Aurone: A biologically attractive scaffold as anticancer agent

European Journal of Medicinal Chemistry 166 (2019) 417e431

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

Mini-review

Aurone: A biologically attractive scaffold as anticancer agent Abdulrahman Alsayari a, Abdullatif Bin Muhsinah a, Mohd Zaheen Hassan a, *, Mohammed Jawed Ahsan a, Jaber Abdullah Alshehri a, Naseem Begum b a b

College of Pharmacy, King Khalid University, Abha, 62529, Saudi Arabia College of Applied Medical Sciences, King Khalid University, Abha, 62529, Saudi Arabia

a r t i c l e i n f o

a b s t r a c t

Article history: Received 30 November 2018 Received in revised form 28 January 2019 Accepted 29 January 2019 Available online 1 February 2019

Aurones are very simple, promising anticancer lead molecules containing three rings (A, B and C). A very slight structural variation in the aurones elicits diverse affinity and specificity towards different molecular targets. The present review discusses the design, discovery and development of natural and synthetic aurones as small molecule anticancer agents. Detailed structure-activity relationship and intermolecular interactions at different targets are also discussed. Due to their rare occurrence in nature and minimal mention in literature, the anticancer potential of aurones is rather recent but in constant progress. © 2019 Elsevier Masson SAS. All rights reserved.

Keywords: Aurone Flavonoid Anticancer Multidrug resistance

1. Introduction Cancer is a serious group of diseases involving uncontrolled cell proliferation, with the cells being malignant and invasive [1]. In 2018 alone, approximately 10 million people died due to cancer, making it the second leading cause of death. A majority of them are from the low- and middle-income countries [2]. The five most common cancers, accounting for more than half of cancer cases, are breast, lung, prostate, colon and skin cancers [3]. The possible causes of cancer include, obesity, hormonal imbalance, environmental pollutants, carcinogens, several drugs and radiation [4]. The treatment of cancer often involves surgeries and, radiation therapy followed by chemotherapy as a maintenance therapy. Despite the severe consequences of high toxicity and emergence of multidrug resistance (MDR) against anticancer drugs, chemotherapy continues to be a basic regimen in the clinical management of all types of cancer [5,6]. Recently, molecular targeted therapy (also known as the magic bullet) has received considerable attention in the field of oncology research. This strategy improves the specificity of anticancer agents and reduces non-selective resistance and toxicity [7]. Many different targeted therapies have been approved for use in cancer treatment, including growth factors, signalling molecules, cell-cycle proteins, modulators of apoptosis, hormone, gene

* Corresponding author., E-mail addresses: [email protected], [email protected] (M.Z. Hassan). https://doi.org/10.1016/j.ejmech.2019.01.078 0223-5234/© 2019 Elsevier Masson SAS. All rights reserved.

expression modulators, immunotherapies, angiogenesis inhibitors and monoclonal antibodies [8]. Many potent small molecule anticancer agents have been discovered by High Throughput Screening (HTS) of a large array of synthetic and natural small molecules against the validated targets, then “hit-to-lead” approaches and finally, lead optimization [9]. Not surprisingly, since the 1940s, 131 of the 174-small molecule anticancer agents identified are either natural products or inspired by natural lead molecules. Representative natural anticancer molecules, such as vinca alkaloids, semi-synthetic epipodophyllotoxins, taxanes, and camptothecin have received FDA approval as first line treatments for cancer [10,11]. In addition, a number of other natural lead molecules can be used as adjuvants e.g. curcumin, resveratrol, isoflavone, lycopene and phytosterol [12]. Many of these chemically diverse agents are potentially interesting in the context of biological activity due to their admirable biocompatibility, physicochemical properties and safety profiles. 2. Aurone: A golden flavonoid In the past few years, the naturally occurring molecule aurone has gained significant attention from medicinal chemists. Aurones (from Latin Aurum ¼ Gold), or benzalcoumaranones, are fascinating scaffolds which confer the bright golden colour and characteristic fluorescence to some ornamental flowers such as sunflowers [13]. Chemically, aurones (8) are a benzofuranone heterocyclic ring

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containing a phenyl group linked through a carbon-carbon exocyclic double bond. In 1943, Geissman and Heaton discovered the anthochlor pigment aurone in the flowers Coreopsis grandiflora; this was the first representative structure to be isolated from a natural source. In addition to flowering plants, aurones have also been isolated from gymnosperms, bryophytes, and brown algae [14]. These constituents are mainly secondary plant metabolites produced by the oxidative cyclization of 20 -hydroxychalcones in the presence of enzymes aurone synthases [15]. Aurones belong to the family of flavonoids that also includes flavones (1), flavonols (2), flavanones (3), flavanonols (4), flavanols or catechins (5), anthocyanins (6) and chalcones (7) [16] (Fig. 1). All of these flavonoids possess significant biological activities, but the major advantage of aurone is its high stability as compared to chalcones, which can easily undergo a cyclization to yield flavanones. The beauty of aurone lies in its simplicity and its excellent drug-likeness scores, which render these small molecules an interesting source of potential leads. Although aurones have a very limited presence in nature, they are a very promising bioactive moiety with diverse biological activities [17,18] including antiinflammatory [19], antimicrobial [20], antimalarial [21], antileishmanial [22], and anti-Alzheimer [23,24] properties. During the last two decades, several natural, semisynthetic and synthetic aurone analogues have been identified as potential anticancer agents, effective against the various cell lines of in vitro and in vivo models, although acting through different mechanisms. This is the first comprehensive review to cover all the reported anticancer aurones and to feature the schematic representations from hit to lead optimization. The anticancer activities of these compounds are discussed based on their preclinical screenings and strong interactions with molecular targets. 3. Aurone analogues as anticancer agents Aurones are simple, and planar molecules demonstrating a

Fig. 1. Different sub-classes of bioactive flavonoids.

significant role in anticancer drug development. They exhibit lower toxicity and a broad spectrum of anticancer mechanisms by interacting targets such as cyclin dependent kinase, histone deacetylase, DNA scissoring, adenosine receptor, telomerase, sirtuins, and microtubule inhibition. 3.1. DNA strand-scission activity Natural flavonoids were known to exhibit a wide range of beneficial effects with regard to different forms of cancer. Therefore, tremendous efforts were made to isolate novel bioactive flavonoids from medicinal plants [25]. In an attempt to identify novel small molecule in plants with the potential for use in cancer chemotherapy, Thai scientists Huang et al. isolated the aurone derivative hamiltrone (9) from the plant Uvaria hamiltonii Hook by bioassay-guided fractionations (Fig. 2). A literature survey revealed that this is the first study where the anticancer activity of any aurone analogue was explored. The DNA in a cell is largely responsible for gene expression, gene transcription, mutagenesis and carcinogenesis. Therefore, DNA scissoring agents can be used alone or as a combined treatment modality against cancer due to their extreme ability to damage the DNA on proliferating cells. In the DNA strand scission assay, hamiltrone showed very high (83%) relaxation of supercoiled DNA with 10 bleomycin units at 2.5 mg/ mL. It is believed that the presence of a 3,4-catechol pharmacophore is essential for DNA strand-scission activity. Furthermore, a cytotoxicity assay on 9 KB cells revealed the non-cytotoxic nature of the compound (IC50 value of >20 mg/mL) [26]. 3.2. Topoisomerase inhibitors Topoisomerase is the key enzyme regulating DNA replicationtranscription, thus being the primary cellular target for a number of antitumor drugs. The inhibition of topoisomerase converts it into a cellular toxin which fragments the genome. Since cancer cells divide rapidly, thus cancer cells are affected excessively by topoisomerase inhibition [27]. In the quest for topoisomerase inhibitors, Suzuki et al. screened several microorganisms and isolated some potential inhibitors. Among these, one extremely rare isoaurone (10) analogue, isoaurostatin (E-6-hydroxy-3-(4-hydroxybenzylidene)benzo[b]furan-2-one) (11), was identified (Fig. 3). It is a fungal metabolite obtained from Thermomonospora alba. This isoaurone was found to be a specific inhibitor of topoisomerase-I relaxation activity in wheat germ (IC50 67 mM) and calf thymus gland (IC50 307 mM). Additionally, it was found to be an inhibitor belonging to a cleavable complex-nonforming type without DNA intercalation [28]. Considering the intriguing significance of isoaurostatin as a lead molecule, Rizzi and co-workers reported on an efficient synthesis of a series of isoaurones via Heck intramolecular cyclization of cinnamic esters of 2-iodophenols. They presumed the isoaurones as the conformationally restricted analogues of combretastatins (12). A cytotoxicity evaluation against the human non-small lung carcinoma cell line H460 model which has very high sensitivity towards the topoisomerase I inhibitors, revealed that the cytotoxic effects of

Fig. 2. Bioassay guided fractionation of bioactive aurone-hamiltrone from U. hamiltonii.

