this hybrid also regulated the phosphorylation of EGFR and HER2, as well as histone H3 hyperacetylation on the cellular level, inducing remarkable apoptosis in BT-474 cells.

3.4. Miscellaneous 1,2,3-triazole tethered hybrids

Anticancer agents are indispensable for the control and eradication of cancer, but the severe anticancer scenario and the emergence of drug-resistant especially multidrug-resistant cancers have already put a heavy burden on the world health system. Thus, it is imperative to develop novel anticancer agents with low side effects and excellent potency against both drug-susceptible and drugresistant cancers. 1,2,3-Triazole, a ubiquitous moiety with biodiversity and versatibilty for the development of novel drugs, occupies an important position in the context of the cancer control, and hybridization of 1,2,3-triazole with other anticancer pharmacophores may provide valuable therapeutic intervention for the treatment of cancer. In recent 5 years, numerous of 1,2,3-triazole hybrids were developed for this purpose. In particular, hybrids 58b, 97, 115a, 132a and 171a,b possess broad spectrum anticancer activity, conjugates 13, 64a,b and 120 with IC50 values in nanomolar level were highly active against various cancer cells, compounds 57a, 72a, 99a-c, 115a, 133a and 137a exhibited great in vitro and in vivo potency

The majority of 1,2,3-triazole tethered sugar hybrids were inactive or only exhibited weak to moderate anticancer activity [329e336], while sugar-1,2,3-triazole-podophyllotoxin hybrids demonstrated promising activity against various cancer cell lines [337e339]. Among them, the representative conjugates 166a (IC50: 0.67e7.41 mM, MTT assay) and 167a (IC50: 0.49e6.70 mM, MTT assay) possessed broad spectrum anticancer activity against HL-60, SMMC-7721, A549, MCF-7, and SW480 cell lines, and both of them were no inferior to the references Etoposide (IC50: 0.31e32.82 mM) and Cisplatin (IC50: 1.28e16.33 mM) [338,339]. 1,2,3-Triazole tethered betulin-azidothymidine hybrids 168 (IC50: 0.3e34.6 mM, MTT assay) showed considerable activity against KB and HepG2 cancer cells. The SAR indicated that the ester between betulin and 1,2,3-triazole was critical for the activity, and replacement of ester by amide led to great loss of activity [340]. The linker between the two esters influenced the activity remarkably,

4. Conclusions

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against drug-sensitive and/or drug-resistant cancers, demonstrating the potential of 1,2,3-triazole hybrids as novel anticancer candidates. This review summaries the 1,2,3-triazole-containing hybrids with potential in vitro and in vivo anticancer activity which were developed at recent five years. The structure-activity relationships (SARs) and mechanisms of action are also discussed to set up the direction for the design and development of 1,2,3-triazole-containing hybrids with high efficiency and low toxicity. Acknowledgements This work was supported by The Guizhou Domestic First-class Construction Project (Chinese Materia Medical) (GNYL [2017] 008e7) and The 2019 Doctoral Research Start-up Funds in Guizhou University of Traditional Chinese Medicine. References [1] M. Govindarajan, Amphiphilic glycoconjugates as potential anti-cancer chemotherapeutics, Eur. J. Med. Chem. 143 (2018) 1208e1253. [2] M. Montana, F. Mathias, T. Terme, P. Vanelle, Antitumoral activity of quinoxaline derivatives: a systematic review, Eur. J. Med. Chem. 163 (2019) 136e147. [3] M.S. Islam, C.Y. Wang, J.Y. Zheng, N. Paudyal, Y.L. Zhu, H.X. Sun, The potential role tubeimosides in cancer prevention and treatment, Eur. J. Med. Chem. 162 (2019) 109e121. [4] J.Y. Zhang, S. Wang, Y. Bai, Z. Xu, Tetrazole hybrids with potential anticancer activity, Eur. J. Med. Chem. 178 (2019) 341e351. [5] U.M. Ammar, M.S. Abdel-Maksoud, C.H. Oh, Recent advances of RAF (rapidly accelerated fibrosarcoma) inhibitors as anti-cancer agents, Eur. J. Med. Chem. 158 (2018) 144e166. [6] F. Gao, X. Zhang, T.F. Wang, J.Q. Xiao, Quinolone hybrids and their anti-cancer activities: an overview, Eur. J. Med. Chem. 165 (2019) 59e79. [7] C.L. Zhuang, X.H. Guan, H. Ma, H. Cong, W.N. Zhang, Z.Y. Miao, Small molecule-drug conjugates: a novel strategy for cancer targeted treatment, Eur. J. Med. Chem. 163 (2019) 883e895. [8] B. Zhang, Comprehensive review on the anti-bacterial activity of 1,2,3triazole hybrids, Eur. J. Med. Chem. 168 (2019) 357e372. [9] D. Dheer, V. Singh, R. Shankar, Medicinal attributes of 1,2,3-triazoles: current developments, Bioorg. Chem. 71 (2017) 30e54. [10] X.M. Chu, C. Wang, W.L. Wang, L.L. Liang, W. Liu, K.K. Gong, K.L. Sun, Triazole derivatives and their antiplasmodial and antimalarial activities, Eur. J. Med. Chem. 166 (2019) 206e223. [11] P.N. Kalaria, S.C. Karad, D.K. Raval, A review on diverse heterocyclic compounds as the privileged scaffolds in antimalarial drug discovery, Eur. J. Med. Chem. 158 (2018) 917e936. [12] S. Emami, E. Ghobadi, S. Saednia, S.M. Hashemi, Current advances of triazole alcohols derived from fluconazole: design, in vitro and in silico studies, Eur. J. Med. Chem. 170 (2019) 173e194. [13] M.V. Castelli, M.G. Derita, S.N. Lopez, Novel antifungal agents: a patent review (2013-present), Expert Opin. Ther. Pat. 27 (2017) 415e426. [14] Y. Tian, Z. Liu, J. Liu, B. Huang, D. Kang, H. Zhang, E. de Clercq, D. Daelemans, C. Pannecouque, K. Lee, C.H. Chen, P. Zhang, X. Liu, Targeting the entrance channel of NNIBP: discovery of diarylnicotinamide 1,4-disubstituted 1,2,3triazoles as novel HIV-1 NNRTIs with high potency against wild-type and E138K mutant virus, Eur. J. Med. Chem. 151 (2018) 339e350. [15] H. Kaoukabi, Y. Kabri, C. Curti, M. Taourirte, J.C. Rodriguez, R. Snoeck, G. Andrei, P. Vanelle, H.B. Lezrek, Dihydropyrimidinone/1,2,3-triazole hybrid molecules: synthesis and anti-varicella-zoster virus (VZV) evaluation, Eur. J. Med. Chem. 155 (2018) 772e781. [16] S. Zhang, Z. Xu, C. Gao, Q.C. Ren, L. Chang, Z.S. Lv, L.S. Feng, Triazole derivatives and their anti-tubercular activity, Eur. J. Med. Chem. 138 (2017) 501e513. [17] R.S. Keri, S.A. Patil, S. Budagumpi, B. M. Nagaraja Triazole, A promising antitubercular agent, Chem. Biol. Drug Des. 86 (2015) 410e423. [18] K. Lal, P. Yadav, Recent advancements in 1,4-disubstituted 1H-1,2,3-triazoles as potential anticancer agents, Anti Cancer Agents Med. Chem. 18 (2018) 21e37. [19] J. Akhtar, A.A. Khan, Z. Ali, R. Haider, Y. Shahar, Structure-activity relationship (SAR) study and design strategies of nitrogen-containing heterocyclic moieties for their anticancer activities, Eur. J. Med. Chem. 125 (2017) 143e189. [20] B. Meunier, Hybrid molecules with a dual mode of action: dream or reality? Acc. Chem. Res. 41 (2008) 69e77. [21] S.S. Mishra, P. Singh, Hybrids molecules: the privileged scaffolds for various pharmaceuticals, Eur. J. Med. Chem. 124 (2016) 500e536. [22] Y.Q. Hu, S. Zhang, Z. Xu, Z.S. Lv, M.L. Liu, L.S. Feng, 4-Quinolone hybrids and their antibacterial activities, Eur. J. Med. Chem. 141 (2017) 335e345.

[23] Z. Xu, S. Zhang, C. Gao, J. Fan, F. Zhao, Z.S. Lv, L.S. Feng, Isatin hybrids and their anti-tuberculosis activity, Chin. Chem. Lett. 28 (2017) 159e167. [24] Y. Tu, Artemisinin-a gift from traditional Chinese medicine to the world (Nobel lecture), Angew. Chem., Int. Ed. Engl. 55 (2016) 10210e10226. [25] A. Kumari, M. Karnatak, D. Singh, R. Shankar, J.L. Jat, S. Sharma, D. Yadav, R. Shrivastava, V.P. Verma, Current scenario of artemisinin and its analogues for antimalarial activity, Eur. J. Med. Chem. 163 (2019) 804e829. [26] J. Wang, C. Xu, F.L. Liao, T. Jiang, S. Krishna, Y.Y. Tu, A temporizing solution to artemisinin resistance, N. Engl. J. Med. 380 (2019) 2087e2089. [27] N.S. Lam, X. Long, J.W. Wong, R.C. Griffin, J.C.G. Doery, Artemisinin and its derivatives: a potential treatment for leukemia, Anti Canccer Drugs 30 (2019) 1e18. [28] Y.K. Wong, C. Xu, K.A. Kalesh, Y. He, Q. Lin, W.S.F. Wong, H.M. Shen, J. Wang, Artemisinin as an anticancer drug: recent advances in target profiling and mechanisms of action, Med. Res. Rev. 37 (2017) 1492e1517. [29] X. Liu, J. Cao, G. Huang, Q. Zhao, J. Shen, Biological activities of artemisinin derivatives beyond malaria, Curr. Top. Med. Chem. 19 (2019) 205e222. [30] L.H. Binh, N.T.T. Van, V.T. Kien, N.T.T. My, L. van Chinh, N.T. Nga, H.X. Tien, D.T. Thao, T.K. Vu, Synthesis and in vitro cytotoxic evaluation of new triazole derivatives based on artemisinin via click chemistry, Med. Chem. Res. 25 (2016) 738e750. [31] D.S. Kapkoti, S. Singh, S. Luqman, R.S. Bhakuni, Synthesis of novel 1,2,3triazole based artemisinin derivatives and their antiproliferative activity, New J. Chem. 42 (2018) 5918e5995. [32] S. Jana, S. Iram, J. Thomas, S. Liekens, W. Dehaen, Synthesis and anticancer activity of novel aza-artemisinin derivatives, Bioorg. Med. Chem. 25 (2017) 3671e3676. [33] Y. Li, J. Geng, Y. Liu, S. Yu, G. Zhao, Thiadiazole-A promising structure in medicinal chemistry, ChemMedChem 8 (2013) 27e41. [34] A. Alianadi, 1,3,4-Thiadiazole based anticancer agents, Anti Cancer Agents Med. Chem. 16 (2016) 1301e1314. [35] J.Y. Zhang, S. Wang, Y. Ba, Z. Xu, 1,2,4-Triazole-quinoline/quinolone hybrids as potential anti-bacterial agents, Eur. J. Med. Chem. 174 (2019) 1e8. [36] F. Gao, T. Wang, J. Xiao, G. Huang, Antibacterial activity study of 1,2,4-triazole derivatives, Eur. J. Med. Chem. 173 (2019) 274e281. [37] A. Chauhan, R. Paul, M. Debnath, I. Bessi, S. Mandal, H. Schwalbe, J. Dash, Synthesis of fluorescent binaphthyl amines that bind c-MYC G-Quadruplex DNA and repress c-MYC expression, J. Med. Chem. 59 (2019) 7275e7281. [38] M. Debnath, S. Ghosh, A. Chauhan, R. Paul, K. Bhattacharyya, J. Dash, Preferential targeting of i-motifs and Gquadruplexes by small molecules, Chem. Sci. 8 (2017) 7448e7456. [39] A. Chauhan, S. Paladhi, M. Debnath, J. Dash, Selective recognition of c-MYC Gquadruplex DNA using prolinamide derivatives, Org. Biomol. Chem. 14 (2016) 5761e5767. [40] A.M.S. Altamimi, A.M. Alafeefy, A. Balode, I. Vozny, A. Pustenko, M.E.E. Shikh, F.A.S. Alasmary, S.A. Abdel-Gawad, R. Zalubovskis, Symmetric molecules with 1,4-triazole moieties as potent inhibitors of tumour-associated lactate dehydrogenase-A, J. Enzym. Inhib. Med. Chem. 33 (2018) 147e150. [41] A.A. Abd-Rabou, B.F. Abdel-Wahab, M.S. Bekheit, Synthesis, molecular docking, and evaluation of novel bivalent pyrazolinyl-1,2,3-triazoles as potential VEGFR TK inhibitors and anti-cancer agents, Chem. Pap. 72 (2018) 2225e2231. [42] V.D. da Silva, B.M. de Faria, E. Colombo, L. Ascari, G.P.A. Freitas, L.S. Flores, Y. Cordeiro, L. Romao, C.D. Buarque, Design, synthesis, structural characterization and in vitro evaluation of new 1,4-disubstituted-1,2,3-triazole derivatives against glioblastoma cells, Bioorg. Chem. 83 (2019) 87e97. [43] R. Kumar, P. Gahlyan, A. Verma, R. Jain, S. Das, R. Konwar, A.K. Prasad, Design and synthesis of fluorescent symmetric bis-triazolylated-1,4dihydropyridines as potent antibreast cancer agents, Synth. Commun. 48 (2018) 778e785. [44] M.W. Pertino, C. Theoduloz, E. Butassi, S. Zacchino, C. Schmeda-Hirschmann, Synthesis, antiproliferative and antifungal activities of 1,2,3-triazolesubstituted carnosic acid and carnosol derivatives, Molecules 20 (2015) 8666e8686. [45] N.A. Kheder, F. A. Altalbawy Synthesis, In vitro antimicrobial, anti-liver cancer evaluation of some novel bis-cyanocrylamide and bis-azoles derivatives, Int. J. Pharm. Sci. 8 (2016) 420e427. [46] K. Chojnacki, P. Winska, K. Skierka, M. Wielechowska, M. Bretner Synthesis, In vitro antiproliferative activity and kinase profile of new benzimidazole and benzotriazole derivatives, Bioorg. Chem. 72 (2017) 1e10. [47] Y.C. Zheng, L.Z. Wang, L.J. Zhao, L.J. Zhao, Q.N. Zhan, J.N. Ma, B. Zhang, M.M. Wang, Z.R. Wang, J.F. Li, Y. Liu, Z.S. Chen, D.D. Shen, X.Q. Liu, M. Ren, W.L. Lv, W. Zhao, Y.C. Duan, H.M. Liu, 1,2,3-Triazole-dithiocarbamate hybrids, a group of novel cell active SIRT1 inhibitors, Cell. Physiol. Biochem. 38 (2016) 185e193. [48] G. Wu, H. Wang, W. Zhou, B. Zeng, W. Mo, K. Zhu, R. Liu, J. Zhou, C. Chen, H. Chen, Synthesis and structure-activity relationship studies of MI-2 analogues as MALT1 inhibitors, Bioorg. Med. Chem. 26 (2018) 3321e3344. [49] Y.L. Fan, X.H. Jin, Z.P. Huang, H.F. Yu, L.S. Feng, Recent advances of imidazolecontaining derivatives as anti-tubercular agents, Eur. J. Med. Chem. 150 (2018) 347e365. [50] S. Niinivehmas, P.A. Postila, S. Rauhamaki, E. Manivannan, S. Kortet, M. Ahinko, P. Huuskonen, N. Nyberg, P. Koskimies, S. Latti, E. Multamaki, R.O. Juvonen, H. Raunio, M. Pasanen, J. Huuskonen, O.T. Pentikainen, Blocking oestradiol synthesis pathways with potent and selective coumarin

Z. Xu et al. / European Journal of Medicinal Chemistry 183 (2019) 111700 derivatives, J. Enzym. Inhib. Med. Chem. 33 (2018) 743e754. [51] A. Bistrovic, L. Krstulovic, A. Harej, P. Grbcic, M. Sedic, S. Kostrun, S.K. Pavelic, M. Bajic, S. Raic-Malic, Design, synthesis and biological evaluation of novel benzimidazole amidines as potent multi-target inhibitors for the treatment of non-small cell lung cancer, Eur. J. Med. Chem. 143 (2018) 1616e1634. [52] I.I. Sahay, P.S. Ghalsasi, Synthesis of new 1,2,3-triazole linked benzimidazole molecules as anti-proliferative agents, Synth. Commun. 47 (2017) 825e829. [53] S.P. Shaik, V.L. Nayak, F. Sultana, A.V.S. Rao, A.B. Shaik, K.S. Babu, A. Kamal, Design and synthesis of imidazo[2,1-b]thiazole linked triazole conjugates: microtubule-destabilizing agents, Eur. J. Med. Chem. 126 (2017) 36e51. [54] I.B. Sayeed, M.V.P.S. Vishnuvardhan, A. Nagarajan, S. Kantevari, A. Kamal, Imidazopyridine linked triazoles as tubulin inhibitors, effectively triggering apoptosis in lung cancer cell line, Bioorg. Chem. 80 (2018) 714e720. [55] A.E.M. Abdallah, M.H.E. Helal, N. I. I. Elakabawy Heterocyclization, Dyeing applications and anticancer evaluations of benzimidazole derivatives: novel synthesis of thiophene, triazole and pyrimidine derivatives. Egypt, J. Chem. 58 (2015) 699e719. [56] H.Z. Zhang, Z.L. Zhao, C.H. Zhou, Recent advance in oxazole-based medicinal chemistry, Eur. J. Med. Chem. 144 (2018) 444e492. [57] R. Kaur, K. Palta, M. Kumar, M. Bhargava, L. Dahiya, Therapeutic potential of oxazole scaffold: a patent review (2006-2017), Expert Opin. Ther. Pat. 28 (2018) 783e812. [58] G. Valdomir, M. de los A. Fernandez, I. Lagunes, J.I. Padron, V.S. Martin, J.M. Padron, D. Davyt, Oxa/thiazole-tetrahydropyran triazole-linked hybrids with selective antiproliferative activity against human tumour cells, New J. Chem. 42 (2018) 13784e13789. [59] A. Srivastava, L. Aggarwal, N. Jain, One-pot sequential alkynylation and cycloaddition: regioselective construction and biological evaluation of novel benzoxazole-triazole derivatives, ACS Comb. Sci. 17 (2015) 39e48. [60] Z. Najafi, M. Mahdavi, M. Safavi, M. Saeedi, H. Alinezhad, M. Pordeli, S.K. Ardestani, A. Shafiee, A. Foroumadi, T. Akbarzadeh, Synthesis and in vitro cytotoxic activity of novel triazole-isoxazole derivatives, J. Heterocycl. Chem. 52 (2015) 1743e1747. [61] N. Ashwini, M. Grag, C.D. Mohan, J.E. Fuchs, S. Rangappa, S. Anusha, T.R. Swaroop, K.S. Rakesh, D. Kanojia, V. Madan, A. Bender, H.P. Koeffler, K. S. Rangappa Basappa, Synthesis of 1,2-benzisoxazole tethered 1,2,3-triazoles that exhibit anticancer activity in acute myeloid leukemia cell lines by inhibiting histone deacetylases, and inducing p21 and tubulin acetylation, Bioorg. Med. Chem. 23 (2015) 6157e6165. [62] B. Madhavilatha, D. Bhattacharjee, G. Sabitha, B.V.S. Reddy, J.S. Yadav, N. Jain, B.J.M. Reddy, Synthesis and in vitro anticancer activity of novel 1,3,4oxadiazole-linked 1,2,3-triazole/isoxazole hybrids, J. Heterocycl. Chem. 55 (2018) 863e870. [63] Z. Xu, C. Gao, Q.C. Ren, X.F. Song, L.S. Feng, Z.S. Lv, Recent advances of pyrazole-containing derivatives as anti-tubercular agents, Eur. J. Med. Chem. 139 (2017) 429e440. [64] S. Ganguly, S.K. Jacob, Therapeutic outlook of pyrazole analogs: a mini review, Mini Rev. Med. Chem. 17 (2017) 959e983. [65] J.J. Liu, M.Y. Zhao, X. Zhang, X. Zhao, H.L. Zhu, Pyrazole derivatives as antitumor, anti-inflammatory and antibacterial agents, Mini Rev. Med. Chem. 13 (2013) 1957e1966. [66] S. Chauhan, S. Paliwal, R. Chauhan, Anticancer activity of pyrazole via different biological mechanisms, Synth. Commun. 44 (2014) 1333e1374. [67] T.S. Reddy, H. Kulhari, V.G. Reddy, A.V.S. Rao, V. Bansal, A. Kamal, R. Shukla, Synthesis and biological evaluation of pyrazolo-triazole hybrids as cytotoxic and apoptosis inducing agents, Org. Biomol. Chem. 13 (2015) 10136e10149. [68] V.G. Reddy, T.S. Reddy, V.L. Nayak, B. Prasad, A.P. Reddy, A. Ravikumar, S. Taj, A. Kamal, Design, synthesis and biological evaluation of N-((1-benzyl-1H1,2,3-triazol-4-yl)methyl)-1,3-diphenyl-1H-pyrazole-4-carboxamides as CDK1/Cdc2 inhibitors, Eur. J. Med. Chem. 122 (2016) 164e177. [69] S.A. Amin, N. Adhikari, R.K. Agrawal, T. Jha, S. Gayen, Possible binding mode analysis of pyrazolo-triazole hybrids as potential anticancer agents through validated molecular docking and 3D-QSAR modeling approaches, Lett. Drug Des. Discov. 14 (2017) 515e527. [70] B. Manjunatha, G.K. Nagaraja, K. Reshma, R.P.K. Sreedhara, B. Subhankar, S.R. Mohammed, 1,2,3-Triazolyl pyrazole derivatives as anti-cancer agents: biological evaluation and molecular docking, Der Pharma Chem. 8 (2016) 200e221. [71] M.F. Khan, T. Anwer, A. Bakht, G. Verma, W. Akhtar, M.M. Alam, M.A. Rizvi, M. Akhter, M. Shaquiquzzaman, Unveiling novel diphenyl-1H-pyrazole based acrylates tethered to 1,2,3-triazole as promising apoptosis inducing cytotoxic and anti-inflammatory agents, Bioorg. Chem. 87 (2019) 667e678. [72] B. Madhavilatha, N. Fatima, G. Sabitha, B.V.S. Reddy, J.S. Yadav, D. Bhattacharjee, N. Jain, Synthesis of 1,2,3-triazole and isoxazole-linked pyrazole hybrids and their cytotoxic activity, Med. Chem. Res. 26 (2017) 1753e1759. [73] P.K.N. Sarangi, J. Sahoo, B.D. Swain, S.K. Paidesetty, Thiazoles as potent anticancer agents: a review, Indian Drugs 53 (2016) 5e11. [74] M.R. Aouad, M.A. Soliman, M.O. Alharbi, S.K. Bardaweel, P.K. Sahu, A.A. Ali, M. Messali, N. Rezki, Y.A. Al-Soud, Design, synthesis and anticancer screening of novel benzothiazole-piperazine-1,2,3-triazole hybrids, Molecules 23 (2018) e2788. [75] R.M. Kumbhare, T.L. Dadmal, M.J. Ramaiah, K.S. Kishore, S.N. Pushpa Valli, S.K. Tiwari, K. Appalanaidu, Y.K. Rao, M.P. Bhadra, Synthesis and anticancer evaluation of novel triazole linked N-(pyrimidin-2-yl)benzo[d]thiazol-2-

[76]

[77]

[78]

[79] [80]

[81]

[82]

[83]

[84]

[85]

[86]

[87]

[88]

[89] [90] [91] [92]

[93]

[94]

[95]

[96]

[97]

[98]

[99]

[100]

[101]

31

amine derivatives as inhibitors of cell survival proteins and inducers of apoptosis in MCF-7 breast cancer cells, Bioorg. Med. Chem. Lett 25 (2015) 654e658. S.P. Shaik, M.V.P.S. Vishnuvardhan, F. Sultana, A.V.S. Rao, C. Bagul, D. Bhattacharjee, J.S. Kapure, N. Jain, A. Kamal, Design and synthesis of 1,2,3triazolo linked benzo[d]imidazo[2,1-b]thiazole conjugates as tubulin polymerization inhibitors, Bioorg. Med. Chem. 25 (2017) 3285e3297. V.R. Nagavelli, S. Narsimha, K.S. Battula, L. Sudhakar, R.K. Thatipamula, Synthesis, cytotoxic and antibacterial activities of 6-bromobenzo[d]thiazol2(3H)-one-[1,2,3]triazole hybrids, Org. Commun. 9 (2016) 32e41. V.R. Yadav, S. Prasad, B. Sung, B.B. Aggarwal, The role of chalcones in suppression of NF-kB-mediated inflammation and cancer, Int. Immunopharmacol. 11 (2011) 295e309. V. Sharma, V. Kumar, P. Kumar, Heterocyclic chalcone analogues as potential anticancer agents, Anti Cancer Agents Med. Chem. 13 (2013) 422e432. S.M.A. Hussaini, P. Yedla, K.S. Babu, T.B. Shaik, G.K. Chityal, A. Kamal, Synthesis and biological evaluation of 1,2,3-triazole tethered pyrazoline and chalcone derivatives, Chem. Biol. Drug Des. 88 (2016) 97e109. Y. Chinthala, S. Thakur, S. Thakur, S. Tirunagari, S. Chinde, A.K. Dimatti, N.K. Arigari, K.V.N.S. Srinivas, S. Alam, K.K. Jonnala, F. Khan, A. Tiwari, P. Grover Synthesis, Docking and ADMET studies of novel chalcone triazoles for anti-cancer and anti-diabetic activity, Eur. J. Med. Chem. 93 (2015) 564e573. P. Yadav, K. Lal, A. Kumar, S.K. Guru, S. Jaglan, S. Bhushan, Green synthesis and anticancer potential of chalcone linked-1,2,3-triazoles, Eur. J. Med. Chem. 126 (2017) 944e953. D.J. Fu, S.Y. Zhang, Y.C. Liu, X.X. Yue, J.J. Liu, J. Song, R.H. Zhao, F. Li, H.H. Sun, Y.B. Zhang, H.M. Liu, Design, synthesis and antiproliferative activity studies of 1,2,3-triazole-chalcones, MedChemComm 7 (2016) 1664e1671. N. Hari, S. Aravind, G.A. Kurian, R. Rajmohan, R. Ravikumar, Green synthesis, characterization of novel 1,2,3-triazole-chalcone hybrids and evaluation of their antibacterial, antifungal and antiproliferation activity, Der Pharma Chem. 8 (2016) 275e280. H.R.M. Rashdan, H.M.F. Roaiah, Z.A. Muhammad, J. Wietrzyk, M. Milczarek, A.M. Soliman, Design, efficient synthesis, mechanism of reaction and antiproliferative activity against cancer and normal cell lines of a novel class of fused pyrimidine derivatives, Acta Pol. Pharm. 75 (2018) 679e688. B. Aneja, R. Arif, A. Perwez, J.V. Napoleon, P. Hasan, M.M.A. Rizvi, A. Azam, Rahisuddin, M. Abid, N-Substituted 1,2,3-triazolyl-appended indolechalcone hybrids as potential DNA intercalators endowed with antioxidant and anticancer properties, ChemistrySelect 3 (2018) 2638e2645. A. Thakur, R. Singla, V. Jaitak, Coumarins as anticancer agents: a review on synthetic strategies, mechanism of action and SAR studies, Eur. J. Med. Chem. 101 (2015) 476e495. J. Dandriyal, R. Singla, M. Kumar, V. Jaitak, Recent developments of C-4 substituted coumarin derivatives as anticancer agents, Eur. J. Med. Chem. 119 (2016) 141e168. F. Teillet, A. Boumendjel, J. Boutonnat, X. Ronot, Flavonoids as RTK inhibitors and potential anticancer agents, Med. Res. Rev. 28 (2008) 715e745. D. Maggioni, L. Biffi, G. Nicolini, W. Garavello, Flavonoids in oral cancer prevention and therapy, Eur. J. Cancer Prev. 24 (2015) 517e528. Y.L. Fan, X. Ke, M. Liu, Coumarin-triazole hybrids and their biological activities, J. Heterocycl. Chem. 55 (2018) 791e802. T.G. Kraljevic, A. Harej, M. Sedic, S.K. Pavelic, V. Stepanic, D. Drenjancevic, J. Talapko, S. Raic-Malic Synthesis, In vitro anticancer and antibacterial activities and in silico studies of new 4-substituted 1,2,3-triazole-coumarin hybrids, Eur. J. Med. Chem. 124 (2016) 794e808. A. Bistrovic, N. Stipanicev, T. Opacak-Bernardi, M. Jukic, S. Martinez, L. Glavas-Obrovas, S. Raic-Malic, Synthesis of 4-aryl-1,2,3-triazolyl appended natural coumarin related compounds with antiproliferative, radical scavenging activities and intracellular ROS production modification, New J. Chem. 41 (2017) 7531e7543. R. An, Z. Hou, J.T. Li, H.N. Yu, Y.H. Mou, C. Guo, Design, synthesis and biological evaluation of novel 4-substituted coumarin derivatives as antitumor agents, Molecules 23 (2018) e2281. D.J. Fu, P. Li, B.W. Wu, X.X. Cui, C.B. Zhao, S.Y. Zhang, Molecular diversity of trimethoxyphenyl-1,2,3-triazole hybrids as novel colchicine site tubulin polymerization inhibitors, Eur. J. Med. Chem. 165 (2019) 309e322. C.M. Farley, D.F. Dibwe, J. Ueda, E.A. Hall, S. Awale, J. Magolan, Evaluation of synthetic coumarins for antiausterity cytotoxicity against pancreatic cancers, Bioorg. Med. Chem. Lett 26 (2016) 1471e1474. Y.C. Duan, Y.C. Ma, E. Zhang, X.J. Shi, M.M. Wang, X.W. Ye, H.M. Liu, Design and synthesis of novel 1,2,3-triazole-dithiocarbamate hybrids as potential anticancer agents, Eur. J. Med. Chem. 62 (2013) 11e19. S. Sinha, A.P. Kumaran, D. Mishra, P. Paira, Synthesis and cytotoxicity study of novel 3-(triazolyl)coumarins based fluorescent scaffolds, Bioorg. Med. Chem. Lett 26 (2016) 5557e5561. Q.K. Shen, C.F. Liu, H.J. Zhang, Y.S. Tian, Z.S. Quan, Design and synthesis of new triazoles linked to xanthotoxin for potent and highly selective antigastric cancer agents, Bioorg. Med. Chem. Lett 27 (2017) 4871e4875. A.V. Lipeeva, M.A. Pokrovsky, D.S. Baev, M.M. Shakirov, I.Y. Bagryanskaya, T.G. Tolstikova, A.G. Pokrovsky, E.E. Shults, Synthesis of 1H-1,2,3-triazole linked aryl(arylamidomethyl)-dihydrofurocoumarin hybrids and analysis of their cytotoxicity, Eur. J. Med. Chem. 100 (2015) 119e128. I. Ansary, H. Roy, A. Das, D. Mitra, A.K. Bandyopadhyay, Regioselective synthesis, molecular descriptors of (1,5-disubstituted 1,2,3-triazolyl)coumarin/