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Fig. 3. Optimization of fungal metabolite lead molecule iosaurostatin

isoaurones (13) were moderate [29]. On the basis of the structures of known topoisomerase II inhibitor lead molecules, aurones (14,15) and imidazopyridines (16), Priyadarshani et al. considered the scaffold hopping of these bioactive moieties into novel azaurone like molecules. Scaffold hopping has been widely applied for lead optimization to discover potent compounds with novel backbones through the modification of the central core structure of lead molecules. The anticancer potency of most newer analogues was found to be in the nanomolar range (manifold higher), as compared to their lead molecule. These compounds have promising effects, such as tubulin polymerization, and CDK1, pCDK1 and hTopoIIa inhibitions. A para-methoxybenzylidene derivative (17) significantly arrested (80.1%) the cell cycle at the G2/M phase with an IC50 concentration of 50 nM (Fig. 4) [30]. 3.3. Cyclin-dependent kinase (CDKs) inhibitors The cyclin-dependent kinase (CDKs) are important targets in cancer drug discovery as they play an imperative role in cell cycle transitions and cellular transcription. Cancer is a disease of uncontrolled proliferation, and since CDKs are a central component of the cell cycle engine, great effort has been expended in developing CDK inhibitors as anticancer agents [31]. Twenty years ago, flavopiridol (Alvocidib®) (19), which is a flavonoid based potent

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inhibitor of CDKs, was developed by Sanofi-Aventis after extensive optimization of the alkaloid rohitukine (18) [32]. No reports have been published on the clinical progress of flavopiridol after Phase II studies. However, the FDA recently granted an “orphan drug” designation for flavopiridol for the treatment of patients with acute myeloid leukemia [33]. Detailed X-ray crystallography studies of CDK2, in complex with flavopiridol revealed that its 4-keto and 5hydroxy groups form a bidentate hydrogen bonds with the residues Leu 83 and Glu 81. This similar to the purine moiety of ATP indicating the essential pharmacophore for CDK inhibitory activity. Inspired by this, Schoepfer et al. from the oncology department of Novartis Pharma designed several novel aurone analogues (20e22) to mimic flavopiridol, keeping all the essential pharmacophores. This structure-based designing (SBD) of aurone analogues resulted in more potent and selective CDK 1 and 2 inhibitors than the drug flavopiridol. They performed a series of modifications in the chromenone ring, the phenyl ring, and the piperidinyl ring, which gave the compounds better binding interactions at CDK2 [34]. Prompted by the significant results of earlier modifications Huang et al. carried out a further modification of the benzylidene ring by shifting the heterocyclic ring from 7th position to the position of 2benzylidene. They also developed a highly efficient microwave assisted protocol for the synthesis of piperazinyl-aurone analogues (23,24). These compounds were found to arrest the cell cycle in the G0/G1 phase and displayed an apoptosis-inducing effect on Hep2 cells (Fig. 5) [35]. Over the years, many other natural plant-based aurones have been reported as potential anticancer agents. In 2014, Ragab et al. prepared flavonoid scaffold-based furoaurone derivatives and evaluated them for antiproliferative activity against a panel of 60 cancer cell lines comprising nine types of tumours. Allyl substituted furoaurone (25) emerged as the most promising anticancer agent; however, weak inhibition was observed against the CDK4/Cyclin D1 protein kinase target, as compared to the control [36]. Hassan et al. also reported the synthesis of phenylacetamide (26), furano (27) and morpholinomethyl (28) containing aurones. These compounds were then screened for their anticancer activity at 10 mM against 60 cell lines, including tumour cells, by NCI. The introduction of a phenylacetamide core at the aurone scaffold was shown to have more inhibitory effects than hydroxy aurone. A compound containing an unsubstituted phenylacetamide furoaurone (27) derivative emerged as the most active anticancer agent, exhibiting a promising percentage of growth inhibition (%GI) in the range of 67.10e79.61%. It induced apoptosis in both cell lines by the activation of CASP3 9.6- and 7.9-fold and had a potent inhibitory effect on CDK2 with IC50 1.11 (leukemia) and 1.14 mM, when compared to the reference drug erlotinib. In-silico molecular docking studies revealed that it binds with CDK2 through one hydrogen bond by Leu 83 (binding energy 15.08 kcal/mol). A morpholino furoaurone derivative (28) showed moderate activity with a %GI of 56.43e65.22% (Fig. 6) [37]. 3.4. Tubulin polymerization inhibitors

Fig. 4. Scaffold hopping of aurones as topoisomerase II inhibitors.

Tubulin polymerization inhibitors are widely employed in cancer chemotherapy. The colchicine binding site is one of the most important pockets for potential tubulin polymerization destabilizers and its inhibitors exert their biological effects by inhibiting tubulin assembly and suppressing microtubule formation. Tubulin inhibitors, such as colchicine (29), combretastatin A-4 (12) and chalcone analogues (30), have characteristic two aromatic rings (A & B) as common pharmacophore. The spatial relationship between these two aromatic rings is an important structural feature that determines their ability to bind to tubulin [38]. Furthermore, aurones are conformationally restricted analogues of chalcones

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Fig. 5. Lead optimization of flavopiridol based aurones as potent CDK inhibitors by Novartis Pharma.

is in Phase II clinical trial for the treatment of multiple myeloma. Previously, it was reported that O-alkylated derivatization at the 7th position resulted in compounds with more than hundred-fold higher activity. Therefore, Mishra et al. observed a 7-hydroxy noscapine analogue with a different steric bulk substituent which resembled in structure with aurone analogues (33). Most cancer cells (lung, lymphoma, pancreatic and prostate) significantly responded to an acetyl derivative (34) and displayed much lower IC50 values in the range of 1e15 mM. Additionally, they induced apoptotic cell death in PC-3 cells which was associated with decreased expression of the anti-apoptotic protein, survivin. Insilico molecular modelling was performed to obtain better insight into the molecular interaction of the tubulin heterodimercolchicine models (Fig. 8) [40]. 3.5. ATP-binding cassette transporter inhibitors Fig. 6. Furoaurone analogues as CDK inhibitors.

with proven DNA-strand scission activity [26]. Based on these information, Lawrence et al. developed a total synthesis of natural aurone from the key benzofuranone. The results of anticancer activity studies showed that some of the aurones (31) caused a significant arrest of the cell cycle at the G2/M point and interacted at the colchicine binding site. In general, conformational flexibility was seen as essential for the tubulin inhibition activity (Fig. 7) [39]. Noscapinoids a benzofuranone analogue, represent an emerging class of microtubule-modulating anticancer agent, based upon the parent molecule noscapine (32), which is a naturally-occurring non-toxic cough-suppressant opium alkaloid. Currently, noscapine

The multi-drug resistance (MDR) of cancer cells is an obstacle to effective chemotherapy. The ATP-binding cassette (ABC) transporters, including P-glycoprotein (ABCB1), multi-drug resistance protein 1 (MRP1) (ABCC1) and ABCG2, play an important role in the development of this resistance. A useful approach to overcoming MDR is the inhibition of the pumping action of these transporters [41]. A French research group led by Boumendjel synthesised a series of 4-hydroxy-6-methoxyaurones and 4,6-dimethoxyaurones and tested them for their binding affinity toward the nucleotidebinding domain of P-glycoprotein. They extensively studied the results of modifying the rings B, C and ring substituents to optimize the lead molecule. Their preliminary results showed that 4,6dimethoxyaurones (35) were less active than their corresponding

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Fig. 7. Conformationally restricted comberstatin analogues as tubulin inhibitors.

Fig. 8. Noscapinoid containing aurone like fragment as tubulin inhibitor.

4-hydroxy-6-methoxyaurones (36), while halogenated aurones were the most active [42]. Further studies regarding their ability to modulate P-glycoprotein (Pgp)-mediated multidrug resistance (MDR) was carried out by in vitro rhodamine-123 accumulation assay on adriamycin resistant K562 cells. The compound 4,6dimethoxyaurone (35) potentiated daunorubicin cytotoxicity and increased the intracellular accumulation of rhodamine-123, a fluorescent molecule which acts as a probe of Pgp-mediated MDR [43]. To further develop anticancer agents targeting MDR, they investigated the effect of related aurone derivatives on [14C]paclitaxel transport in two human breast cancer cell lines, the adriamycin-resistant NCI/ADR-RES and the sensitive MDA-MB-435. Some of the aurones effectively inhibited Pgp-related transport in the resistant line and accordingly increased the accumulation of [14C]paclitaxel, as well as decreased its efflux. Thus, these aurone derivatives could increase the efficiency of chemotherapy with paclitaxel in Pgp highly expressing breast tumours better than the natural flavonoid quercetin [44]. The use of aurone in combating the resistance to another anticancer drug, doxorubicin, has also been studied. Aurones did not inhibit the formation of doxorubicinol when compared to quercetin and also did not significantly

affect the transport of [14C]doxorubicin in human resistant breast cancer. Therefore, this was found to have less effect on doxorubicin metabolism and was not able to increase the accumulation of doxorubucin in resistant human cancer cells [45]. A modification was then carried out on rings B and C for the lead optimization process, which resulted in the discovery of an indolylmethylene aurone analogue (39) as a potential inhibitor of ABCC2. A cellular flow cytometry assay for monitoring the drug efflux was carried out by ABCC2 against a large array of chemo-libraries. Detailed SAR studies revealed that a linkage of the indole to benzofuranone through C-3 is slightly more advantageous than through C-2. Also, the substitution of an alkyl chain at the indolic nitrogen is more favourable than at the aryl groups [46]. Encouraged by the positive results from the modification of ring C, they investigated the impact of the ferrocenyl ring (at the position of ring C) on MRP1- mediated glutathione (GSH) efflux. Studies have shown that GSH depletion in cells is connected with cell death. Therefore, the synthesised compounds were evaluated for their ability to induce the efflux of glutathione (GSH) from tumour cells. 4-Methoxy-substituted ferrocenylaurone (40) was found to be the most effective agent inducing 73% GSH efflux at 20 mM concentration (Fig. 9) [47]. The promising results of aurones is expected to encourage further synergistic studies with other anticancer drugs and binding affinity studies with the proteins other than Pgp, responsible for cancer MDR mechanism. Sim et al. did parallel research for the development of anticancer agents effective against drug resistant cancer. They performed extensive SAR studies on dimethoxyaurones as ABCG2 (breast cancer resistance protein) inhibitors. To this end, various analogues were designed with modifications at rings A and B of the aurone template. The 30 -chloro substituted aurone derivative resensitized ABCG2-overexpressing cancer cells to the anticancer drug mitoxantrone at sub-micromolar concentrations and was found to target ABCG2 to a greater extent than ABCB1. The SAR analysis showed that substitution of the benzylidene ring B of the aurone template was less important for ABCG2 inhibition, with little variation in activity noted between compounds with a substituted or unsubstituted ring B. In contrast, a substitution of ring B gave rise to better inhibitors of ABCB1. A preference for the 30 position of ring B was noted. The data indicated that aurones with good ABCG2 inhibitory activity were poor ABCB1 inhibitors, and vice versa. Further studies with substitution at ring A were also carried out. A methoxylated ring A appeared as the key structural feature for interactions with both ABCG2 and ABCB1, while a derivative with a hydroxyl group at ring A did not show any promising effects. They

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Fig. 9. Development of multidrug resistance (MDR) modulators.

also postulated a pharmacophore model of an ABCG2 modulator which would be helpful for future optimization of the aurone scaffold; this may yield broad-spectrum or single-targeting ABCG2 modulators. Detailed cell-based assays, accumulation of intracellular mitoxantrone (MX) by cell cytometry, interaction with ABCG2 by biochemical assays and in-vivo efficacy in MX resistant nude mice xenografts revealed that methoxylated aurones (41) interacted directly with ABCG2 to inhibit efflux activity, possibly by competing for occupancy of one of the substrate binding sites on ABCG2 (Fig. 10) [48,49]. 3.6. Hypoxia-inducible Factor-1 (HIF-1) inhibitors Hypoxia is a characteristic feature of tumour cells activated by mediators, such as hypoxia-inducible factor 1 (HIF-1). HIF-1 is usually overexpressed in many human cancer cells, and the levels of its activity in cells is correlated with tumorigenicity and angiogenesis. Thus, HIF-1 is a useful intrinsic marker for tumours [50]. In search of antitumor agents, isoaurone 40 ,6-Dihydroxy-4-methoxyisoaurone (ISOA) (42) was isolated from the seeds of Trichosanthes kirilowii as a tumour growth inhibitor. ISOA was found to act through the downregulation of HIF-1a by decreasing its protein expression without affecting mRNA levels [51]. Previously, this compound was also found to inhibit HIF-1a accumulation and VEGF secretion under hypoxic conditions. The tumour cell growth inhibitory activity of T. kirilowii is likely associated with the inhibition of HIF-1 and NF-kB activities (Fig. 11) [52].

Fig. 11. HIF-1 inhibitor- ISOA.

workers to undertake further detailed studies of this remarkable compound. They synthesised dimethoxyazaaurones (44) as structural analogues of DMA and evaluated this against urothelial cell carcinomas (UCC). The 2-flourobenzylidene derivative emerged as the most active compound by suppressing cell proliferations in the DAG-1, RT112, and J82 cell lines (decreased 48e97% cell viability) through decreasing the fibroblast growth factor receptors (FGFRs) protein signal expression. FGFRs are a type of tyrosine kinase receptor which are known to assist in controlling angiogenesis (Fig. 12) [53]. 3.8. Sphingosine kinase inhibitors

The conspicuous anticancer properties of dimethoxyaurones (DMA) (43) in previous studies, prompted Boumendjel and co-

Sphingosine kinases (SKs) are lipid kinases that catalyse the formation of sphingosine 1-phosphate (S1P), a potent signalling molecule having both intra- and extracellular functions. SKs are noted to be over-expressed in tumours, so their inhibition has been

Fig. 10. Dimethoxyaurone as potential ABCG2 inhibitors.

Fig. 12. Azaaurone as structural analogue of DMA.

3.7. Fibroblast growth factor receptor (FGFR) inhibitors

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Fig. 13. Dihydroxyaurone as novel non-lipid SK inhibitor.

shown to slow tumour growth, as well as sensitise cancer cells to chemotherapeutics. Therefore, SKs have emerged as a new molecular target for cancer chemotherapy [54]. French et al. screened a library consisting of ~16000 synthetic compounds through medium throughput assay for recombinant human SKs. Among these, they identified a benzothiophenone chemotype (45) hit as the most easily synthesisable template. Bioisosteric replacement of benzothiophenone with benzofuranone provided dihydroxyaurone (46) as the first nonlipid SK inhibitor lead molecule with moderate in vivo antitumor activity (Fig. 13) [55].

3.9. Discoidin domain receptor (DDR) kinase inhibitors Discoidin domain receptors (DDR) are transmembrane receptors from the family of tyrosine kinases (TK). DDR is involved in cell adhesion, proliferation, differentiation and migration. The altered function of DDR results in atherosclerosis, inflammation, cancer, and tissue fibrosis. Various clinically available anticancer agents such as imatinib, dasatinib, and nilotinib have been reported to inhibit DDR kinase activity [56]. Plancyol B (47), an isobenzofuranone analogue isolated from the Chinese insect Polyphaga plancyi Bolivar, inhibited Janus kinase 3 (JAK3) in the micromolar range (Fig. 14) [57].

Fig. 14. Natural isobenzofuranone as potential anti-DDR kinase.

3.10. Tyrosinase inhibitors Tyrosinase (Ty) is an important copper-containing enzyme which converts l-tyrosine into dopaquinone, which is a key product for melanin pigment biosynthesis. It is found inside melanosomes which are synthesised in the skin melanocytes. The mutation of the Ty gene results in an impaired Ty level, leading to albinism. Recently, medical and cosmetic industries are focusing their research on Ty inhibitors to treat skin disorders such as the hyperpigmentation of the skin. Researchers have identified Ty as a therapeutic target for the treatment of melanoma [58]. The French scientist Boumendjel and co-workers studied the effects of aurones on tyrosinase activity and found extraordinarily versatile effects of the aurone structure on mushroom Ty activity. Naturally occurring trihydroxyaurone (48) was found to induce 75% inhibition of Ty at 0.1 mM [59]. The position of the -OH group at the benzylidene ring was found to be crucial for the substrate or hyperbolic activator. Replacement of the benzylidene ring with 2-hydroxypyridine Noxide (HOPNO) led to a good metal chelate as a new, efficient, mixed inhibitor (49) for mushroom tyrosinase, having an IC50 value of 1.5 ± 0.2 mM (Fig. 15) [60]. 3.11. Histone deacetylase (HDAC) inhibitors Histone acetylation induced by histone acetyl transferases (HATs) is associated with gene transcription, while histone hypoacetylation induced by histone deacetylase (HDAC) activity is associated with gene silencing. Altered expressions and mutations of genes that encode HDACs have been linked to tumour development since they both induce the aberrant transcription of key genes regulating important cellular functions such as cell proliferation, cell-cycle regulation and apoptosis. Thus, HDACs are among the most promising therapeutic targets for cancer treatment, inspiring researchers to study and develop HDAC inhibitors. HDACs are classified into four classes - I, II, III and IV that are often conserved from yeast to humans. The class III HDACs are known as sirtuins which consist of seven mammalian proteins, SIRT1-7 [61]. Collaborative endeavours by Pal's group at the University of Hyderabad (India)

Fig. 15. 2-Hydroxypyridine N-oxide (HOPNO) derivative of aurone as Ty inhibitor.

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resulted in a series of novel promising aurones as sirtuin inhibitors. They designed some aurone analogues by systematic structural manipulations of the sirtuins inhibitor lead molecule, thiobarbiturate (50), having an IC50 ~10 mM. Some of the synthesised compounds have shown SIRT1 inhibiting, as well as antiproliferative properties against two cancer cell lines in vitro. Compound [(Z)-2(5-bromo-2-hydroxybenzylidene)benzofuran-3(2H)-one] (51) was identified as a potent inhibitor of SIRT1 (IC50 ¼ 1 mM) which showed a dose dependent increase in the acetylation of p53 resulting in induction of apoptosis (Fig. 16) [62]. Subsequently, Zwick et al. designed a series of twenty aurone analogues and evaluated them for their HDAC inhibitory activity. Some of the hydroxylated aurones exhibited an IC50 lower than 20 mM and were considered active. The most active aurones were hydroxylated (Z)-2benzylidenebenzofuran-3-(2H)-one compounds (52 and 53), which seem to play a key role on HDAC modulation via zinc chelation (Fig. 17) [63]. However, a group of Japanese scientists reported that 3,4-dihdroxylated benzylidenebenzofuran-3-(2H)-one, which had been reported as a histone deacetylase (HDAC) inhibitor, gave false-positive results. Although it was identified by an in vitro HDAC fluorescence assay, it did not show HDAC inhibitory activity in a cellbased assay, leading them to suspect its in vitro HDAC inhibitory activity. As a result of verification experiments, they found that this compound interfered with the HDAC fluorescence assay by quenching the HDAC fluorescence signal [64].