32

[102]

[103]

[104]

[105]

[106]

[107]

[108]

[109]

[110]

[111]

[112] [113]

[114]

[115]

[116]

[117]

[118]

[119]

[120]

[121]

[122]

[123]

Z. Xu et al. / European Journal of Medicinal Chemistry 183 (2019) 111700 quinolone derivatives and their docking studies against cancer targets, ChemistrySelect 4 (2019) 3486e3494. K.R. Reddy, P.S. Rao, G.J. Dev, Y. Poornachandra, C.G. Kumar, P.S. Rao, B. Narsaiah, Synthesis of novel 1,2,3-triazole/isoxazole functionalized 2Hchromene derivatives and their cytotoxic activity, Bioorg. Med. Chem. Lett 24 (2014) 1661e1663. P.J. Raj, D. Bahulayan, “MCR-Click” synthesis of coumarin-tagged macrocycles with large Stokes shift values and cytotoxicity against human breast cancer cell line MCF-7, Tetrahedron Lett. 58 (2017) 2122e2126. S. Chekir, M. Debbabi, A. Regazzetti, D. Dargere, O. Laprevote, H.B. Jannet, R. Gharbi, Design, synthesis and biological evaluation of novel 1,2,3-triazole linked coumarinopyrazole conjugates as potent anticholinesterase, anti-5lipoxygenase, anti-tyrosinase and anti-cancer agents, Bioorg. Chem. 80 (2018) 189e194. T. Sowjanya, Y.J. Rao, N.Y.S. Murthy, Synthesis and antiproliferative activity of new 1,2,3-triazole/flavone hybrid heterocycles against human cancer cell lines, Russ. J. Gen. Chem. 87 (2017) 1864e1871. Y. Qi, Z. Ding, Y. Yao, D. Ma, F. Ren, H. Yang, A. Chen, Novel triazole analogs of apigenin-7-methyl ether exhibit potent antitumor activity against ovarian carcinoma cells via the induction of mitochondrial-mediated apoptosis, Exp. Ther. Med. 17 (2019) 1670e1676. J. Wu, Y. Chen, X. Liu, Y. Gao, J. Hu, H. Chen, Discovery of novel negletein derivatives as potent anticancer agents for acute Myeloid Leukemia, Chem. Biol. Drug Des. 91 (2018) 924e932. Y.J. Rao, T. Sowjanya, G. Thirupathi, N.Y.S. Murthy, S.S. Kotapalli, Synthesis and biological evaluation of novel flavone/triazole/benzimidazole hybrids and flavone/isoxazole-annulated heterocycles as antiproliferative and antimycobacterial agents, Mol. Divers. 22 (2018) 803e811. B. Mistry, R.V. Patel, Y.S. Keum, Access to the substituted benzyl-1,2,3triazolyl hesperetin derivatives expressing antioxidant and anticancer effects, Arab. J. Chem. 10 (2017) 157e166. X. Li, Y. Wu, Y. Wang, Q. You, X. Zhang, ‘Click chemistry’ synthesis of novel natural product-like caged Xanthones bearing a 1,2,3-triazole moiety with improved druglike properties as orally active antitumor agents, Molecules 22 (2017) e1834. S.A. Patil, R. Patil, D.D. Miller, Indole molecules as inhibitors of tubulin polymerization: potential new anticancer agents, Future Med. Chem. 4 (2012) 2085e2115. Z. Xu, S. Zhang, C. Gao, J. Fan, F. Zhao, Z.S. Lv, L.S. Feng, Isatin hybrids and their anti-tuberculosis activity, Chin. Chem. Lett. 28 (2017) 159e167. N.R. Penthala, L. Madhukuri, S. Thakkar, N.R. Madadi, G. Lamture, R.L. Eoff, P.A. Crooks, Synthesis and anti-cancer screening of novel heterocyclic-(2H)1,2,3-triazoles as potential anti-cancer agents, MedChemComm 6 (2015) 1535e1541. S. Narsimha, N.S. Kumar, K.S. Battula, V.R. Nagavelli, S.K.A. Hussain, M.S. Rao, Indole-2-carboxylic acid derived mono and bis 1,4-disubstituted 1,2,3triazoles: synthesis, characterization and evaluation of anticancer, antibacterial, and DNA-cleavage activities, Bioorg. Med. Chem. Lett 26 (2016) 1639e1644. F. Naaz, M.C.P. Pallavi, S. Shafi, N. Mulakayala, M.S. Yar, H.M.S. Kumar, 1,2,3Triazole tethered indole-3-glyoxamide derivatives as multiple inhibitors of 5-LOX, COX-2 & tubulin: their anti-proliferative & anti-inflammatory activity, Bioorg. Chem. 81 (2018) 1e20. M.L. Lolli, I.M. Carnovale, A.C. Pippione, W.Y. Wahlgren, D. Bonanni, E. Marini, D. Zonari, M. Gallicchio, W. Boscaro, P. Goyal, R. Friemann, B. Rolando, R. Bagnati, S. Adinolfi, S. Oliaro-Bosso, D. Boschi, Bioisosteres of indomethacin as inhibitors of aldo-keto reductase 1C3 (AKR1C3), ACS Med. Chem. Lett. 10 (2019) 437e444. B. Kummari, N. Polkam, P. Ramesh, H. Anantaraju, P. Yogeeswari, J.S. Anireddy, S.D. Guggilapu, B.N. Babu, Design and synthesis of 1,2,3triazole-etodolac hybrids as potent anticancer molecules, RSC Adv. 7 (2017) 23680e23686. T. Humphries-Bickley, L. Castillo-Pichardo, E. Hernandez-O’Farrill, L.D. Borrero-Garcia, I. Forestier-Roman, Y. Gerena, M. Blanco, M.J. RiveraRobles, J.R. Rodriguez-Medina, L.A. Cubano, C.P. Vlaar, S. Dharmawardhane, Characterization of a dual Rac/Cdc42 inhibitor MBQ-167 in metastatic cancer, Mol. Cancer Ther. 16 (2017) 805e819. N. Panathur, N. Gokhale, U. Dalimba, P.V. Koushik, P. Yogeeswari, D. Sriram, Synthesis of novel 5-[(1,2,3-triazol-4-yl)methyl]-1-methyl-3H-pyridazino [4,5-b]indol-4-one derivatives by click reaction and exploration of their anticancer activity, Med. Chem. Res. 25 (2016) 135e148. N. Shankaraiah, C. Jadala, S. Nekkanti, K.R. Senwar, N. Nagesh, S. Shrivastava, V.G.M. Naidu, M. Sathish, A. Kamal, Design and synthesis of C3-tethered 1,2,3-triazolo-b-carboline derivatives: anticancer activity, DNA-binding ability, viscosity and molecular modeling studies, Bioorg. Chem. 64 (2016) 42e50. W.P. Hu, K.K. Kou, G.C. Senadi, L.S. Chang, J.J. Wang, Photodynamic therapy using indolines-fused-triazoles induces mitochondrial apoptosis in human non-melanoma BCC cells, Anticancer Res. 37 (2017) 5499e5505. B. Yu, S.Q. Wang, P.P. Qi, D.X. Yang, K. Tang, H.M. Liu, Design and synthesis of isatin/triazole conjugates that induce apoptosis and inhibit migration of MGC-803 cells, Eur. J. Med. Chem. 124 (2016) 350e360. A. Nagarsenkar, L. Guntuku, S.D. Guggilapu, B.K. Danthi, S. Gannoju, V.G.M. Naidu, N.B. Bathini, Synthesis and apoptosis inducing studies of triazole linked 3-benzylidene isatin derivatives, Eur. J. Med. Chem. 124 (2016)

782e793. [124] B. Aneja, N.S. Khan, P. Khan, A. Queen, A. Hussain, M.T. Rehman, M.A. Alajmi, H.R. El-Seedi, S. Ali, M.I. Hassan, M. Abid, Design and development of isatintriazole hydrazones as potential inhibitors of microtubule affinity-regulating kinase 4 for the therapeutic management of cell proliferation and metastasis, Eur. J. Med. Chem. 163 (2018) 840e852. [125] K.R. Senwar, P. Sharma, T.S. Reddy, M.K. Jeengar, V.L. Nayak, V.G.M. Naidu, A. Kamal, N. Shankaraiah, Spirooxindole-derived morpholine-fused-1,2,3triazoles: design, synthesis, cytotoxicity and apoptosis inducing studies, Eur. J. Med. Chem. 102 (2015) 413e424. [126] P.V. Chavan, U.V. Desai, P.P. Wadgaonkar, S.R. Tapase, K.M. Kodam, A. Choudhari, D. Sarkar, Click chemistry based multicomponent approach in the synthesis of spirochromenocarbazole tethered 1,2,3-triazoles as potential anticancer agents, Bioorg. Med. 85 (2019) 475e486. [127] Y. Lu, L. Wang, X. Wang, T. Xi, J. Liao, Z. Wang, F. Jiang, Design, combinatorial synthesis and biological evaluations of novel 3-amino-10-((1-aryl-1H-1,2,3triazol-5-yl)methyl)-20-oxospiro[benzo[a]pyrano[2,3-c]phenazine-1,30indoline]-2-carbonitrile antitumor hybrid molecules, Eur. J. Med. Chem. 135 (2017) 125e141. [128] R. Jain, P. Gahlyan, S. Dwivedi, R. Konwar, S. Kumar, M. Bhandari, R. Arora, R. Kakkar, R. Kumar, A.K. Prasad, Design, synthesis and evaluation of 1H1,2,3-triazol-4-yl-methyl tethered 3-pyrrolylisatins as potent anti-breast cancer agents, ChemistrySelect 3 (2018) 5263e5268. [129] S. Prachayasittikul, R. Pingaew, A. Worachartcheewan, N. Sinthupoom, V. Prachayasittikul, S. Ruchirawat, V. Prachayasittikul, Roles of pyridine and pyrimidine derivatives as privileged scaffolds in anticancer agents, Mini Rev. Med. Chem. 17 (2017) 869e901. [130] R. Goel, V. Luxami, K. Paul, Imidazo[1,2-a]pyridines: promising drug candidate for antitumor therapy, Curr. Top. Med. Chem. 16 (2016) 3590e3616. [131] J. Akhtar, A.A. Khan, Z. Ali, R. Haider, Y. Shahar, Structure-activity relationship (SAR) study and design strategies of nitrogen-containing heterocyclic moieties for their anticancer activities, Eur. J. Med. Chem. 125 (2017) 143e189. [132] A. Kamal, A.V.S. Rao, M.V.P.S. Vishnuvardhan, T.S. Reddy, K. Swapna, C. Bagul, N.V.S. Reddy, V. Srinivasulu, Synthesis of 2-anilinopyridyl-triazole conjugates as antimitotic agents, Org. Biomol. Chem. 13 (2015) 4879e4895. [133] B. Prasad, V.L. Nayak, P.S. Srikanth, M.F. Baig, N.V.S. Reddy, K.S. Babu, A. Kamal, Synthesis and biological evaluation of 1-benzyl-N-(2-(phenylamino)pyridin-3-yl)-1H-1,2,3-triazole-4-carboxamides as antimitotic agents, Bioorg. Chem. 83 (2019) 535e548. [134] J. Bai, C. Liao, Y. Liu, X. Qin, J. Chen, Y. Qiu, D. Qin, Z. Li, Z.C. Tu, S. Jiang, Structure-based design of potent nicotinamide phosphoribosyltransferase inhibitors with promising in vitro and in vivo antitumor activities, J. Med. Chem. 59 (2016) 5766e5779. [135] G. Dong, W. Chen, X. Wang, X. Yang, Y. Xu, P. Wang, W. Zhang, Y. Rao, C. Miao, C. Sheng, Small molecule inhibitors simultaneously targeting cancer metabolism and epigenetics: discovery of novel nicotinamide phosphoribosyltransferase (NAMPT) and histone deacetylase (HDAC) dual inhibitors, J. Med. Chem. 60 (2017) 7965e7983. [136] C. Travelli, S. Aprile, R. Rahimian, A.A. Grolla, F. Rogati, M. Bertolotti, F. Malagnino, R. Paola, D. Impellizzeri, R. Fusco, V. Mercalli, A. Massarotti, G. Stortini, S. Terrazzino, E.D. Grosso, G. Fakhfouri, M.P. Troiani, M.A. Alisi, G. Grosa, G. Sorba, P.L. Canonico, G. Orsomando, S. Cuzzocrea, A.A. Genazzani, U. Galli, G.C. Tron, Identification of novel triazole-based nicotinamide phosphoribosyltransferase (NAMPT) inhibitors endowed with antiproliferative and antiinflammatory activity, J. Med. Chem. 60 (2017) 1768e1792. [137] S. Theeramunkong, U. Galli, A.A. Grolla, A. Caldarelli, C. Travelli, A. Massarotti, M.P. Troiani, M.A. Alisi, G. Orsomando, A.A. Genazzani, G.C. Tron, Identification of a novel NAMPT inhibitor by combinatorial click chemistry and chemical refinement, MedChemComm 6 (2015) 1891e1897. [138] W. Ye, Q. Yao, S. Yu, P. Gong, M. Qin, Synthesis and antitumor activity of triazole-containing sorafenib analogs, Molecules 22 (2017) e1759. [139] S. Murugavel, C. Ravikumar, G. Jaabil, P. Alagusundaram, Synthesis, crystal structure analysis, spectral investigations (NMR, FTIR, UV), DFT calculations, ADMET studies, molecular docking and anticancer activity of 2-(1-benzyl-5methyl-1H-1,2,3-triazol-4-yl)-4-(2-chlorophenyl)-6-methoxypyridine-A novel potent human topoisomerase IIa inhibitor, J. Mol. Struct. 1176 (2019) 729e742. [140] S. Murugavel, C. Ravikumar, G. Jaabil, P. Alagusundaram, Synthesis, computational quantum chemical study, in silico ADMET and molecular docking analysis, in vitro biological evaluation of a novel sulfur heterocyclic thiophene derivative containing 1,2,3-triazole and pyridine moieties as a potential human topoisomerase IIa inhibiting anticancer agent, Comput. Biol. Chem. 79 (2019) 73e82. [141] M.S. Christodoulou, M. Mori, R. Pantano, R. Alfonsi, P. Infante, M. Botta, G. Damia, F. Ricci, P.A. Sotiropoulou, S. Liekens, B. Botta, D. Passarella, Click reaction as a tool to combine pharmacophores: the case of vismodegib, ChemPlusChem 80 (2015) 938e943. [142] M. Gilandoust, K.B. Harsha, C.D. Mohan, A.R. Raquib, S. Rangappa, V. Pandey, P.E. Lobie, K. S. Rangappa Basappa, Synthesis, characterization and cytotoxicity studies of 1,2,3-triazoles and 1,2,4-triazolo[1,5-a]pyrimidines in human breast cancer cells, Bioorg. Med. Chem. Lett 28 (2018) 2314e2319. [143] S.C. Hockey, G.J. Barbante, P.S. Francis, J.M. Altimari, P. Yoganantharajah, Y. Gibert, L.C. Henderson, A comparison of novel organoiridium(III)