3.12. Human Neutrophil Elastase (HNE) inhibitors Human Neutrophil Elastase (HNE) is a serine protease of the chymotrypsin family present in the neutrophils. It hydrolyses elastin and other proteins, while also playing an important role in phagocytosis and defence against infections. Moreover, HNE has been implicated in rheumatoid arthritis, cystic fibrosis, non-small cell lung cancer progression and leukaemia. Thus, HNE could be a therapeutic target, with its inhibitor providing a potential therapeutic drug for the treatment of cancer and leukaemia [65].

Lucas and co-workers, in their search for novel lead structures for HNE inhibition, envisaged the aurone derivatives as potential Cshape candidates toward adequate conformation of HNE noncovalent inhibition. They screened a library of aurone derivatives with varied substitutions against the HNE to establish the conformation-activity relationship. The tendency of aurones to form C-shaped conformation is mainly attributed to the tight binding at the active site of HNE S1 and S2 pockets. Substitution at the benzylidene ring greatly affected the binding properties of aurone analogues. Compounds having para substituted derivatives (54) resulted in a lack of flexibility compared to meta substituted derivatives (55), which favoured C-shaped conformations of aurones (Fig. 18) [66].

3.13. Mitochondrial membrane potential modulators Cancer cells have a more hyperpolarised mitochondrial membrane potential than normal cells. If this hyperpolarisation dissipates, the voltage-sensitive permeability transition pore (PTP) will open and release pro-apoptotic agents (e.g. cytochrome c) into the cytoplasm and drive apoptotic cell death. Thus, mitochondria have emerged as a major target for anticancer therapy, with drugs designed for selective action on mitochondrial targets [67]. Recently, Chen et al. synthesised some novel aurone derivatives and evaluated these against two breast cancer cell lines MDA-MB-231 and MCF-7. Results showed that p-methyl (56) and p-chlorobenzylidene (57) analogues showed excellent anticancer activity, arresting the cell cycle in the G0/G1 phase. Both compounds were found to induce a substantial and time-dependent loss of mitochondrial membrane potential in these cell lines (Fig. 19) [68].

Fig. 18. Structure of HNE in complex with a aurone inhibitor with “C-shape” conformation (PDB 3Q77). Fig. 16. 5-Bromo-2-hydroxyaurone as potent SIRT1 inhibitor.

Fig. 17. Catechol containing aurones as HDAC-1&2 inhibitor.

Fig. 19. Mitochondrial membrane potential modulators.

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Fig. 20. 2,2-Bisaminomethylated aurone as TNF- a inhibitor.

3.14. TNF-a inhibitors Tumour necrosis factor-alpha (TNF-a) is a multifunctional cytokine playing a key role in immune homeostasis, inflammation, and host defence. TNF-a is a cell signalling protein inducing apoptosis, necrosis, angiogenesis, immune cell activation, differentiation, and cell migration. Thus, it plays an important role in tumour development and tumour progression [69]. Bandgar et al. noted the 2,2-bisaminomethylated aurone as a potential TNF-a inhibitor. Compounds containing methylpiperidinyl (58), morpholinyl (59) and pyrrolidinyl (60) moieties exhibited excellent TNF-a inhibition (76e100%) at 10 mM. These compounds also possessed excellent IL-6 inhibitory effects (Fig. 20) [70].

et al. resulted in the isolation and identification of two bioactive aurone analogues viz. sulfuretin (61) and 2-benzyl-2,30 ,40 ,6tetrahydroxybenzo[b]furan-3(2H)-one (62). These aurone analogues showed promising antiproliferative activities against human tumour cell lines A549, SK-OV-3, SKMEL-2, and HCT-15 with IC50 values of 7.43e26.84 mM. Sulfuretin dose-dependently reduced the production of NO and tumour necrosis factor-a (IC50 23.37 mM) [72]. Recent studies by Poudel et al. provided new mechanistic insights into the anticancer properties of sulfuretin through MicroRNA (miRNAs) regulation. They reported that the expression of miR-30C is markedly enhanced in sulfuretin-stimulated cells, consequently promoting apoptosis and cell cycle arrest in human cancer cell lines (Fig. 21) [73].

3.15. Prostaglandin E2 (PGE2) inhibitors

3.17. Quinone reductase inducer: chemo-preventive agents

Prostaglandin E2 (PGE2) is a bioactive lipid that elicits a wide range of biological effects associated with inflammation and cancer. Recently, Shin et. al found that sufuretin (61) has anti-inflammatory properties, as it reduces the production of nitric oxide (NO) and PGE2 induced by lipopolysaccharide (LPS). Encouraged by these results, they synthesised 6-hydroxy- and 6-methoxy-coumaranone analogues and evaluated for their inhibition of NO and PGE2 productions in LPS-induced RAW 267.4 cells. In general, it was found that C-6 hydroxy-substituted aurones (63) were the more potent inhibitors of PGE2 production, while C-6 methoxy substituted aurones (64) were the more potent inhibitors of NO production (Fig. 21) [71].

Chemo-preventive agents are generally used to reduce, delay or reverse carcinogenesis, mainly by decreasing the metabolic enzymes responsible for generating reactive species and interfering with normal cellular processes. These compounds exert their protective effects by inducing phase I and phase II xenobiotic metabolizing enzymes (detoxifying enzymes). Reduction of electrophilic quinones by enzyme quinone reductase (QR), also known as quinone oxidoreductase is an important detoxification pathway, which converts quinones to hydroquinones and prevents oxidative cellular damages. Thus, QR is an imperative biomarker in the chemoprevention of cancer [74]. A number of related natural chemopreventive agents have been previously reported. A bioassayguided fractionation by Jang and co-workers led to the isolation of six potential cancer chemo-preventive constituents from the seeds of Dipteryx odorata (tonka bean). Among these, two of the compounds were 6-hydroxyaurones analogues sulfuretin (61) and 6,40 -dihydroxy-30 -methoxyaurone (65). The QR activity of aurones

3.16. Nitric oxide inhibitors Bioassay-guided fractionation and chemical investigation of the ethanol extract of Toxicodendron vernicifluum bark by Kim

Fig. 21. Natural aurone sulfuretin having broad spectrum of anticancer activity.

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in Hepa 1c1c7 mouse hepatoma cells and mouse mammary organ culture (MMOC) bioassays confirmed these as potential cancer chemo-preventive agents [75]. NUS medicinal chemists also sought to exploit the quinone oxidoreductase 1 (NQO1) induction activity of aurones, as the NQO1 potential of benzofuran had not been fully exploited. They found that 4,6-dimethoxy (66) and 5hydroxyaurones (67) induced NQO1 by activating both the aryl hydrocarbon receptor-xenobiotic-response element AhR/XRE and the nuclear factor-erythroid related factor 2 (Nrf2) pathways. They proposed that the exocyclic location of the olefinic double bond at the benzofuranone ring is responsible for the electrophilic reactivity of the Michael acceptor moiety which increases NQO1 induction activity (Fig. 22) [76].

Fig. 23. Structural features essential for the antioxidant activity of aurones.

3.18. Antioxidant agents Free radicals are highly reactive chemical species that are hazardous to the body because they damage all major components of the cells, including DNA, proteins, and cell membranes. The damage to cells, particularly to DNA, caused by free radicals may play a role in the development of cancer and other health conditions. Thus, antioxidants play not only a chemopreventive role, but also act as potential anticancer substances [77]. Aurones have also been reported to possess high antioxidant potential. Results of an antioxidant assay indicated that the presence of a dimethylamino group (68) at the benzylidene ring increases the antioxidant properties, whereas the presence of a chloro group at the same position decreases its activity. Furthermore, the presence of a hydroxyl group at the aurone ring is favourable for antioxidant activity [78]. Dihydrofurano aurone (DHFA) (69) is a bio-transformed product of xanthohumol isolated from spent hops. The metabolite DHFA was obtained by transformation of xanthohumol in an Aspergillus ochraceus AM465 fungal culture. The DPPH radical scavenging activity of the aurone analogue showed promising antioxidant activity, with an IC50 value of 0.23 mM due to a 30 ,40 -catechol bioactive fragment in the molecule. The other structural elements contributing to this high ability to scavenge free radicals include a conjugated a,b-double bond and a free hydroxyl group at C-0 , which occur in chalcones. Its in-vitro cytotoxic activity against the breast cancer line (MCF-7) showed moderate antiproliferative effects (IC50 48.31 mM) (Fig. 23) [79]. Two hepatoprotective flavonoids, anastatin A (70) and anastatin B (71), a benzofuran analogues with an S-configuration were isolated from Anastatica hierochuntica. Pan et al. reported the total synthesis of these flavonoids as well as their aurone analogues (72e75). The antioxidant activities of these flavonoids and the key intermediates were evaluated by a ferric-reducing antioxidant power (FRAP) assay, and cytotoxicity was evaluated on pheochromocytoma cells (PC12). In general, SAR showed that the aurone analogues of anastatins (72 and 73) were more potent antioxidants than their respective flavone analogues. Also, an a,b-unsaturated

extended double bond (75) reduced the antioxidant potential of aurone analogues. Moreover, the most potent aurone derivative protected the PC12 cell against H2O2 oxidation by 85.94% at 10 mМ (Fig. 24) [80]. 3.19. Miscellaneous agents In recent years, hybridization of bioactive pharmacophores has

Fig. 24. Anastatin analogues of aurone.

Fig. 22. Sulfuretin analogues as chemopreventive agents.

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Fig. 25. Hybrid aurone-chromones/coumarins.

become a very interesting tool in drug discovery, which has led to the development of highly potent medicinal compounds. Towards this end, Zwergel et al. reported on the hybridization of a bioactive anticancer benzofuranone moiety of aureusidine (76) with chromone (77) and coumarin (78) nuclei. The designed molecules (79e81) were tested against the K562 human leukemia cells to evaluate their effects on the cell cycle and apoptosis. These hybrid molecules successfully arrested the cell cycles in the G1 and S phases. SAR analysis revealed that substitution at the chromone ring had no effects on activity, whereas replacement of benzofuranone (80) by naphthofuranone (81) led to a more effective agent against apoptosis (Fig. 25) [81]. In previous studies, many attempts were made to introduce the trifluoromethyl group into the various bioactive molecules in order to improve their bioactivity, stability and lipophilicity. Towards this end, Zheng et al. studied the trifluoromethylated flavone (82) derivatives against the human gastric adenocarcinoma cell line (SGC7901). The results of in-vitro cytotoxicity were very promising. Encouraged by these results, they explored trifluoromethylated aurones (83) as anticancer agents. The results showed that an allyloxy derivative of trifluoromethylated aurones (84) had strong activity against the SGC-7901 [82]. Finally, these compounds were also evaluated against the leucocythemia (HL-60) and colorectal adenocarcinoma (HT-29). A single crystal X-ray analysis was also carried out. Detailed configuration analyses revealed that (Z)-trifluoromethylated aurone derivatives had potential anticancer activities (Fig. 26) [83]. 5-Hydroxy aurones are the least explored aurone analogues. Therefore, Cheng et al. investigated these 5-hydroxyl derivatives of aurones as anti-angiogenesis agents against the proliferation of endothelial cells. SAR studies showed that 40 -substitution at the

phenyl ring with an N,N-diethyl group and hydroxyl group at the 5 position is favourable for the antiproliferation of human umbilical vein endothelial cells (HUVEC). The two most potent N-ethylated compounds (84 and 85) were further evaluated using a twodimensioned Matrigel assay. The results showed that these compounds block in vitro angiogenesis by inhibiting endothelial cell migration and tube formation [84]. Parate et al. studied theanticancer potential of 5-hydroxyaurone derivatives against human umbilical vein endothelial cells (HUVEC). An N,N-Diethylbenzylidene aurone derivative (86) emerged as the most potent anticancer agent, with an IC50 value of 0.23 mM against HUVEC. An attempt has also been made by them to correlate their anticancer activity with the physicochemical descriptors through QSAR studies [85]. Demirayak et al. reported on the synthesis of some oxyphenylethanone derivatives of aurones. The anti-cancer activity of these compounds was explored by the NationalCancer Institute (NCI), USA against 60 human tumour cell lines. Results of anticancer activity showed that the introduction of an oxyphenylethanone moiety at the benzylidene ring demonstrated very good effects on its biological activity. A 5-choloroaurone analogue (87) emerged as the most effective anticancer agent, exhibiting the highest antitumor activity on a leukemia cancer type, with a growth percentage of 49.47%. Shifting the oxyphenylethanone moiety from the benzylidene ring the aurone nucleus also yielded a compound 88 exhibiting high antitumor activity against non-small lung cancer cell lines [86,87]. Elhadi et al. synthesised a new series of 5,7-dichloroaurone derivatives using a different substitution at the benzylidene ring. X-ray crystallography confirmed the molecular structure of aurones as a Z-isomeric form. In general, SAR noted that ortho substituted benzylidene derivatives, were found to be more potent anticancer

Fig. 26. Trifluoromethyl aurone derivatives as potent anticancer agents.

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as compared with the para-substituted derivatives. Two compounds para-methyl (89) and ortho-chloro (90) derivative showed excellent anticancer activities with IC50 values of 20 mM (K-562 cell line) and 23 mM (MCF-7 and K562 cancer cells) [88]. Jing-gong et al. isolated a new aurone glycoside, named (Z)-7, 40 -dimethoxy-6hydroxyl-aurone-4-O-b-glucopyranoside (91), from the roots and rhizomes of Veratrum dahuricum (Turcz.) Loes. f. through column chromatography. In-vitro cytotoxicity evaluation against HepG-2, MCF7 and A549 cell lines revealed that this aurone glycoside has moderate activity, with IC50 values of 121.9, 110.5 and 146.3 mmol/L,

respectively [89]. Two aurone derivatives viz. leptosin (92) and leptosidine (a glycoside) (93), were isolated along with other flavonoids, from a bioactive guided fractionation of an ethyl acetate fraction of Coreopsis lanceolata flowers by column chromatography. Evaluation of the antileukemic activity of these aurone analogues indicated their weak inhibitory effects as compared to other flavonoids present in the plant [90]. Sudhakar et al. reported on the facile synthesis of aurones using amberlyst-15 as a reusable catalyst. The in-vitro cytotoxic activities of the synthesised compounds against two metastatic breast cancer

Fig. 27. Miscellaneous anticancer agents.

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cell lines, MDA-MB-468 and MCF-7, were assayed by MTT assay. The antiproliferative activity of these compounds was found to be higher than the standard drug 5-fluorouracil. To further understand the mechanism of their antiproliferative action on cell cycle progression, flow-activated cell sorting analysis was carried out. Results indicated that a compound having para-methyl (94) benzylidene caused cell cycle arrest in the G0/G1 phase [91]. Alsaif et al. prepared a series of aurone derivatives and evaluated their antiproliferative activities against the human cancer cell lines A549 (lung), BT20 (breast) and MCF7 (breast), as well as exploring antimetastasis activity against A549. Most of the compounds showed remarkable inhibition at the micromolar level. Those compounds where the phenyl ring in the benzylidene fragments was replaced by five-membered heteroaryl rings (95 and 96) showed significant anticancer activities [92]. Uesawa et al. studied seventeen aurone derivatives against three human oral squamous cell carcinoma cell lines and three oral mesenchymal cells by subjecting them to QSAR. Among them, (Z)-2[(4-hydroxyphenyl)methylene]-3(2H)-benzofuranone (97) emerged with the highest tumour specificity (TS) value, comparable to that of doxorubicin and higher than 5-FU [93]. Recently, Mouineer et al. also reported on the anticancer NCI screenings of a series of benzo[b]thiophene analogues (98). In the one dose assay, all the compounds showed weak anticancer activities; however, cyclization into their tricyclic analogues resulted in a dramatic increase in activity [94]. Li et al. explored the synthesis of a series of bromoaurone derivatives, evaluating them by using the MTT method on HT-29, K562, and HepG2 cell lines. The compound 5-bromo-2-(4nitrobenzylidene)benzofuran-3(2H)-one (99) demonstrated good antitumor activity against the K562 cells, with an IC50 of 0.37 mM [95]. Recently, ferrocenyl-aurones ((Z)-R-2-(ferrocene-ylidene) benzofuran-3-ones) were synthesised and all compounds were evaluated for their cytotoxic effects on the cancer cell line (B16 murine melanoma) and for their morphological effects on endothelial cells (EAhy 926). Some interesting SAR were disclosed; of all the compounds, the halogen-substituted aurones (100) showed the best cytotoxic activity, with an IC50 12 mM (Fig. 27) [96]. 4. Conclusion Since 1998, aurones have emerged as the most promising anticancer lead molecules. Aurones have been associated with several modes of actions, including DNA strand scission, topoisomerase, tubulin, cyclin dependent kinase, ATP binding cassette, tyrosinase, sphingosine kinase, TNFa, PGE2, and nitric oxide, which clearly shows the therapeutic efficacy and specifity of aurones against different types of cancers. However, not a single aurone based molecule is currently in clinical use as an anticancer agent, in spite of the excellent drug-likeness, in-vitro and in-vivo results that have been demonstrated by the aurone analogues. Thus, the smallmolecule aurone holds great promise for the development of novel anticancer agents either as a stand-alone agent or as an adjuvant that potentiates other anticancer drugs. Conflicts of interest The authors confirm that this article content has no conflicts of interest. Acknowledgements The authors would like to express their gratitude to King Khalid University, Abha, Saudi Arabia for providing administrative and technical support.