Z. Xu et al. / European Journal of Medicinal Chemistry 183 (2019) 111700

[144]

[145]

[146]

[147]

[148]

[149]

[150]

[151]

[152] [153]

[154]

[155]

[156]

[157]

[158]

[159]

[160]

[161]

[162]

[163]

[164]

complexes and their ligands as a potential treatment for prostate cancer, Eur. J. Med. Chem. 109 (2016) 305e313. Y.T. Li, J.H. Wang, C.W. Pan, F.F. Meng, X.Q. Chu, Y.H. Ding, W.Z. Qu, H.Y. Li, C. Yang, Q. Zhang, C.G. Bai, Y. Chen, Syntheses and biological evaluation of 1,2,3-triazole and 1,3,4-oxadiazole derivatives of imatinib, Bioorg. Med. Chem. Lett 26 (2016) 1419e1427. Q. Tang, L. Wang, Y. Tu, W. Zhu, R. Luo, Q. Tu, P. Wang, C. Wu, P. Gong, P. Zheng, Discovery of novel pyrrolo[2,3-b]pyridine derivatives bearing 1,2,3-triazole moiety as c-Met kinase inhibitors, Bioorg. Med. Chem. Lett 26 (2016) 1680e1684. S. Narva, S. Chitti, B.R. Bala, M. Alvala, N. Jain, V.G.C.S. Kondapalli, Synthesis and biological evaluation of pyrrolo[2,3-b]pyridine analogues as antiproliferative agents and their interaction with calf thymus DNA, Eur. J. Med. Chem. 114 (2016) 220e231. M. Gilandoust, K.B. Harsha, C.D. Mohan, A.R. Raquib, S. Rangappa, V. Pandey, P.E. Lobie, B. Asappa, K.S. Rangappa, Synthesis, characterization and cytotoxicity studies of 1,2,3-triazoles and 1,2,4-triazolo[1,5-a]pyrimidines in human breast cancer cells, Bioorg. Med. Chem. Lett 28 (2018) 2314e2319. I. Steiner, N. Stojanovic, A. Bolje, A. Brozovic, D. Polancec, A. AmbriovicRistov, M.R. Stojkovic, I. Piantanida, D. Eljuga, J. Kosmrlj, M. Osmak, Discovery of ‘click’ 1,2,3-triazolium salts as potential anticancer drugs, Radiol. Oncol. 50 (2016) 280e288. V. Banda, S.K. Gautham, S.R. Pillalamarri, K. Chavva, N. Banda, Synthesis of novel 1,2,3-triazole/isoxazole-functionalized imidazo[4,5-b]pyridin-2(3H)one derivatives, their antimicrobial and anticancer activity, J. Heterocycl. Chem. 53 (2016) 1168e1175. S. Cherukupalli, R. Karpoormath, B. Chandrasekaran, G.A. Hampannavar, N. Thapliyal, V.N. Palakollu, An insight on synthetic and medicinal aspects of pyrazolo[1,5-a]pyrimidine scaffold, Eur. J. Med. Chem. 126 (2017) 298e352. Y. Wang, S. Chen, G. Hu, J. Wang, W. Gou, D. Zuo, Y. Gu, P. Gong, X. Zhai, Discovery of novel 2,4-diarylaminopyrimidine analogues as ALK and ROS1 dual inhibitors to overcome crizotinib-resistant mutants including G1202R, Eur. J. Med. Chem. 143 (2018) 123e136. J. Robert, C. Jarry, Multidrug resistance reversal agents, J. Med. Chem. 46 (2003) 4805e4817. B. Wang, B. Zhao, Z.S. Chen, L.P. Pang, Y.D. Zhao, Q. Guo, X.H. Zhang, Y. Liu, G.Y. Liu, H. Zhang, X.Y. Zhang, L.Y. Ma, H.M. Liu, Exploration of 1,2,3-triazolepyrimidine hybrids as potent reversal agents against ABCB1-mediated multidrug resistance, Eur. J. Med. Chem. 143 (2018) 1535e1542. P.F. Geng, X.Q. Liu, T.Q. Zhao, C.C. Wang, Z.H. Li, J. Zhang, H.M. Wei, B. Hu, L.Y. Ma, H.M. Liu, Design, synthesis and in vitro biological evaluation of novel [1,2,3]triazolo[4,5-d]pyrimidine derivatives containing a thiosemicarbazide moiety, Eur. J. Med. Chem. 146 (2018) 147e156. Z.H. Li, D.X. Yang, P.F. Geng, J. Zhang, H.M. Wei, B. Hu, Q. Guo, X.H. Zhang, W.G. Guo, B. Zhao, B. Yu, L.Y. Ma, H.M. Liu, Design, synthesis and biological evaluation of [1,2,3]triazolo[4,5-d]pyrimidine derivatives possessing a hydrazone moiety as antiproliferative agents, Eur. J. Med. Chem. 124 (2016) 967e980. L. Wang, S. Xu, X. Liu, X. Chen, H. Xiong, S. Hou, W. Zou, Q. Tang, P. Zheng, W. Zhu, Discovery of thinopyrimidine-triazole conjugates as c-Met targeting and apoptosis inducing agents, Bioorg. Chem. 77 (2018) 370e380. S.M. Lee, K.B. Yoon, H.J. Lee, J. Kim, Y.K. Chung, W.J. Cho, C. Mukai, S. Choi, K.W. Kang, S.Y. Han, H. Ko, Y.C. Kim, The discovery of 2,5-isomers of triazolepyrrolopyrimidine as selective Janus kinase 2 (JAK2) inhibitors versus JAK1 and JAK3, Bioorg. Med. Chem. 24 (2016) 5036e5046. A. Bistrovic, P. Grbcic, A. Harej, M. Sedic, S. Kraljevic-Pavelic, S. Kostrun, J. Plavec, D. Makuc, S. Taic-Malic, Small molecule purine and pseudopurine derivatives: synthesis, cytostatic evaluations and investigation of growth inhibitory effect in non-small cell lung cancer A549, J. Enzym. Inhib. Med. Chem. 33 (2018) 271e285. R.N. Kumar, G.J. Dev, N. Ravikumar, D.K. Swaroop, B. Debanjan, G. Bjarath, B. Narsaiah, S.N. Jain, A.G. Rao, Synthesis of novel triazole/isoxazole functionalized 7-(trifluoromethyl)pyrido[2,3-d]pyrimidine derivatives as promising anticancer and antibacterial agents, Bioorg. Med. Chem. Lett 26 (2016) 2927e2930. S.V. Vasilyeva, A.A. Shtil, A.S. Petrova, S.M. Balakhnin, P.Y. Achigecheva, D.A. Stetsenko, V.N. Silnikov, Conjugates of phosphorylated zalcitabine and lamivudine with SiO2 nanoparticles: synthesis by CuAAC click chemistry and preliminary assessment of anti-HIV and antiproliferative activity, Bioorg. Med. Chem. 25 (2017) 1696e1702. M.S. Babic, A. Ratkovic, M. Jukic, L. Glavas-Obrovac, D. Drenjancevic Synthesis, Cytostatic and antibacterial evaluations of novel 1,2,3-triazolyl-tagged pyrimidine and furo[2,3-d]pyrimidine derivatives, Croat. Chem. Acta 90 (2017) 197e205. T. Gregoric, M. Sedic, P. Grbcic, A.T. Paravic, S.K. Pavelic, M. Vetina, R. Vianello, S. Raic-Malic, Novel pyrimidine-2,4-dione-1,2,3-triazole and furo [2,3-d]pyrimidine-2-one-1,2,3-triazole hybrids as potential anti-cancer agents: synthesis, computational and X-ray analysis and biological evaluation, Eur. J. Med. Chem. 125 (2017) 1247e1267. M. Allam, A.K.D. Bhavani, A. Mudiraj, N. Ranjan, M. Thippana, P.P. Babu, Synthesis of pyrazolo[3,4-d]pyrimidin-4(5H)-ones tethered to 1,2,3-triazoles and their evaluation as potential anticancer agents, Eur. J. Med. Chem. 156 (2018) 43e52. R.R. Ruddarraju, A.C. Murugulla, R. Kotla, M.C.B. Tirumalasetty, R. Wudayagiri, S. Donthabakthuni, R. Maroju, Design, synthesis, anticancer

[165]

[166]

[167]

[168]

[169] [170]

[171]

[172]

[173]

[174]

[175]

[176]

[177]

[178]

[179] [180]

[181]

[182]

[183]

[184]

[185]

[186]

[187]

33

activity and docking studies of theophylline containing 1,2,3-triazoles with variant amide derivatives, MedChemComm 8 (2017) 176e185. A. Kumar, B.S. Kumar, E. Sreenivas, T. Subbaiah Synthesis, Biological evaluation, and molecular docking studies of novel 1,2,3-triazole tagged 5-[(1Hindol-3-yl)methylene]pyrimidine-2,4,6(1H,3H,5H)trione derivatives, Russ. J. Gen. Chem. 88 (2018) 587e595. A.P. Montgomery, D. Skropeta, H. Yu, Transition state-based ST6Gal I inhibitors: mimicking the phosphodiester linkage with a triazole or carbamate through an enthalpy-entropy compensation, Sci. Rep. 7 (2017) 14428e14438. G.Q. Lu, X.Y. Li, K. Mohamed, D. Wang, F.H. Meng, Design, synthesis and biological evaluation of novel uracil derivatives bearing 1, 2, 3-triazole moiety as thymidylate synthase (TS) inhibitors and as potential antitumor drugs, Eur. J. Med. Chem. 171 (2019) 282e296. A. Hameed, M. Al-Rashida, M. Uroos, S.A. Ali, Arshia, M. Ishtiaq, K.M. Khan, Quinazoline and quinazolinone as important medicinal scaffolds: a comparative patent review (2011-2016), Expert Opin. Ther. Pat. 28 (2018) 281e297. P.C. Li, G. Liu, K. Gao, L. Sun, Q.W. Wen, Research progress in quinazoline derivatives with anticancer activity, Chin. Pharmaceut. J. 51 (2016) 867e874. S. Rave, O. Castillo-Aguilera, P. Depreux, L. Goossens, Quinazoline derivatives as anticancer drugs: a patent review (2011-present), Expert Opin. Ther. Pat. 25 (2015) 789e804. B. Banerji, K. Chandrasekhar, K. Sreenath, S. Roy, S. Nag, K.D. Saha, Synthesis of triazole-substituted quinazoline hybrids for anticancer activity and a lead compound as the EGFR blocker and ROS inducer agent, ACS Omega 3 (2018) 16134e16142. G. Le-Nhat-Thuy, T.V. Dinh, H. Pham-The, H.N. Quang, N.N. Thi, T.A.D. Thi, P.H. Thi, T.A.L. Thi, H.T. Nguyen, P.N. Thanh, T.L. Duc, T.V. Nguyen, Design, synthesis and evaluation of novel hybrids between 4-anilinoquinazolines and substituted triazoles as potent cytotoxic agents, Bioorg. Med. Chem. Lett 28 (2018) 3741e3747. P. Song, F. Cui, N. Li, J. Xin, Q. Ma, X. Meng, C. Wang, Q. Cao, Y. Gu, Y. Ke, Q. Zhang, H. Liu Synthesis, Cytotoxic activity evaluation of novel 1,2,3triazole linked quinazoline derivatives, Chin. J. Chem. 35 (2017) 1633e1639. Y.H. Shi, W. Zhang, L.X. Li, Z.S. Tong, C.G. Bai, Design and synthesis of novel triazolo-lapatinib hybrids as inhibitors of breast cancer cells, Med. Chem. Res. 27 (2018) 2437e2445. R. Venkatesh, M.J. Ramaiah, H.K. Gaikwad, S. Janardhan, R. Bantu, L. Nagarapu, G.N. Sastry, A.R. Ganesh, M. Bhadra, Luotonin-A based quinazolinones cause apoptosis and senescence via HDAC inhibition and activation of tumor suppressor proteins in HeLa cells, Eur. J. Med. Chem. 94 (2015) 87e101. K.K. Vasu, H.D. Ingawale, S.R. Sagar, J.A. Sharma, D.H. Pandya, M. Agarwal, 2((1H-1,2,3-Triazol-1-yl)methyl)-3-phenylquinazolin-4(3H)-ones: design, synthesis and evaluation as anti-cancer agents, Curr. Bioact. Compd. 14 (2018) 254e263. M. Safavi, A. Ashtari, F. Khalili, S.S. Mirfazli, M. Saeedi, S.K. Ardestani, P.R. Ranjbar, M.B. Tehrani, B. Larijani, M. Mahdavi, Novel quinazolin-4(3H)one linked to 1,2,3-triazoles: synthesis and anticancer activity, Chem. Biol. Drug Des. 92 (2018) 1373e1380. P.N. Batalha, M.C.B. Souza, E. Pena-Cabrera, D.C. Cruz, F.C.S. Boechat, Quinolone in the search for new anticancer agents, Curr. Pharmaceut. Des. 22 (2016) 6009e6020. J.H. Xu, Y.L. Fan, J. Zhou, Quinolone-triazole hybrids and their biological activities, J. Heterocycl. Chem. 55 (2018) 1854e1862. P.J. Boratynski, J. Galezowska, K. Turkowiak, A. Anisiewicz, R. Kowalczyk, J. Wietrzyk, Triazole biheterocycles from Cinchona alkaloids: coordination and antiproliferative properties, ChemistrySelect 3 (2018) 9368e9373. L.U. Nordstrom, J. Sironi, E. Aranda, J. Maisonet, R. Perez-Soler, P. Wu, E.L. Schwartz, Discovery of autophagy inhibitors with antiproliferative activity in lung and pancreatic cancer cells, ACS Med. Chem. Lett. 6 (2015) 134e139. K.R. Begnini, W.R. Duarte, L.P. da Silva, J.H. Buss, B.S. Goldani, M. Fronza, N.V. Segatto, D. Alves, L. Savegnago, F.K. Seixas, T. Collares, Apoptosis induction by 7-chloroquinoline-1,2,3-triazoyl carboxamides in triple negative breast cancer cells, Biomed. Pharmacother. 91 (2017) 510e516. S.R. Dasari, S. Tondepu, L.R. Vadali, N. Seelam, Design, synthesis and molecular modeling of nonsteroidal anti-inflammatory drugs tagged substituted 1,2,3-triazole derivatives and evaluation of their biological activities, J. Heterocycl. Chem. 56 (2019) 1318e1329. M. Irfan, S.I. Khan, N. Manzoor, M. Abid, Biological activities and in silico physico-chemical properties of 1,2,3-triazoles derived from natural bioactive alcohols, Anti-Infect. Agents 14 (2016) 126e132. M. Korcz, F. Saczewski, P.J. Bednarski, A. Kornicka, Synthesis, structure, chemical stability, and in vitro cytotoxic properties of novel quinoline-3carbaldehyde hydrazones bearing a 1,2,4-triazole or benzotriazole moiety, Molecules 23 (2018) e1497. F. Zhao, L.D. Zhang, Y. Hao, N. Chen, R. Bai, Y.J. Wang, C.C. Zhang, G.S. Li, L.J. Hao, C. Shi, J. Zhang, Y. Mao, Y. Fan, G.X. Xia, J.X. Yu, Y.J. Liu, Identification of 3-substituted-6-(1-(1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)ethyl)quinoline derivatives as highly potent and selective mesenchymal-epithelial transition factor (c-Met) inhibitors via metabolite profiling-based structural optimization, Eur. J. Med. Chem. 134 (2017) 147e158. N.R. Madadi, N.R. Penthala, K. Howk, A. Ketkar, R.L. Eoff, M.J. Borrelli,