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Abbreviations ABC ABCG ATP CASP CDK DNA DMA DDR FDA FRAP GSH HDAC HTS HOPNO HNE HIF-1 ISOA IC50 LPS MX MDR MMOC NCI NO Pgp PTP PGE2 QR SAR SK TNF- a Ty UCC VEGF

ATP-Binding Cassette ATP-Binding Cassette sub-family G Adenosine Triphosphate Cytohesin-Associated Scaffolding Protein Cyclin-Dependent Kinase Deoxyribonucleic Acid Dimethoxyaurones Discoidin Domain Receptor Food and Drug Administration Ferric Reducing Antioxidant Power Glutathione Histone Deacetylase High Throughput Screening 2-Hydroxypyridine N-oxide Human Neutrophil Elastase Hypoxia-Inducible Factor 1 40 ,6-Dihydroxy-4-methoxyisoaurone Half Maximal Inhibitory Concentration Lipopolysaccharide Mitoxantrone Multidrug Resistance Mammary Organ Culture National Cancer Institute, US Nitric oxide P-glycoprotein Permeability Transition Pore Prostaglandin E2 Quinone Reductase StructureeActivity Relationship Sphingosine Kinases Tumour Necrosis Factor-alpha Tyrosinases Urothelial Cell Carcinomas Vascular endothelial growth factor

References [1] I.J. Fidler, Molecular biology of cancer: invasion and metastasis, in: V.T. De Vita Jr., S. Hellman, S.A. Rosenberg (Eds.), Cancer: Principles and Practice of Oncology, fifth ed., Lippincott-Raven, New York, 1997, pp. 135e152. [2] WHO Fact-Sheets. http://www.who.int/news-room/fact-sheets/detail/cancer (Accessed 12 October 2018). [3] American Cancer Society, Cancer Facts and Figures 2018, American Cancer Society, Atlanta, Ga, 2018. https://www.cancer.org/research/cancer-factsstatistics/all-cancer-facts-figures/cancer-facts-figures-2018.html. (Accessed 12 October 2018). [4] P. Vineis, C.P. Wild, Global cancer patterns: causes and prevention, Lancet 8 (2014) 549e557. [5] K.D. Miller, R.L. Siegel, C.C. Lin, A.B. Mariotto, J.L. Kramer, J.H. Rowland, K.D. Stein, R. Alteri, A. Jemal, Cancer treatment and survivorship statistics, 2016, CA Canc, J. Clin. 62 (2016) 348. [6] G. Housman, S. Byler, S. Heerboth, K. Lapinska, M. Longacre, N. Snyder, S. Sarkar, Drug resistance in cancer: an overview, Cancers 6 (2014) 1769e1792. [7] X. Ke, L. Shen, Molecular targeted therapy of cancer: the progress and future prospect, Front. Lab. Med. 1 (2017) 69e75. [8] Y.T. Lee, Y.J. Tan, C.E. Oon, Molecular targeted therapy: treating cancer with specificity, Eur. J. Pharmacol. 834 (2018) 188e196. [9] S. Hoelder, P.A. Clarke, P. Workman, Discovery of small molecule cancer drugs: successes, challenges and opportunities, Mol. Oncol. 6 (2012) 155e176. [10] D.J. Newman, G.M. Cragg, Natural products as sources of new drugs from 1981 to 2014, J. Nat. Prod. 79 (2016) 629e661. [11] G.M. Cragg, J.M. Pezzuto, Natural products as a vital source for the discovery of cancer chemotherapeutic and chemopreventive agents, Med. Princ. Pract. 25 (2016) 41e59. [12] A. Agbarya, N. Ruimi, R. Epelbaum, E. Ben-Arye, J. Mahajna, Natural products as potential cancer therapy enhancers: a preclinical update, SAGE Open Med 2 (2014), 2050312114546924. [13] B. Boucherle, M. Peuchmaur, A. Boumendjel, R. Haudecoeur, Occurrences, biosynthesis and properties of aurones as high-end evolutionary products, Phytochemistry 142 (2017) 92e111.

430

A. Alsayari et al. / European Journal of Medicinal Chemistry 166 (2019) 417e431

[14] T.A. Geissman, C.D. Heaton, Anthochlor pigments. IV. The pigments of Coreopsis grandiflora, Nutt. J. Am. Chem. Soc. 65 (1943) 677e683. [15] T. Nakayama, K. Yonekura-Sakakibara, T. Sato, S. Kikuchi, Y. Fukui, M. FukuchiMitzutani, T. Ueda, M. Nakao, Y. Tanaka, T. Kusumi, T. Nishino, Aureusidin synthase: a polyphenol oxidase homolog responsible for flower coloration, Science 290 (2000) 1163e1166. [16] A.N. Panche, A.D. Diwan, S.R. Chandra, Flavonoids: an overview, J. Nutr. Sci. 5 (2016) e47. [17] G.S. Hassan, H.H. Georgey, R.F. George, E.R. Mohamed, Aurones and furoaurones: biological activities and synthesis, Bull. Fac. Pharm. Cairo Univ. 56 (2018) 121e127. [18] A. Boumendjel, Aurones: a subclass of flavones with promising biological potential, Curr. Med. Chem. 10 (2003) 1241e1253. [19] G.S. Hassan, S.M. Abou-Seri, G. Kamel, M.M. Ali, Celecoxib analogs bearing benzofuran moiety as cyclooxygenase-2 inhibitors: design, synthesis and evaluation as potential anti-inflammatory agents, Eur. J. Med. Chem. 76 (2014) 482e493. [20] H.H. Jardosh, M.P. Patel, Antimicrobial and antioxidant evaluation of new quinolone based aurone analogs, Arab. J. Chem. 10 (2017) 3781e3791.
is, M. Machado, J. Gut, [21] M.P. Carrasco, A.S. Newton, L. Gonçalves, A. Go €nscheid, R.C. Guedes, D.J.V.A. dos Santos, P.J. Rosenthal, F. Nogueira, T. Ha R. Moreira, Probing the aurone scaffold against Plasmodium falciparum: design, synthesis and antimalarial activity, Eur. J. Med. Chem. 80 (2014) 523e534. [22] M. Roussaki, S.C. Lima, A.-M. Kypreou, P. Kefalas, A. Cordeiro da Silva, A. Detsi, Aurones: a promising heterocyclic scaffold for the development of potent antileishmanial agents, Int, J. Med. Chem. (2012) 1e8. [23] R. Sheng, Y. Xu, C. Hu, J. Zhang, X. Lin, J. Li, B. Yang, Q. He, Y. Hu, Design, synthesis and AChE inhibitory activity of indanone and aurone derivatives, Eur. J. Med. Chem. 44 (2009) 7e17. [24] Y. Li, X. Qiang, L. Luo, X. Yang, G. Xiao, Q. Liu, J. Ai, Z. Tan, Y. Deng, Aurone Mannich base derivatives as promising multifunctional agents with acetylcholinesterase inhibition, anti-b-amyloid aggragation and neuroprotective properties for the treatment of Alzheimer's disease, Eur. J. Med. Chem. 27 (2017) 762e775. [25] M.K. Chahar, N. Sharma, M.P. Dobhal, Y.C. Joshi, Flavonoids: a versatile source of anticancer drugs, Pharm. Rev. 5 (2011) 1e12. [26] L. Huang, M.E. Wall, M.C. Wani, H. Navarro, T. Santisuk, V. Reutrakul, E.K. Seo, N.R. Farnsworth, A.D. Kinghorn, New compounds with DNA strand-scission activity from the combined leaf and stem of Uvaria hamiltonii, J. Nat. Prod. 61 (1998) 446e450. [27] A.L. Bodley, L.F. Liu, Topoisomerases as novel targets for cancer chemotherapy, Bio Technology 6 (1998) 1315e1319. [28] K. Suzuki, S. Yahara, K. Maehata, M. Uyeda, Isoaurostatin, a novel topoisomerase inhibitor produced by Thermomonospora alba, J. Nat. Prod. 64 (2001) 204e207. [29] E. Rizzi, S. Dallavalle, L. Merlini, G.L. Beretta, G. Pratesi, F. Zunino, A new synthesis of isoaurones: cytotoxic activity of compounds related to the alleged structure of isoaurostatin, Bioorg. Med. Chem. Lett 15 (2005) 4313e4316. [30] G. Priyadarshani, A. Nayak, S.M. Amrutkar, S. Das, S.K. Guchhait, C.N. Kundu, U.C. Banerjee, Scaffold-hopping of aurones: 2-Arylideneimidazo[1,2-a]pyridinones as topoisomerase IIa-inhibiting anticancer agents, ACS Med. Chem. Lett. 20 (2016) 1056e1061. [31] U. Asghar, A.K. Witkiewicz, N.C. Turner, E.S. Knudsen, The history and future of targeting cyclin-dependent kinases in cancer therapy, Nat. Rev. Drug Discov. 14 (2015) 130e146. [32] G. Kaur, M. Stetler-Stevenson, S. Sebers, P. Worland, H. Sedlacek, C. Myers, J. Czech, R. Naik, E. Sausville, Growth inhibition with reversible cell cycle arrest of carcinoma cells by flavone L86-8275, J. Natl. Cancer Inst. 84 (1992) 1736e1740. [33] P.H. Wiernik, Alvocidib (flavopiridol) for the treatment of chronic lymphocytic leukemia, Expert Opin. Investig. Drugs 25 (2016) 729e734. [34] J. Schoepfer, H. Fretz, B. Chaudhuri, L. Muller, E. Seeber, L. Meijer, O. Lozach, E. Vangrevelinghe, P. Furet, Structure-based design and synthesis of 2benzylidene-benzofuran-3-ones as flavopiridol mimics, J. Med. Chem. 45 (2002) 1741e1747. [35] W. Huang, M.Z. Liu, Y. Li, Y. Tan, G.F. Yang, Design, syntheses, and antitumor activity of novel chromone and aurone derivatives, Bioorg. Med. Chem. 15 (2007) 5191e5197. [36] F.A. Ragab, T.A.A. Yahya, M.M. El-Naa, R.K. Arafa, Design, synthesis and structure-activity relationship of novel semi-synthetic flavonoids as antiproliferative agents, Eur. J. Med. Chem. 82 (2014) 506e520. [37] G.S. Hassan, H.H. Georgey, R.F. George, E.R. Mohammed, Construction of some cytotoxic agents with aurone and furoaurone scaffolds, Future Med. Chem. 10 (2018) 27e52. [38] M.C. Lin, H.H. Ho, G.R. Pettit, E. Hamel, Antimitotic natural products combretastatin A-4 and combretastatin A-2: studies on the mechanism of their inhibition of the binding of colchicine to tubulin, Biochemistry 28 (1989) 6984e6991. [39] N.J. Lawrence, D. Rennison, A.T. McGown, J.A. Hadfield, The total synthesis of an aurone isolated from Uvaria hamiltonii: aurones and flavones as anticancer agents, Bioorg. Med. Chem. Lett 13 (2003) 3759e3763. [40] R.C. Mishra, P. Karna, S.R. Gundala, V. Pannu, R.A. Stanton, K.K. Gupta, M. Robinson, M. Lopus, L. Wilson, M. Henary, R. Aneja, Second generation benzofuranone ring substituted noscapine analogs: synthesis and biological