34

[188]

[189]

[190]

[191]

[192]

[193]

[194]

[195]

[196]

[197] [198]

[199]

[200]

[201]

[202]

[203]

[204]

[205]

[206] [207]

[208]

Z. Xu et al. / European Journal of Medicinal Chemistry 183 (2019) 111700 P.A. Crooks, Synthesis and biological evaluation of novel 4,5-disubstituted 2H-1,2,3-triazoles as cis-constrained analogues of combretastatin A-4, Eur. J. Med. Chem. 103 (2015) 123e132. M. Liu, Y. Hou, W. Yin, S. Zhou, P. Qian, Z. Guo, L. Xu, Y. Zhao, Discovery of a novel 6,7-disubstituted-4-(2-fluorophenoxy)quinolines bearing 1,2,3triazole-4-carboxamide moiety as potent c-Met kinase inhibitors, Eur. J. Med. Chem. 119 (2016) 96e108. D.Y. Zeng, G.T. Kuang, S.K. Wang, W. Peng, S.L. Lin, Q. Zhang, X.X. Su, M.H. Hu, H. Wang, J.H. Tan, Z.S. Huang, L.Q. Gu, T.M. Ou, Discovery of novel 11-triazole substituted benzofuro[3,2-b]quinolone derivatives as c-myc G-Quadruplex specific stabilizers via click chemistry, J. Med. Chem. 60 (2017) 5407e5423. S. Theeramunkong, O. Vajragupta, C. Mudjupa, Synthesis and biological evaluation of simplified analogs of lophocladine B as potential antitumor agents, Med. Chem. Res. 25 (2016) 2959e2964. X. Jin, L. Yan, H.J. Li, R.L. Wang, Z.L. Hu, Y.Y. Jiang, Y.B. Cao, T.H. Yan, Q.Y. Sun, Novel triazolyl berberine derivatives prepared via CuAAC click chemistry: synthesis, anticancer activity and structure-activity relationships, Anti Cancer Agents Med. Chem. 15 (2015) 89e98. B. Liu, Q. Liu, T. Zhao, L. Jiao, Y. Li, W. Huang, H. Qian, 6,7-Dimethoxy-2-{2-[4(1H-1,2,3-triazol-1-yl)phenyl]ethyl}-1,2,3,4-tetrahydroisoquinolines as superior reversal agents for P-glycoprotein-mediated multidrug resistance, ChemMedChem 10 (2015) 336e345. S. Arabiyat, V. Kasabri, Y. Al-Hiari, Y.K. Bustanji, R. Albashiti, I.M. Almasri, D.A. Sabbah, Antilipase and antiproliferative activities of novel fluoroquinolones and triazolofluoroquinolones, Chem. Biol. Drug Des. 90 (2017) 1282e1294. T. Pirali, E. Ciraolo, S. Aprile, A. Massarotti, A. Berndt, A. Griglio, M. Serafini, V. Mercalli, C. Landoni, C.C. Campa, J.P. Margaria, R.L. Silva, G. Grosa, G. Sorba, R. Williams, E. Hirsch, G.C. Tron, Identification of a potent phosphoinositide 3-kinase pan inhibitor displaying a strategic carboxylic acid group and development of its prodrugs, ChemMedChem 12 (2017) 1542e1555. M. Mohammadi-Khanaposhtani, M. Safavi, R. Sabourian, M. Mahdavi, M. Pordeli, M. Saeedi, S.K. Ardestani, A. Foroumadi, A. Shafiee, T. Akbarzadeh, Design, synthesis, in vitro cytotoxic activity evaluation, and apoptosisinduction study of new 9(10H)-acridinone-1,2,3-triazoles, Mol. Divers. 19 (2015) 787e795. T.P. Thi, T.G.L. Nhat, T.N. Hanh, T.L. Quang, C.P. The, T.A.D. Thi, H.T. Nguyen, T.H. Nguyen, P.H. Thi, T.V. Nguyen, Synthesis and cytotoxic evaluation of novel indenoisoquinoline-substituted triazole hybrids, Bioorg. Med. Chem. Lett 26 (2016) 3652e3657. C. Asche, Antitumour quinones, Mini Rev. Med. Chem. 5 (2005) 449e467. Vlachogianni Siatis, Valavanidis, Quinones and quinone derivatives as pharmaceutical agents for the treatment of cancer recent advances in synthesis and evaluation of cytotoxicity and antitumour activities, Pharmakeftiki 23 (2010) 1e15. T.H. Coulidiati, B.B. Dantas, G.V. Faheina-Martins, J.C.R. Goncalves, W.S. do Nascimento, R.N. de Oliveira, C.A. Camara, E.J. Oliveira, A. Lara, E.R. Gomes, D.A.M. Araujo, Distinct effects of novel naphtoquinone-based triazoles in human leukaemic cell lines, J. Pharm. Pharmacol. 67 (2015) 1682e1695. C.V. Prasad, V.L. Nayak, S. Ramakrishna, U.V. Mallavadhani, Novel menadione hybrids: synthesis, anticancer activity, and cell-based studies, Chem. Biol. Drug Des. 91 (2018) 220e233. M. Gholampour, S. Ranjbar, N. Edraki, M. Mohabbati, O. Firuzi, M. Khoshneviszadeh, Click chemistry-assisted synthesis of novel aminonaphthoquinone-1,2,3-triazole hybrids and investigation of their cytotoxicity and cancer cell cycle alterations, Bioorg. Med. 88 (2019) e102967. D.C.S. Costa, G.S. de Almeida, V.W.H. Rabelo, L.M. Cabral, P.C. Sathler, P.A. Abreu, V.F. Ferreira, L.C.R.P. da Silva, F. de C. da Silva, Synthesis and evaluation of the cytotoxic activity of furanaphthoquinones tethered to 1H1,2,3-triazoles in Caco-2, Calu-3, MDA-MB231 cells, Eur. J. Med. Chem. 156 (2018) 524e533. I.C. Chipoline, E. Alves, P. Branco, L. Costa-Lotufo, V.F. Ferreira, F.C.D. Silva, Synthesis and cytotoxic evaluation of 1H-1,2,3-triazol-1-ylmethyl-2,3dihydronaphtho[1.2-b]furan-4,5-diones, Ann. Acad. Bras. Ciencias 90 (2018) 1027e1033. E.H.G. da Cruz, M.A. Silvers, G.A.M. Jardim, J.M. Resende, B.C. Cavalcanti, I.S. Bomfim, C. Pessoa, C.A. de Simone, G.V. Botteselle, A.L. Braga, D.K. Nair, I.N.N. Namboothiri, D.A. Boothman, E.N. da S. Junior, Synthesis and antitumor activity of selenium-containing quinone-based triazoles possessing two redox centres, and their mechanistic insights, Eur. J. Med. Chem. 122 (2016) 1e16. S.B.B. Bahia, W.J. Reis, G.A.M. Jardim, F.T. Souto, C.A. de Simone, C.C. Gatto, R.F.S. Menna-Barreto, S.L. de Castro, B.C. Cavalcanti, C. Pessoa, M.H. Aeaujo, E.N. da S. Junior, Molecular hybridization as a powerful tool towards multitarget quinoidal systems: synthesis, trypanocidal and antitumor activities of naphthoquinone-based 5-iodo-1,4-disubstituted-, 1,4- and 1,5disubstituted-1,2,3-triazoles, MedChemComm 7 (2016) 1555e1563. A. Gupta, K. Sathish, A.S. Negi, Current status on development of steroids as anticancer agents, J. Steroid Biochem. Mol. Biol. 137 (2013) 242e270. M.L. Navacchia, A. Fraix, N. Chinaglia, E. Gallerani, D. Perrone, V. Cardile, A.C.E. Graziano, M.L. Capobianco, S. Sortino, NO photoreleaserdeoxyadenosine and -bile acid derivative bioconjugates as novel potential photochemotherapeutics, ACS Med. Chem. Lett. 7 (2016) 939e943. R. Minorics, I. Zupko, Steroidal anticancer agents: an overview of estradiolrelated compounds, Anti Cancer Agents Med. Chem. 18 (2018) 652e666.

[209] V.C.O. Najr, A.M.H. Bridie, Discovery and development of Galeterone (TOK001 or VN/124-1) for the treatment of all stages of prostate cancer, J. Med. Chem. 58 (2015) 2077e2087. [210] M. Rahman, Y. Mohammad, K.M. Fazili, K.A. Bhat, T. Ara, Synthesis and biological evaluation of novel 3-O-tethered triazoles of diosgenin as potent antiproliferative agents, Steroids 118 (2017) 1e14. [211] E. Mernyak, I. Kovacs, R. Minorics, P. Sere, D. Czegany, I. Sinka, J. Wolfling, G. Schneider, Z. Ujfaludi, I. Doros, I. Ocsovszki, M. Varga, I. Zupko, Synthesis of trans-16-triazolyl-13a-methyl-17-estradiol diastereomers and the effects of structural modifications on their in vitro antiproliferative activities, J. Steroid Biochem. Mol. Biol. 150 (2015) 123e134. [212] V. Zuco, R. Supino, S.C. Righetti, Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells, Cancer Lett. 175 (2002) 17e25. [213] E. Chrobak, M. Kadela-Tomanek, E. Bebenek, K. Marciniec, J. Wietrzyk, J. Trynda, B. Pawelczak, New phosphate derivatives of betulin as anticancer agents: synthesis, crystal structure, and molecular docking study, Bioorg. Chem. 87 (2019) 613e628. [214] V.V. Grishko, I.A. Tolmacheva, V.O. Nebogatikov, N.V. Galaiko, A.V. Nazarov, M.V. Nazarov, M.V. Dmitriev, I.B. Ivshina, Preparation of novel ring-A fused azole derivatives of betulin and evaluation of their cytotoxicity, Eur. J. Med. Chem. 125 (2017) 629e639. [215] V. Sidova, P. Zoufaly, J. Pokorny, P. Dzubak, M. Hajduch, I. Popa, M. Urban, Cytotoxic conjugates of betulinic acid and substituted triazoles prepared by Huisgen Cycloaddition from 30-azidoderivatives, PLoS One 12 (2017) e0717621. [216] P. Suman, A. Patel, L. Solano, G. Jampana, Z.S. Gardner, G.M. Holt, S.C. Jonnalagadda, Synthesis and cytotoxicity of Baylis-Hillman template derived betulinic acid-triazole conjugates, Tetrahedron 73 (2017) 4214e4226. [217] I. Khan, S.K. Guru, S.K. Rath, P.K. Chinthakindi, B. Singh, S. Koul, S. Bhushan, P.L. Sangwan, A novel triazole derivative of betulinic acid induces extrinsic and intrinsic apoptosis in human leukemia HL-60 cells, Eur. J. Med. Chem. 108 (2016) 104e116. [218] N.A. Dangroo, J. Singh, S.K. Rath, N. Gupta, A. Qayum, S. Singh, P.L. Sangwan, A convergent synthesis of novel alkyne-azide cycloaddition congeners of betulinic acid as potent cytotoxic agent, Steroids 123 (2017) 1e12. [219] B. Chakraborty, D. Dutta, S. Mukherjee, D. Das, N.C. Maiti, P. Das, C. Chowdhury, Synthesis and biological evaluation of a novel betulinic acid derivative as an inducer of apoptosis in human colon carcinoma cells (HT29), Eur. J. Med. Chem. 102 (2015) 93e105. [220] E. Bebenek, M. Jastrzebska, M. Kadela-Tomanek, E. Chrobak, B. Orzechowska, K. Zwolinska, M. Latocha, A. Mertas, Z. Czuba, S. Boryczka, Novel triazole hybrids of betulin: synthesis and biological activity profile, Molecules 22 (2017) e1876. [221] R. Majeed, A. Hussain, P.L. Sangwan, P.K. Chinthakindi, I. Khan, P.R. Sharma, S. Koul, A.K. Saxena, A. Hamid, PI3K target based novel cyano derivative of betulinic acid induces its signalling inhibition by down-regulation of pGSK3b and cyclin D1 and potentially checks cancer cell proliferation, Mol. Carcinog. 55 (2016) 964e976. [222] T.S. Dalidovich, A.L. Hursko, G.E. Morozevich, A.S. Latysheva, T.A. Sushko, N.V. Strushkevich, A.,A. Gilep, A.Y. Misharin, V.N. Zhabinskoo, V.A. Khripach, New azole derivatives of [17(20)E]-21-norpregnene: synthesis and inhibition of prostate carcinoma cell growth, Steroids 147 (2019) 10e18. [223] G. Wei, W. Luan, S. Wang, S. Cui, F. Li, Y. Liu, Y. Liu, M. Cheng, A library of 1,2,3-triazole-substituted oleanolic acid derivatives as anticancer agents: design, synthesis, and biological evaluation, Org. Biomol. Chem. 13 (2015) 1507e1514. [224] Z.H. Mohamed, N.A. El-Koussi, N.M. Mahfouz, A.F. Youssef, G.A.A. Jaleel, S.A. Shouman, Cu (I) catalyzed alkyne-azide 1,3-dipolar cycloaddition (CuAAC): synthesis of 17a-[1-(substituted phenyl)-1,2,3-triazol-4-yl]-19nortestosterone-17b-yl acetates targeting progestational and antiproliferative activities, Eur. J. Med. Chem. 97 (2015) 75e82. [225] R.N. Khaybullin, X. Liang, K. Cisneros, X. Qi, Synthesis and anticancer evaluation of complex unsaturated isosteviol derived triazole conjugates, Future Med. Chem. 7 (2015) 2419e2428. [226] K. Chouaib, S. Delemasure, P. Dutartre, H.B. Jannet, Microwave-assisted synthesis, anti-inflammatory and anti-proliferative activities of new maslinic acid derivatives bearing 1,5- and 1,4-disubstituted triazoles, J. Enzym. Inhib. Med. Chem. 31 (2016) 130e147. [227] D. Anandkumar, P. Rajakumar, Synthesis and anticancer activity of bile acid dendrimers with triazole as bridging unit through click chemistry, Steroids 125 (2017) 37e46. [228] S. Pinho, C.A. Reis, Glycosylation in cancer: mechanisms and clinical implications, Nat. Rev. Cancer 15 (2015) 540e555. [229] L.S. Feng, S.L. Hong, J. Rong, Q.C. You, P. Dai, R.B. Huang, Y.H. Tan, W.Y. Hong, C. Xie, J. Zhao, X. Chen, Bifunctional unnatural sialic acids for dual metabolic labeling of cell-surface sialylated glycans, J. Am. Chem. Soc. 135 (2013) 9244e9247. [230] H. Amdouni, G. Robert, M. Driowya, N. Furstoss, C. Metier, A. Dubois, M. Dufies, M. Zerhouni, F. Orange, S. Lacas-Gervais, K. Bougrin, A.R. Martin, P. Auberger, R. Benhida, In vitro and in vivo evaluation of fully substituted (5(3-ethoxy-3-oxopropynyl)-4-(ethoxycarbonyl)-1,2,3-triazolyl-glycosides as original nucleoside analogs to circumvent resistance in myeloid malignancies, J. Med. Chem. 60 (2017) 1523e1533. [231] H.N. Li, H. Wang, Z.P. Wang, H.N. Yan, M. Zhang, Y. Liu, M.S. Cheng, Synthesis,

Z. Xu et al. / European Journal of Medicinal Chemistry 183 (2019) 111700

[232]

[233]

[234]

[235]

[236] [237]

[238]

[239]

[240]

[241]

[242]

[243]

[244]

[245]

[246]

[247]

[248]

[249]

[250]

[251]

[252]

[253]

[254]

antitumor activity evaluation and mechanistic study of novel hederacolchiside A1 derivatives bearing an aryl triazole moiety, Bioorg. Med. Chem. 26 (2018) 4025e4033. K.T. Petrova, T.M. Potewar, P. Correia-de-Silva, M.T. Barros, R.C. Calhelha, A. Ciric, M. Sokovic, I.C.F.R. Ferreira, Antimicrobial and cytotoxic activities of 1,2,3-triazole-sucrose derivatives, Carbohydr. Res. 417 (2015) 66e72. J. Zayas, M. Annoual, J.K. Das, Q. Felty, W.G. Gonzalez, J. Miksovska, N. Sharifai, A. Chiba, S.F. Wnuk, Strain promoted click chemistry of 2- or 8azidopurine and 5-azidopyrimidine nucleosides and 8-azidoadenosine triphosphate with cyclooctynes. Application to living cell fluorescent imaging, Bioconjug. Chem. 26 (2015) 1519e1532. B. Boens, T.S. Ouk, Y. Champavier, R. Zarrouki, Synthesis and biological evaluations of click-generated nitrogen mustards, Nucleosides Nucleotides Nucleic Acids 34 (2015) 500e514. M. Massaro, V. Cina, M. Labbozzetta, G. Lazzara, P.L. Meo, P. Poma, S. Riela, R. Noto, Chemical and pharmaceutical evaluation of the relationship between triazole linkers and pore size on cyclodextrin-calixarene nanosponges used as carriers for natural drugs, RSC Adv. 6 (2016) 50858e50866. G.Q. Wang, L.L. Yan, Q.A. Wang, Synthesis and antiproliferative activity of flavonoid triazolyl glycosides, Heterocycl. Commun. 24 (2018) 119e124. M.O. Igual, P.S.G. Nunes, R.M. da Costa, S.P. Mantoani, R.C. Tostes, I. Carvalho, Novel glucopyranoside C2-derived 1,2,3-triazoles displaying selective inhibition of O-GlcNAcase (OGA), Carbohydr. Res. 471 (2019) 43e55. C.H. Hsieh, J.P. Wang, C.C. Chiu, C.Y. Liu, C.F. Yao, K. Fang, A triazole-conjugated benzoxazone induces reactive oxygen species and promotes autophagic apoptosis in human lung cancer cells, Apoptosis 23 (2018) 1e15. C.L. Su, C.L. Tseng, C. Ramesh, H.S. Liu, C.Y.F. Huang, C.F. Yao, Using gene expression database to uncover biology functions of 1,4-disubstituted 1,2,3triazole analogues synthesized via a copper (I)-catalyzed reaction, Eur. J. Med. Chem. 132 (2017) 90e107. V.R. Nagavelli, S.K. Nukala, S. Narsimha, K.S. Battula, S.J. Tangeda, Y.N. Reddy, Synthesis, characterization and biological evaluation of 7-substituted-4-((1aryl-1H-1,2,3-triazol-4-yl)methyl)-2H-benzo[b][1,4]oxazin-3(4H)-ones as anticancer agents, Med. Chem. Res. 25 (2016) 1781e1793. M.H. Shaikh, D.D. Subhedar, M. Arkile, V.M. Khedkar, N. Jadhav, D. Sarkar, B.B. Shingate, Synthesis and bioactivity of novel triazole incorporated benzothiazinone derivatives as antitubercular and antioxidant agent, Bioorg. Med. Chem. Lett 26 (2016) 561e569. S. Narsimha, K.S. Battula, Y.N. Reddy, V.R. Nagavelli, Microwave-assisted Cucatalyzed C-C bond formation: one-pot synthesis of fully substituted 1,2,3triazoles using nonsymmetrical iodoalkynes and their biological evaluation, Chem. Heterocycl. Comp. 54 (2018) 1161e1167. F. Reichart, M. Horn, I. Neundorf, Cyclization of a cell-penetrating peptide via click-chemistry increases proteolytic resistance and improves drug delivery, J. Pept. Sci. 22 (2016) 421e426. A.H. Cumming, S.L. Brown, X. Tao, C. Cuyamendous, J.J. Field, J.H. Miller, J.E. Harvey, P.H. Teesdale-Spittle, Synthesis of a simplified triazole analogue of pateamine, A. Org. Biol. Chem. 14 (2016) 5117e5127. E. Hernandez-Vazquez, A. Chavez-Riveros, A. Romo-Perez, M.T. RamirezApan, A.D. Chavez-Blanco, R. Morales-Barcenas, A. Duenas-Gonzalez, L.D. Miranda, Cytotoxic activity and structure-activity relationship of triazole-containing bis(aryl ether) macrocycles, ChemMedChem 13 (2018) 1193e1210. S. Tapadar, S. Fathi, I. Raji, W. Omesiete, J.R. Kornacki, S.C. Mwakwari, M. Miyata, K. Mitsutake, J.D. Li, M. Mrksich, A.K. Oyelere, A structure-activity relationship of non-peptide macrocyclic histone deacetylase inhibitors and their anti-proliferative and anti-inflammatory activities, Bioorg. Med. Chem. 23 (2015) 7543e7564. Q. Huang, L. Xie, X. Chen, H. Yu, Y. Lv, X. Huang, J. Ying, C. Zheng, Y. Cheng, J. Huang, Synthesis and anticancer activity of novel rapamycin C-28 containing triazole moiety compounds, Arch. Pharm. 351 (2018) e1800123. L. Xie, J. Huang, X. Chen, H. Yu, K. Li, D. Yang, X. Chen, J. Ying, F. Pan, Y. Lv, Y. Cheng, Synthesis of rapamycin derivatives containing the triazole moiety used as potential mTOR-targeted anticancer agents, Arch. Pharm. Chem. Life Sci. 349 (2016) 428e441. W. Hou, G. Zhang, Z. Luo, L. Su, H. Xu, Click chemistry-based synthesis and cytotoxic activity evaluation of 4a-triazole acetate podophyllotoxin derivatives, Chem. Biol. Drug Des. 93 (2019) 473e486. M.V.P.S. Vishnuvardhan, V. SaidiReddy, K. Chandrasekhar, V. LakshmaNayak, I.B. Sayeed, A. Alarifi, A. Kamal, Click chemistry-assisted synthesis of triazolo linked podophyllotoxin conjugates as tubulin polymerization inhibitors, MedChemComm 8 (2017) 1817e1823. P. Kumari, V. Dixit, A.K. Tiwari, S. Saxena, N.K. Vishvakarma, P.K. Naik, D. Shukla, Computer-assisted drug designing of triazole derivative of noscapine as tubulin-binding anticancer drug, Asian J. Pharmaceut. Clin. Res. 11 (2018) 69e75. V.G. Reddy, S.R. Bonam, T.S. Reddy, R. Akunuri, V.G.M. Naidu, V.L. Nayak, S.K. Bhargava, H.M.S. Kumar, P. Srihari, A. Kamal, 4a-Amidotriazole linked podophyllotoxin congeners: DNA topoisomerase-IIa inhibition and potential anticancer agents for prostate cancer, Eur. J. Med. Chem. 144 (2018) 595e611. C.T. Zi, L. Yang, F.Q. Xu, F.W. Dong, D. Yang, Y. Li, Z.T. Ding, J. Zhou, Z.H. Jiang, J.M. Hu, Synthesis and anticancer activity of dimeric podophyllotoxin derivatives, Drug Des. Dev. Ther. 12 (2018) 3393e3406. B. Poornima, B. Siva, A. Venkana, G. Shankaraiah, N. Jain, D.K. Yadav, S. Misra,

[255]

[256]

[257]

[258]

[259]

[260]

[261]

[262]

[263]

[264]

[265]

[266]

[267]

[268]

[269]

[270]

[271]

[272]

[273]

[274]

[275]

[276]