evaluation, Biochem. Pharmacol. 82 (2011) 110e121. [41] Y.L. Sun, A. Patel, P. Kumar, Z.S. Chen, Role of ABC transporters in cancer chemotherapy, Chin, J. Canc. 31 (2012) 51e57. [42] A. Boumendjel, C. Beney, N. Deka, A.M. Mariotte, M.A. Lawson, D. Trompier, H. Baubichon-Cortay, A. Di Pietro, 4-Hydroxy-6-methoxyaurones with highaffinity binding to cytosolic domain of P-glycoprotein, Chem. Pharm. Bull. 50 (2002) 854e856. [43] M. Hadjeri, M. Barbier, X. Ronot, A.M. Mariotte, A. Boumendjel, J. Boutonnat, Modulation of P-glycoprotein-mediated multidrug resistance by flavonoid derivatives and analogues, J. Med. Chem. 46 (2003) 2125e2131.
, A. Boumendjel, M. Ehrlichova
, J. Kova
r, I. Gut, Modulation of [44] R. V
aclavíkova paclitaxel transport by flavonoid derivatives in human breast cancer cells. Is there a correlation between binding affinity to NBD of P-gp and modulation of transport? Bioorg. Med. Chem. 14 (2006) 4519e4525.
, M. Ehrlichov
[45] R. V
aclavíkov
a, E. Kondrova a, A. Boumendjel, J. Kov
ar, P. Stopka, P. Soucek, I. Gut, The effect of flavonoid derivatives on doxorubicin transport and metabolism, Bioorg. Med. Chem. 16 (2008) 2034e2042. [46] E. Baiceanu, K.A. Nguyen, L. Gonzalez-Lobato, R. Nasr, H. Baubichon-Cortay, F. Loghin, M. Le Borgne, L. Chow, A. Boumendjel, M. Peuchmaur, P. Falson, 2Indolylmethylenebenzofuranones as first effective inhibitors of ABCC2, Eur. J. Med. Chem. 122 (2016) 408e418.
re s, R. Nasr, M. Zarioh, F. Lecerf-Schmidt, A. Di Pietro, H. Baubichon[47] B. Pe Cortay, A. Boumendjel, Ferrocene-embedded flavonoids targeting the Achilles heel of multidrug-resistant cancer cells through collateral sensitivity, Eur. J. Med. Chem. 130 (2017) 346e353. [48] H.M. Sim, C.P. Wu, S.V. Ambudkar, M.L. Go, In vitro and in vivo modulation of ABCG2 by functionalized aurones and structurally related analogs, Biochem. Pharmacol. 82 (2011) 1562e1571. [49] H.M. Sim, K.Y. Loh, W.K. Yeo, C.Y. Lee, M.L. Go, Aurones as modulators of ABCG2 and ABCB1: synthesis and structureeactivity relationships, ChemMedChem 6 (2011) 713e724. [50] H. Harada, Hypoxia-inducible factor 1emediated characteristic features of cancer cells for tumor radioresistance, J. Radiat. Res. 57 (2016) i99ei105. [51] C. Mi, J. Ma, H. Shi, J. Li, F. Wang, J.J. Lee, X. Jin, 40 ,6-dihydroxy-4methoxyisoaurone inhibits the HIF-1a pathway through inhibition of Akt/ mTOR/p70S6K/4E-BP1 phosphorylation, J. Pharmacol. Sci. 125 (2014) 193e201. [52] N.T. Dat, X. Jin, Y.S. Hong, J.J. Lee, An isoaurone and other constituents from Trichosanthes kirilowii seeds inhibit hypoxia-inducible factor-1 and nuclear factor-kappaB, J. Nat. Prod. 73 (2010) 1167e1169.
, [53] B. Gerby, A. Boumendjel, M. Blanc, P.P. Bringuier, P. Champelovier, A. Fortune X. Ronot, J. Boutonnat, 2-Arylidenedihydroindole-3-ones: design, synthesis, and biological activity on bladder carcinoma cell lines, Bioorg. Med. Chem. Lett 17 (2007) 208e213. [54] K.J. French, J.J. Upson, S.N. Keller, Y. Zhuang, J.K. Yun, C.D. Smith, Antitumor activity of sphingosine kinase inhibitors, J. Pharmacol. Exp.Therap. 38 (2006) 596e603. [55] K.J. French, R.S. Schrecengost, B.D. Lee, Y. Zhuang, S.N. Smith, J.L. Eberly, J.K. Yun, C.D. Smith, Discovery and evaluation of inhibitors of human sphingosine kinase 1, Cancer Res. 63 (2003) 5962e5969. [56] R.R. Valiathan, M. Marco, B. Leitinger, C.G. Kleer, R. Fridman, Discoidin domain receptor tyrosine kinases: new players in cancer progression, Can. Meta. Rev. 31 (2012) 295e321. [57] H.J. Zhu, Y.M. Yan, Z.C. Tu, J.F. Luo, R. Liang, T.H. Yang, Y.X. Cheng, S.M. Wang, Compounds from Polyphaga plancyi and their inhibitory activities against JAK3 and DDR1 kinases, Fitoterapia 114 (2016) 163e167.
, R. Haudecoeur, H. Jamet, C. Belle, A. Boumendjel, [58] E. Buitrago, R. Hardre
glier, Are human tyrosinase and related proteins suitable L. Bubacco, M. Re targets for melanoma therapy? Curr. Top. Med. Chem. 16 (2016) 3033e3047. [59] S. Okombi, D. Rival, S. Bonnet, A.M. Mariotte, E. Perrier, A. Boumendjel, Discovery of benzylidenebenzofuran-3(2H)-one (aurones) as inhibitors of tyrosinase derived from human melanocytes, J. Med. Chem. 49 (2006) 329e333. [60] C. Dubois, R. Haudecoeur, M. Orio, C. Belle, C. Bochot, A. Boumendjel, R. Hardre, Jamet, M. Reglier, Versatile effects of aurone structure on mushroom Tyrosinase activity, Chembiochem 13 (2012) 559e565. [61] S. Ropero, M. Esteller, The role of histone deacetylases (HDACs) in human cancer, Mol. Oncol. 1 (2007) 19e25. [62] K. Manjulatha, S. Srinivas, N. Mulakayala, D. Rambabu, M. Prabhakar, K.M. Arunasree, M. Alvala, M.V.B. Rao, M. Pal, Ethylenediamine diacetate (EDDA) mediated synthesis of aurones under ultrasound: their evaluation as inhibitors of SIRT1, Bioorg. Med. Chem. Lett 22 (2012) 6160e6165. ~ es-Pires, [63] V. Zwick, A.O. Chatzivasileiou, N. Deschamps, M. Roussaki, C.A. Simo A. Nurisso, I. Denis, C. Blanquart, N. Martinet, P.A. Carrupt, A. Detsi, M. Cuendet, Aurones as histone deacetylase inhibitors: identification of key features, Bioorg. Med. Chem. Lett 24 (2014) 5497e5501. [64] Y. Itoh, M. Suzuki, T. Matsui, Y. Ota, Z. Hui, K. Tsubaki, T. Suzuki, False HDAC inhibition by aurone compound, Chem. Pharm. Bull. 64 (2016) 1124e1128. [65] G. Moroy, A.J. Alix, J. Sapi, W. Hornebeck, E. Bourguet, Neutrophil elastase as a target in lung cancer, Antican. Agen. Med. Chem. 12 (2012) 565e579. [66] S.D. Lucas, M.P. Carrasco, L.M. Gonçalves, R. Moreira, R.C. Guedes, Discovery of C-shaped aurone human neutrophil elastase inhibitors, Med. Chem. Commun. 6 (2015) 1508e1512. [67] S. Wen, D. Zhu, P. Huang, Targeting cancer cell mitochondria as a therapeutic approach, Future Med. Chem. 5 (2013) 53e67.