35

K.S. Babu, Novel Gomisin B analogues as potential cytotoxic agents: design, synthesis, biological evaluation and docking studies, Eur. J. Med. Chem. 139 (2017) 441e453. J. Mareddy, N. Suresh, C.G. Kumar, R. Kapavarapu, A. Jayasree, S. Pal, 1,2,3Triazole-nimesulide hybrid: their design, synthesis and evaluation as potential anticancer agents, Bioorg. Med. Chem. Lett 27 (2017) 518e523. J. Slawinski, K. Szafranski, A. Pogorzelska, B. Zolnowska, A. Kawiak, K. Macur, M. Belka, T. Baczek, Novel 2-benzylthio-5-(1,3,4-oxadiazol-2-yl)benzenesulfonamides with anticancer activity: synthesis, QSAR study, and metabolic stability, Eur. J. Med. Chem. 132 (2017) 236e248. K.A.A. Qader, A.W. Maser, M.S. Farhan, S.J. Salih, Synthesis, characterization and cytotoxic activity of some new 1,2,3-triazole, oxadiazole and aza-blactam derivatives, Orient. J. Chem. 34 (2018) 2350e2360. D.K. Swaroop, N.R. Kumar, K. Ratnakarreddy, G. Raja, K. Srigiridhar, Y. Poornachandra, C.G. Kumar, N.J. Babu, G.S. Kumar, B. Narsaiah, Novel 1,2,3triazole-functionalized 1,2-benzothiazine 1,1-dioxide derivatives: regioselective synthesis, biological evaluation and docking studies, ChemistrySelect 3 (2018) 2398e2401. Y. Ke, W. Wang, L.F. Zhao, J.J. Liang, Y. Liu, X. Zhang, K. Feng, H.M. Liu, Design, synthesis and biological mechanisms research on 1,2,3-triazole derivatives of Jiyuan Oridonin A, Bioorg. Med. Chem. 26 (2018) 4761e4773. Q.K. Shen, H. Deng, S.B. Wang, Y.S. Tian, Z.S. Quan, Synthesis, and evaluation of in vitro and in vivo anticancer activity of 14-substituted oridonin analogs: a novel and potent cell cycle arrest and apoptosis inducer through the p53MDM2 pathway, Eur. J. Med. Chem. 173 (2019) 15e31. M. Chandrashekhar, V.L. Nayak, S. Ramakrishna, U.V. Mallavadhani, Novel triazole hybrids of myrrhanone C, a natural polypodane triterpene: synthesis, cytotoxic activity and cell based studies, Eur. J. Med. Chem. 114 (2016) 293e307. B. Poornima, B. Siva, G. Shankaraiah, A. Venkanna, V.L. Nayak, S. Ramakrishna, C.V. Rao, K.S. Babu, Novel sesquiterpenes from Schisandra grandiflora: isolation, cytotoxic activity and synthesis of their triazole derivatives using “click” reaction, Eur. J. Med. Chem. 92 (2015) 449e458. Y. Chinthala, K. Manjulatha, P. Sharma, S.K.V.N. Satya, K. Jonnala, N.K. Arigari, F. Khan, O.H. Setty, Synthesis and cytotoxicity evaluation of novel andrographolide-1,2,3-triazole derivatives, J. Heterocycl. Chem. 53 (2016) 1902e1910. N. Bozsity, R. Minorics, J. Szabo, E. Mernyak, G. Schneider, J. Wolfling, H.C. Wang, C.C. Wu, I. Ocsovszki, I. Zupko, Mechanism of antiproliferative action of a new D-secoestrone-triazole derivative in cervical cancer cells and its effect on cancer cell motility, J. Steroid Biochem. Mol. Biol. 165 (2017) 247e257. Y. Ding, H. Guo, W. Ge, X. Chen, S. Li, M. Wang, Y. Chen, Q. Zhang, Copper(I) oxide nanoparticles catalyzed click chemistry based synthesis of melampomagnolide B-triazole conjugates and their anti-cancer activities, Eur. J. Med. Chem. 156 (2018) 216e229. V. Janganati, J. Ponder, M. Balasubramaniam, P. Bhat-Nakshatri, E.E. Bar, H. Nakshatri, C.T. Jordan, P.A. Crooks, MMB triazole analogs are potent NF-kB inhibitors and anti-cancer agents against both hematological and solid tumor cells, Eur. J. Med. Chem. 157 (2018) 562e581. M. Zaki, H. Allouchi, A.E. Bouakher, E. Duverger, A.E. Hakmaoui, R. Daniellou, G. Guillaumet, M. Akssira, Synthesis and anticancer evaluation of novel 9asubstituted-13-(1,2,3-triazolo)-parthenolides, Tetrahedron Lett. 57 (2016) 2591e2594. N. Liu, Z. Jin, J. Zhang, J. Jin, Antitumor evaluation of novel phenothiazine derivatives that inhibit migration and tubulin polymerization against gastric cancer MGC-803 cells, Investig. New Drugs 37 (2019) 188e198. X.H. Ma, N. Liu, J.L. Lu, J. Zhao, X.J. Zhang, Design, synthesis and antiproliferative activity of novel phenothiazine-1,2,3-triazole analogues, J. Chem. Res. 41 (2017) 696e698. J.X. Zhang, J.M. Guo, T.T. Zhang, H.J. Lin, N.S. Qi, Z.G. Li, J.C. Zhou, Z.Z. Zhang, Antiproliferative phenothiazine hybrids as novel apoptosis inducers against MCF-7 breast cancer, Molecules 23 (2018) e1288. Y. Li, Q. Shi, J. Shao, Y. Yuan, Z. Yang, S. Chen, X. Zhou, S. Wen, Z.X. Jiang, Synthesis and biological evaluation of 20-epi-amino-20-deoxysalinomycin derivatives, Eur. J. Med. Chem. 148 (2018) 279e290. M. Huang, Z. Deng, J. Tian, T. Liu, Synthesis and biological evaluation of salinomycin triazole analogues as anticancer agents, Eur. J. Med. Chem. 127 (2017) 900e908. J. Cao, J. Zang, X. Kong, C. Zhao, T. Chen, Y. Ran, H. Dong, W. Xu, Y. Zhang, Leucine ureido derivatives as aminopeptidase N inhibitors using click chemistry. Part II, Bioorg. Med. Chem. 27 (2019) 978e990. J.Q. Li, X. Han, Synthesis and anti-tumor activity of novel histone deacetylase inhibitors based on dihydropyridin-2-one scaffold, Acta Pharm. Sin. 51 (2016) 1734e1744. D. Mandalapu, K.S. Saini, S. Gupta, V. Sharma, M.Y. Malik, S. Chaturedi, V. Bala, Hamidullah, S. Thakur, J.P. Maikhuri, M. Wahajuddin, R. Knowar, G. Gupta, V.L. Sharma, Synthesis and biological evaluation of some novel triazole hybrids of curcumin mimics and their selective anticancer activity against breast and prostate cancer cell lines, Bioorg. Med. Chem. Lett 26 (2016) 4223e4232. K.S. Saini, Hamidullah, R. Ashraf, D. Mandalapu, S. Das, M.Q. Siddiqui, S. Dwivedi, J. Sarkar, V.L. Sharma, R. Konwar, New orally active DNA minor groove binding small molecule CT-1 acts against breast cancer by targeting tumor DNA damage leading to p53-dependent apoptosis, Mol. Carcinog. 56

36

Z. Xu et al. / European Journal of Medicinal Chemistry 183 (2019) 111700

(2017) 1266e1270. [277] N. Gupta, A. Qayum, A. Raina, R. Shankar, S. Gairola, S. Singh, P.L. Sangwan, Synthesis and biological evaluation of novel bavachinin analogs as anticancer agents, Eur. J. Med. Chem. 145 (2018) 511e523. [278] N. Sudhapriya, A. Nandakumar, Y. Arun, P.T. Perumal, C. Balachandran, N. Emi, An expedient route to highly diversified [1,2,3]triazolo[1,5-a][1,4] benzodiazepines and their evaluation for antimicrobial, antiproliferative and in silico studies, RSC Adv. 5 (2015) 66260e66272. [279] C.P. Kumar, T.S. Reddy, P.S. Mainkar, V. Bansal, R. Shukla, S. Chandrasekhar, H.M. Hugel, Synthesis and biological evaluation of 5,10-dihydro-11Hdibenzo[b,e][1,4]diazepin-11-one structural derivatives as anti-cancer and apoptosis inducing agents, Eur. J. Med. Chem. 108 (2016) 674e686. [280] K. Park, H.E. Lee, S.H. Lee, D. Lee, T. Lee, Y.M. Lee, Molecular and functional evaluation of novel HIF inhibitor, benzopyranyl 1,2,3-triazole compound, Oncotarget 8 (2018) 7801e7813. [281] N. Kuntala, J.R. Telu, V. Banothu, S. Babu, J.S. Anireddy, S. Pal, Novel benzoxepine-1,2,3-triazole hybrids: synthesis and pharmacological evaluation as potential antibacterial and anticancer agents, MedChemComm 6 (2015) 1612e1618. [282] X. Xu, Y. Wu, W. Liu, C. Sheng, J. Yao, G. Dong, K. Fang, J. Li, Z. Yu, X. Min, H. Zhang, Z. Miao, W. Zhang, Discovery of 7-methyl-10hydroxyhomocamptothecins with 1,2,3-triazole moiety as potent Topoisomerase I inhibitors, Chem. Biol. Drug Des. 88 (2016) 398e403. [283] U.H. Preya, C. Jeon, H. Lee, Y. Kang, Y.Y. Wang, J.H. Choi, J.H. Park, The cytotoxic activity of honokiol-triazole derivatives in ovarian cancer cells, Bull. Korean Chem. Soc. 40 (2019) 359e365. [284] B.C.Q. Nguyen, H. Takahashi, Y. Uto, M. Shahinozzaman, S. Tawata, H. Maruta, 1,2,3-Triazolyl ester of Ketorolac: a “Click Chemistry”-based highly potent PAK1-blocking cancer-killer, Eur. J. Med. Chem. 126 (2017) 270e276. [285] Y.X. Yang, J.W. Yan, F.L. Yan, Y.Y. Yin, F.F. Zhuang, Z.Y. Ji, Synthesis and antitumor activity evaluation of lamiridosin A derivatives, J. Asian Nat. Prod. Res. 18 (2016) 26e36. [286] B. Ali, L.D.K. Kupa, C.S. Heluany, C.C. Drewes, S.N.S. Vasconcelos, S.H.P. Farsky, H.A. Stfani, Cytotoxic effects of a novel maleimide derivative on epithelial and tumor cells, Bioorg. Chem. 72 (2017) 199e207. [287] A.A. Samra, A. Robert, C. Gow, L. Favre, L. Eloy, E. Jacquet, J. Bignon, J. Wiels, S. Desrat, F. Roussi, Dual inhibitors of the pro-survival proteins Bcl-2 and Mcl-1 derived from natural compound meiogynin A, Eur. J. Med. Chem. 148 (2018) 26e38. [288] N.P. Kumar, S. Nekkanti, S.S. Kumari, P. Sharma, N. Shankaraiah, Design and synthesis of 1,2,3-triazolo-phenanthrene hybrids as cytotoxic agents, Bioorg. Med. Chem. Lett 27 (2017) 2369e2376. [289] K.S.N. Reddy, G. Sabitha, Y. Poornachandra, C.G. Kumar, Synthesis and biological evaluation of Sapinofuranones A, B and 1,2,3-triazole-Sapinofuranone hybrids as cytotoxic agents, RSC Adv. 6 (2016) 101501e101513. [290] M.A.A. Aleixo, T.M. Garcia, D.B. Carvalho, L.H. Viana, M.S. Amaral, N.M. Kassab, M.C. Cunha, I.C. Pereira, P.G. Guerrero Jr., R.T. Perdomo, M.F.C. Maros, A.C.M. Baroni, Design, synthesis and anticancer biological evaluation of novel 1,4-diaryl-1,2,3-triazole retinoid analogues of tamibarotene (AM80), J. Braz. Chem. Soc. 29 (2018) 109e124. [291] K.S. Battula, S. Narsimha, R.K. Thatipamula, Y.N. Reddy, V.R. Nagavelli, Synthesis and biological evaluation of novel thiomorpholine 1,1-dioxide derived 1,2,3-triazole hybrids as potential anticancer agents, ChemistrySelect 2 (2017) 4001e4005. [292] K.S. Battula, S. Narsimha, R.K. Thatipamula, Y.N. Reddy, V.R. Nagavelli, Synthesis and biological evaluation of (N-(3-methoxyphenyl)-4-((aryl-1H-1,2,3triazol-4-yl)methyl)thiomorpholine-2-carboxamide 1,1-dioxide hybrids as antiproliferative agents, ChemistrySelect 2 (2017) 9595e9598. [293] G.V.M. Sharma, K.S. Kumar, S.V. Reddy, A. Nagalingam, K.M. Cunningham, R. Ummanni, H. Hugel, D. Sharma, S.V. Malhotra, Synthesis and biological evaluation of triazole-vanillin molecular hybrids as anti-cancer agents, Curr. Bioact. Compd. 13 (2017) 223e235. [294] S. Mo, Y. Ding, G. Zhang, Z. Zhang, X. Shao, Q. Li, X. Yang, F. Chen, Synthesis and anti-tumor activity evaluation of a novel series of dithiocarbamates bearing 1,2,3-triazole and [1-bi(4-fluorophenyl)methyl]piperazine unit, Chin. J. Org. Chem. 37 (2017) 1000e1008. [295] H. Mousazadeh, M. Milani, N. Zarghami, E. Alizadeh, K.D. Safa, Study of the cytotoxic and bactericidal effects of sila-substituted thioalkyne and mercaptothione compounds based on 1,2,3-triazole scaffold, Basic Clin. Pharmacol. 121 (2017) 390e399. [296] J. Piao, S. Yan, S. Gao, Y. Chen, X. Xu, The antitumor effect of DYC-279 on human hepatocellular carcinoma HepG2 cells, Pharmacol 97 (2016) 177e183. [297] E. Bonandi, M.S. Christodoulou, G. Fumagalli, D. Perdicchia, G. Rastelli, D. Passarella, The 1,2,3-triazole ring as a bioisostere in medicinal chemistry, Drug Discov. Today 22 (2017) 1572e1581. [298] A. Giraudo, J. Krall, B. Nielsen, T.E. Sorensen, K.T. Kongstad, B. Rolando, D. Boschi, B. Frolund, M.L. Lolli, 4-Hydroxy-1,2,3-triazole moiety as bioisostere of the carboxylic acid function: a novel scaffold to probe the orthosteric g-aminobutyric acid receptor binding site, Eur. J. Med. Chem. 158 (2018) 311e321. [299] A. Lauria, R. Delisi, F. Mingoia, A. Terenzi, A. MArtorana, G. Barone, A.M. Almerico, 1,2,3-Triazole in heterocyclic compounds, endowed with biological activity, through 1,3-dipolar cycloadditions, Eur. J. Org. Chem. 2014 (2014) 3289e3306.

[300] J. Hou, X. Liu, J. Shen, G. Zhao, P.G. Wang, The impact of click chemistry in medicinal chemistry, Expert Opin. Drug Discov. 7 (2012) 489e501. [301] Y. Tian, H. Xu, Y. Mou, C. Guo, Design, synthesis and cytotoxicity of novel dihydroartemisinin-coumarin hybrids via click chemistry, Molecules 21 (2016) e758. [302] H. Yu, Z. Hou, Y. Tian, Y. Mou, C. Guo, Design, synthesis, cytotoxicity and mechanism of novel dihydroartemisinin-coumarin hybrids as potential anticancer agents, Eur. J. Med. Chem. 151 (2018) 434e449. [303] D.D. Tien, L.N. Thug, D.T.Y. Anh, N.T. Dung, T.N. Ha, N.T.T. Ha, H.T. Phuong, P.T. Chinh, P. van Kiem, N.V. Tuyen, Synthesis and cytotoxic evaluation of artemisinin-triazole hybrids, Nat. Prod. Commun. 11 (2016) 1789e1792. [304] S.Y. Zhang, D.J. Fu, X.X. Yue, X.C. Liu, J. Song, H.H. Sun, H.M. Liu, Y.B. Zhang, Design, synthesis and structure-activity relationships of novel chalcone1,2,3-triazole-azole derivates as antiproliferative agents, Molecules 21 (2016) e653. [305] D.J. Fu, J. Song, R.H. Zhao, Y.C. Liu, Y.B. Zhang, H.M. Liu, Synthesis of novel antiproliferative 1,2,3-triazole hybrids using the molecular hybridisation approach, J. Chem. Res. 40 (2016) 674e677. [306] V. van Truong, T.D. Nam, T.N. Hung, N.T. Nga, P.M. Quan, L. van Chinh, S.H. Jung, Synthesis and anti-proliferative activity of novel azazerumbone conjugates with chalcones, Bioorg. Med. Chem. Lett 25 (2015) 5182e5185. [307] L. Zhao, L. Mao, G. Hong, X. Yang, T. Liu, Design, synthesis and anticancer activity of matrine-1H-1,2,3-triazole-chalcone conjugates, Bioorg. Med. Chem. Lett 25 (2015) 2540e2544. [308] A. Singh, V. Mehra, N. Sadeghiani, S. Mozaffari, K. Parang, V. Kumar, Ferrocenylchalcone-uracil conjugates: synthesis and cytotoxic evaluation, Med. Chem. Res. 27 (2018) 1260e1268. [309] M. Ravivarma, P. Rajakumar, Synthesis, photophysical, electrochemical properties and anticancer, antimicrobial activity of N-n-hexyl-N-phenylanilinochalcone-capped dendrimers, ChemistrySelect 2 (2017) 10167e10175. [310] P. Thasnim, D. Bahulayan, Click-on fluorescent triazolyl coumarin peptidomimetics as inhibitors of human breast cancer cell line MCF-7, New J. Chem. 41 (2017) 13483e13491. [311] S. Chekir, M. Debbabi, A. Regazzetti, D. Dargere, O. Laprevote, H.B. Jannet, R. Gharbi, Design, synthesis and biological evaluation of novel 1,2,3-triazole linked coumarinopyrazole conjugates as potent anticholinesterase, anti-5lipoxygenase, anti-tyrosinase and anti-cancer agents, Bioorg. Chem. 80 (2018) 189e194. [312] D.J. Fu, J. Song, Y.H. Hou, R.H. Zhao, J.H. Li, R.W. Mao, J.J. Yang, P. Li, X.L. Zi, Z.H. Li, Q.Q. Zhang, F.Y. Wang, S.Y. Zhang, Y.B. Zhang, H.M. Liu, Discovery of 5,6-diaryl-1,2,4-triazines hybrids as potential apoptosis inducers, Eur. J. Med. Chem. 138 (2017) 1076e1088. [313] R. Pathoor, D. Dahulayan, MCR-Click synthesis, molecular docking and cytotoxicity evaluation of a new series of indole-triazole-coumarin hybrid peptidomimetics, New J. Chem. 41 (2018) 6810e6817. [314] S. Guo, Y. Zhen, M. Guo, L. Zhang, G. Zhou, Design, synthesis and antiproliferative evaluation of novel sulfanilamide-1,2,3-triazole derivatives as tubulin polymerization inhibitors, Investig. New Drugs 36 (2018) 1147e1157. [315] M. Cai, J. Hu, J.L. Tian, H. Yan, C.G. Zheng, W.L. Hu, Novel hybrids from Nhydroxyarylamide and indole ring through click chemistry as histone deacetylase inhibitors with potent antitumor activities, Chin. Chem. Lett. 26 (2015) 675e680. [316] C.P. Kumar, A. Devi, P.A. Yadav, R.R. Vadaparthi, G. Shankaraiah, P. Sowjanya, N. Jain, S. Babu, “Click” reaction mediated synthesis of costunolide and dehydrocostuslactone derivatives and evaluation of their cytotoxic activity, J. Asian Nat. Prod. Res. 18 (2016) 1063e1074. [317] A. Nagarsenkar, S.K. Prajapti, S.D. Guggilapu, S. Birineni, S.S. Kotapalli, R. Ummanni, B.N. Babu, Investigation of triazole linked indole and oxindole glycoconjugates as potential anticancer agents: novel Akt/PKB signaling pathway inhibitors, MedChemComm 7 (2016) 646e653. [318] C.B. Baltus, R. Jorda, C. Marot, K. Berka, V. Bazgier, V. Krystof, G. Prie, M.C. Viaud-Massuard Synthesis, Biological evaluation and molecular modeling of a novel series of 7-azaindole based tri-heterocyclic compounds as potent CDK2/Cyclin E inhibitors, Eur. J. Med. Chem. 108 (2016) 701e719. [319] S. Kumar, S.T. Saha, L. Gu, G. Palma, S. Perumal, A. Singh-Pillay, P. Singh, A. Anand, M. Kaur, V. Kumar, 1H-1,2,3-triazole tethered nitroimidazoleisatin conjugates: synthesis, docking, and anti-proliferative evaluation against breast cancer, ACS Omega 3 (2018) 12106e12113. [320] T.T.L. Huong, D.T.M. Dung, N.V. Huan, L.V. Cuong, P.T. Hai, L.T.T. Huong, J. Kim, Y.G. Kim, S.B. Han, N.H. Nam, Novel N-hydroxybenzamides incorporating 2-oxoindoline with unexpected potent histone deacetylase inhibitory effects and antitumor cytotoxicity, Bioorg. Chem. 71 (2017) 160e169. [321] D.T.M. Dung, P.T. Tai, D.T. Anh, L.T.T. Huong, N.T.K. Yen, B.W. Han, E.J. Park, Y.J. Choi, J.S. Kang, V.T.M. Hue, S.B. Han, N.H. Nam, Novel hydroxamic acids incorporating 1-((1H-1,2,3-triazol-4-yl)methyl)-3-hydroxyimino-indolin-2ones: synthesis, biological evaluation, and SAR analysis, J. Chem. Sci. 130 (2018) 63e75. [322] S. Sharma, M.K. Gupta, A.K. Saxena, P.M.S. Bedi, Triazole linked mono carbonyl curcumin-isatin bifunctional hybrids as novel anti-tubulin agents: design, synthesis, biological evaluation and molecular modeling studies, Bioorg. Med. Chem. 23 (2015) 7165e7180. [323] H. Singh, J.V. Singh, M.K. Gupta, A.K. Savena, S. Sharma, K. Nepali, P.M.S. Bedi, Triazole tethered isatin-coumarin based molecular hybrids as novel

Z. Xu et al. / European Journal of Medicinal Chemistry 183 (2019) 111700

[324]

[325]

[326]

[327]

[328]

[329]

[330]

[331]

[332]

[333]

[334]

[335]

[336]

[337]

[338]

[339]

[340]

antitubulin agents: design, synthesis, biological investigation and docking studies, Bioorg. Med. Chem. Lett 27 (2017) 3977e3979. Q.P. Diao, H. Guo, G.Q. Wang, Design, synthesis, and in vitro anticancer activities of diethylene glycol tethered isatin-1,2,3-triazole-coumarin hybrids, J. Heterocycl. Chem. 56 (2019) 1667e1671. Z. Xu, S.J. Zhao, Z.S. Lv, F. Gao, Y.L. Wang, F. Zhang, L.Y. Bai, J.L. Deng, Q. Wang, Y.L. Fan, Design, synthesis, and evaluation of tetraethylene glycol-tethered isatin-1,2,3-triazole-coumarin hybrids as novel anticancer agents, J. Heterocycl. Chem. 56 (2019) 1127e1132. Y.L. Fan, Z.P. Huang, M. Liu, Design, synthesis and antitumor activities of 1,2,3-triazole-diethylene glycol tethered isatin dimers, J. Heterocycl. Chem. 55 (2018) 2990e2995. Z. Xu, S.J. Zhao, J.L. Deng, Q. Wang, Z.S. Lv, Y.L. Fan, Design, synthesis, and in vitro anti-tumor activities of 1,2,3-triazoletetraethylene glycol tethered heteronuclear bis-Schiff base derivatives of isatin, J. Heterocycl. Chem. 55 (2019) 3001e3005. B. Yu, P.P. Qi, X.J. Shi, R. Huang, H. Guo, Y.C. Zheng, D.Q. Yu, H.M. Liu, Efficient synthesis of new antiproliferative steroidal hybrids using the molecular hybridization approach, Eur. J. Med. Chem. 117 (2016) 241e254. M.R.E.S. Aly, H.A. Saad, M.A.M. Mohamed, Click reaction based synthesis, antimicrobial, and cytotoxic activities of new 1,2,3-triazoles, Bioorg. Med. Chem. Lett 25 (2015) 2824e2830. A.B. Murray, M. Quadri, H. Li, R. McKenna, N.A. Horestein, Synthesis of saccharin-glycoconjugates targeting carbonic anhydrase using a one-pot cyclization/deprotection strategy, Carbohydr. Res. 476 (2019) 65e70. E. Halay, E. Ay, E. Salva, K. Ay, T. Karayildirim, Synthesis of triazolylmethyllinked nucleoside analogs via combination of azidofuranoses with propargylated nucleobases and study on their cytotoxicity, Chem. Heterocycl. Comp. 54 (2018) 158e166. K. Klich, K. Pyta, M.M. Kubicka, P. Ruszkowski, L. Celewicz, M. Gajecka, P. Przybylski, Synthesis, antibacterial, and anticancer evaluation of novel spiramycin-like conjugates containing C(5) triazole arm, J. Med. Chem. 59 (2016) 7963e7973. C.K. Karayildirim, M. Kotmakci, E. Halay, K. Ay, Y. Baspinar, Formulation, characterization, cytotoxicity and Salmonella/microsome mutagenicity (Ames) studies of a novel 5-fluorouracil derivative, Saudi Pharm. J. 26 (2018) 369e374. N. Dawra, R.N. Ram, An efficient method for the synthesis of some chlorinated and heteroatom rich triazole-linked b-lactam glycoconjugates, Tetrahedron 72 (2016), 7982-1991. A.Y. Spivak, Z.R. Galimshina, D.A. Nedopekina, V.N. Odinoko, Synthesis of new C-2 triazole-linked analogs of triterpenoid pentacyclic saponins, Chem. Nat. Compd. 54 (2018) 315e323. M.L. Navacchia, E. MArchesi, L. Mari, N. Chinaglia, E. Gallerani, R. Gavioli, M.L. Capobianco, D. Perrone, Rational design of nucleoside-bile acid conjugates incorporating a triazole moiety for anticancer evaluation and SAR exploration, Molecules 22 (2017) e1710. K.B. Mishra, N. Tiwari, P. Bose, R. Singh, A.K. Rawat, S.K. Singh, R.C. Mishra, R.K. Singh, V.K. Tiwari, Design, synthesis and pharmacological evaluation of noscapine glycoconjugates, ChemistrySelect 4 (2019) 2644e2648. C.T. Zi, L. Yang, W. Gao, Y. Li, J. Zhou, Z.T. Ding, J. Miao, Z.H. Jiang, Click glycosylation for the synthesis of 1,2,3-triazole-linked picropodophyllotoxin glycoconjugates and their anticancer activity, ChemistrySelect 2 (2017) 5038e5044. C.T. Zi, Z.H. Liu, G.T. Li, Y. Li, J. Zhou, Z.T. Ding, J.M. Hu, Z.H. Jiang, Design, synthesis, and cytotoxicity of perbutyrylated glycosides of 4b-triazolopodophyllotoxin derivatives, Molecules 20 (2015) 3255e3280. D.T.T. Anh, L.N.T. Giang, N.T. Hien, D.T. Cuc, N.H. Thanh, N.T.T. Ha, P.T. Chinh,

[341]

[342]

[343]

[344]

[345]

[346]

[347]

[348]

[349]

[350]

[351]

[352]

37

N. van Tuyen, P. van Kiem, Synthesis and cytotoxic evaluation of betulintriazole-AZT hybrids, Nat. Prod. Commun. 12 (2017) 1567e1570. B. Pattnaik, J.K. Lakshmi, R. Kavitha, B. Jagadeesh, D. Bhattacharjee, N. Jain, U.V. Mallavadhani, Synthesis, structural studies, and cytotoxic evaluation of novel ursolic acid hybrids with capabilities to arrest breast cancer cells in mitosis, J. Asian Nat. Prod. Res. 16 (2017) 260e271. M. Jurasek, M. Cernohorska, J. Rehulka, V. Spiwok, T. Sulimenko, E. Draberova, M. Darmostuk, S. Gurska, I. Frydrych, R. Burianova, T. Ruml, M. Majduch, P. Bartunek, P. Draber, P. Dzubak, P.B. Grasar, D. Sedlak, Estradiol dimer inhibits tubulin polymerization and microtubule dynamics, J. Steroid Biochem. Mol. Biol. 183 (2018) 68e79. J.R. Branco, V.G. Oliveira, A.M. Estenes, I.C. Chipoline, M.F.O. Lima, F.C.S. Boechat, F.C. da Silva, V.F. Ferreira, M. Sola-Penna, M.C.B.V. de Souza, P. Zancan, A novelthotriazolyl-4-oxoquinoline derivative that selectively controls breast cancer cells survival through the induction of apoptosis, Curr. Top. Med. Chem. 18 (2018) 1465e1474. M. Krawczyk, G. Pastuch-Gawolek, A. Mrozek-Wilczkiewicz, M. Kuczak, M. Skonieczna, R. Musiol, Synthesis of 8-hydroxyquinoline glycoconjugates and preliminary assay of their b1,4-GalT inhibitory and anti-cancer properties, Bioorg. Chem. 84 (2019) 326e338. K.S.S. Praveena, E.V.V.S. Ramarao, N.Y.S. Murthy, S. Akkenapally, C.G. Kumar, R. Kapavarapu, S. Pal, Design of new hybrid template by linking quinoline, triazole and dihydroquinoline pharmacophoric groups: a greener approach to novel polyazaheterocycles as cytotoxic agents, Bioorg. Med. Chem. Lett 25 (2015) 1057e1063. A.A. Boezio, K.W. Copeland, K. Rex, B.K. Albrecht, D. Bauer, S.F. Bellon, C. Boezio, M.A. Broome, D. Choquette, A. Coxon, I. Dussault, S. Hirai, R. Lewis, M.H.J. Lin, J. Lohman, J. Liu, E.A. Peterson, M. Potashman, R. Shimanovich, Y. Teffera, D.A. Whittington, K.R. Vaida, J.C. Harmange, Discovery of (R)-6-(1(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl) ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one (AMG 337), a potent and selective inhibitor of MET with high unbound target coverage and robust in vivo antitumor activity, J. Med. Chem. 59 (2016) 2328e2342. K.S.S. Praveena, E.V.V.S. Ramarao, Y. Poornachandra, C.G. Kumar, N.S. Babu, N.Y.S. Murthy, S. Pal, Assembly of quinoline, triazole and oxime ether in a single molecular entity: a greener and one-pot synthesis of novel oximes as potential cytotoxic agents, Lett. Drug Des. Discov. 13 (2016) 210e219. A. Podolski-Renic, S. Bosze, J. Dinic, L. Kocsis, F. Hudecz, A. Csampai, M. Pesic, Ferrocene-cinchona hybrids with triazolyl-chalcone linker act as prooxidants and sensitize human cancer cell Lines to paclitaxel, Metallomics 9 (2017) 1132e1142. S.K. Kandi, S. Manohar, C.E.V. Gerena, B. Zayas, S.V. Malhotra, D.S. Rawat, C5curcuminoid-4-aminoquinoline based molecular hybrids: design, synthesis and mechanistic investigation of anticancer activity, New J. Chem. 39 (2015) 224e234. L.N.T. Ciang, N.T. Nga, D.T. Van, D.T.T. Anh, H.T. Phuong, N.H. Thanh, L.T.T. Anh, V.Q. Trung, N. van Tuyen, P. van Kiem, Design, synthesis and cytotoxic evaluation of 4-anilinoquinazoline-triazole-AZT hybrids as anticancer agents, Nat. Prod. Commun. 13 (2018) 1633e1636. C. Ding, S. Chen, C. Zhang, G. Hu, W. Zhang, L. Li, Y.Z. Chen, C. Tan, Y. Jiang, Synthesis and investigation of novel 6-(1,2,3-triazol-4-yl)-4aminoquinazolin derivatives possessing hydroxamic acid moiety for cancer therapy, Bioorg. Med. Chem. 25 (2017) 27e37. C. Ding, D. Li, Y.W. Wang, S.S. Han, C.M. Gao, C.Y. Tan, Y.Y. Jiang, Discovery of ErbB/HDAC inhibitors by combining the core pharmacophores of HDAC inhibitor vorinostat and kinase inhibitors vandetanib, BMS-690514, neratinib, and TAK-285, Chin. Chem. Lett. 28 (2017) 1220e1227.