A. Alsayari et al. / European Journal of Medicinal Chemistry 166 (2019) 417e431 [68] H. Chen, X.D. Qi, P. Qiu, A novel synthesis of aurones: their in vitro anticancer activity against breast cancer cell lines and effect on cell cycle, apoptosis and mitochondrial membrane potential, Bangladesh J. Pharmacol. 9 (2014) 501e510. [69] I. Zidi, S. Mestiri, A. Bartegi, N.B. Amor, TNF-alpha and its inhibitors in cancer, Med, Oncol. 27 (2010) 185e198. [70] B.P. Bandgar, S.A. Patil, B.L. Korbad, S.C. Biradar, S.N. Nile, C.N. Khobragade, Synthesis and biological evaluation of a novel series of 2,2bisaminomethylated aurone analogues as anti-inflammatory and antimicrobial agents, Eur. J. Med. Chem. 45 (2010) 3223e3227. [71] S.Y. Shin, M.C. Shin, J.S. Shin, K.T. Lee, Y.S. Lee, Synthesis of aurones and their inhibitory effects on nitric oxide and PGE2 productions in LPS-induced RAW 264.7 cells, Bioorg. Med. Chem. Lett 21 (2011) 4520e4523. [72] K.H. Kim, E. Moon, S.U. Choi, C. Pang, S.Y. Kim, K.R. Lee, Identification of cytotoxic and anti-inflammatory constituents from the bark of Toxicodendron vernicifluum (Stokes) F.A. Barkley, J. Ethnopharmacol. 13 (2015) 231e237. [73] S. Poudel, J. Song, E.J. Jin, K. Song, Sulfuretin-induced miR-30C selectively downregulates cyclin D1 and D2 and triggers cell death in human cancer cell lines, Biochem. Biophys. Res. Commun. 431 (2013) 572e578. [74] M. Cuendet, C.P. Oteham, R.C. Moon, J.M. Pezzuto, Quinone reductase induction as a biomarker for cancer chemoprevention, J. Nat. Prod. 69 (2006) 460e463. [75] D.S. Jang, E.J. Park, M.E. Hawthorne, J.S. Vigo, J.G. Graham, F. Cabieses, B.D. Santarsiero, A.D. Mesecar, H.H. Fong, R.G. Mehta, J.M. Pezzuto, A.D. Kinghorn, Potential cancer chemopreventive constituents of the seeds of Dipteryx odorata (tonka bean), J. Nat. Prod. 66 (2003) 583e587. [76] C.Y. Lee, E.H. Chew, M.L. Go, Functionalized aurones as inducers of NAD(P)H: quinone oxidoreductase 1 that activate AhR/XRE and Nrf2/ARE signaling pathways: synthesis, evaluation and SAR, Eur. J. Med. Chem. 45 (2010) 2957e2971. [77] M. Valko, D. Leibfritz, J. Moncol, Free radicals and antioxidants in normal physiological functions and human disease, Int. J. Biochem. Cell Biol. 39 (2007) 44e84. [78] T. Narsinghani, M.C. Sharma, S. Bhargav, Synthesis, docking studies and antioxidant activity of some chalcone and aurone derivatives, Med. Chem. Res. 22 (2013) 4059e4068.
ska, B. Filip-Psurska, J. Wietrzyk, J. Popłon
ski, [79] T. Tronina, A. Bartman E. Huszcza, Fungal metabolites of xanthohumol with potent antiproliferative activity on human cancer cell lines in vitro, Bioorg. Med. Chem. 21 (2013) 2001e2006. [80] G. Pan, X. Li, L. Zhao, M. Wu, C. Su, X. Li, Y. Zhang, P. Yu, Y. Teng, K. Lu, Synthesis and anti-oxidant activity evaluation of (±)-Anastatins A, B and their analogs, Eur. J. Med. Chem. 138 (2017) 577e589. [81] C. Zwergel, S. Valente, A. Salvato, Z. Xu, O. Talhi, A. Mai, A. Silva, L. Altucci, G. Kirsch, Novel benzofuran-chromone and ecoumarin derivatives: synthesis and biological activity in K562 human leukemia cells, Med. Chem. Commun. 4 (2013) 1571e1579. [82] X. Zheng, J.G. Cao, W.D. Meng, F.L. Qing, Synthesis and anticancer effect of Bring trifluoromethylated flavonoids, Bioorg. Med. Chem. Lett 13 (2003)

431

3423e3427. [83] X. Zheng, H. Wang, Y.M. Liu, X. Yao, M. Tong, Y.H. Wang, D.F. Liao, Synthesis, characterization, and anticancer effect of trifluoromethylated aurone derivatives, J. Heterocycl. Chem. 52 (2015) 296e301. [84] H. Cheng, L. Zhang, Y. Liu, S. Chen, H. Cheng, X. Lu, Z. Zheng, G.C. Zhou, Design, synthesis and discovery of 5-hydroxyaurone derivatives as growth inhibitors against HUVEC and some cancer cell lines, Eur. J. Med. Chem. 45 (2010) 5950e5957. [85] A. Parate, R. Sharma, I. Maheshwari, Structural indents for 5-hydroxyaurone derivatives as potent anticancer agents against HUVEC cancer cell lines-kNN MFA approach, Der Pharm. Sin. 4 (2013) 121e129. [86] S. Demirayak, L. Yurttas, N. Gundogdu-Karaburun, A.C. Karaburun, I. Kayagil, Synthesis and anti-cancer activity evaluation of new aurone derivatives, J. Enzym. Inhib. Med. Chem. 30 (2015) 16e25. [87] S. Demirayak, L. Yurttas, A.C. Karaburun, N. Gundogdu-Karaburun, I. Kayagil, Synthesis and antiproliferative activity of 2-arylidene 6-(2-aryl-2-oxoethoxy) Benzofuran-3-one derivatives, Lett. Drug Des. Discov. 13 (2016). [88] A.A. Elhadi, H. Osman, M.A. Iqbal, S.K. Rajeswari, M.B.K. Ahamed, A.M.S.A. Majid, M.M. Rosli, I.A. Razak, A.S.A. Majid, Synthesis and structural elucidation of two new series of aurone derivatives as potent inhibitors against the proliferation of human cancer cells, Med. Chem. Res. 24 (2015) 3504e3515. [89] G.J. Gong, C.Y. Sheng, L. Jing, W.T. Xiao, L.S. Sha, C. Yue, A new aurone glycoside from Veratrum dahuricum (Turcz.), Loes. f. Acta Pharm. Sinica 50 (2015) 337e339. [90] A. Pardede, K. Mashita, M. Ninomiya, K. Tanaka, M. Koketsu, Flavonoid profile and antileukemic activity of Coreopsis lanceolata flowers, Bioorg. Med. Chem. Lett 26 (2016) 2784e2787. [91] H. Sudhakar, N. Mulakayala, Facile synthesis of aurones using amberlyst-15 as a reusable catalyst and their biological evaluation, Indian J. Adv. Chem. Sci. 4 (2016) 160e167. [92] G. Alsaif, N. Almosnid, I. Hawkins, Z. Taylor, D.L.T. Knott, S. Handy, E. Altman, Y. Gao, Evaluation of fourteen aurone derivatives as potential anti-cancer agents, Curr. Pharmaceut. Biotechnol. 18 (2017) 384e390. [93] Y. Uesawa, H. Sakagami, N. Ikezoe, K. Takao, H. Kagaya, Y. Sugita, Quantitative structureecytotoxicity relationship of aurones, Anticancer Res. 37 (2017) 6169e6176. [94] A.A. Mouineer, A.F. Zaher, A.A. El-malah, E.A. Sobh, Design, Synthesis, Antitumor activity, cell cycle analysis and ELISA assay for Cyclin Dependant Kinase-2 of a new (4-aryl-6-flouro-4H-benzo [4, 5]thieno[3, 2-b]pyran) derivatives, Mediter. J. Chem. 6 (2017) 165e179. [95] L. Lv, X. Zhang, J. Lv, Y. Zhou, W. Hu, P. Yu, H. Sun, Y. Teng, Design, synthesis and biological evaluation of the novel antitumor agent 5-bromobenzofuran3(2H)-one and its derivatives, Int. Conf. Appl. Biotech. (2012) 835e841. res, [96] J.P. Monserrat, K.N. Tiwari, L. Quentin, P. Pigeon, G. Jaouen, A. Vessie G.G. Chabot, E.A. Hillard, Ferrocenyl flavonoid-induced morphological modifications of endothelial cells and cytotoxicity against B16 murine melanoma cells, J. Organomet. Chem. 734 (2013) 78e85.