- Email: [email protected]
Synthesis and antitumor activity of bis(arylsulfonyl)dihydroimidazolinone derivatives
Journal Pre-proofs Synthesis and Antitumor Activity of Bis(arylsulfonyl)dihydroimidazolinone Derivatives Satapanawat Sittihan, Watthanachai Jumpathong, Pattarawut Sopha, Somsak Ruchirawat PII: DOI: Reference:
S0960-894X(19)30741-3 https://doi.org/10.1016/j.bmcl.2019.126776 BMCL 126776
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date: Revised Date: Accepted Date:
12 September 2019 20 October 2019 23 October 2019
Please cite this article as: Sittihan, S., Jumpathong, W., Sopha, P., Ruchirawat, S., Synthesis and Antitumor Activity of Bis(arylsulfonyl)dihydroimidazolinone Derivatives, Bioorganic & Medicinal Chemistry Letters (2019), doi: https://doi.org/10.1016/j.bmcl.2019.126776
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Elsevier Ltd. All rights reserved.
Synthesis and Antitumor Activity of Bis(arylsulfonyl)dihydroimidazolinone Derivatives Satapanawat Sittihana,*, Watthanachai Jumpathonga, Pattarawut Sophab, Somsak Ruchirawata,c aProgram
on Chemical Biology, Chulabhorn Graduate Institute, Center of Excellence on Environmental Health and Toxicology (EHT), Ministry of Education, 906 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand bProgram on Applied Biological Sciences, Chulabhorn Graduate Institute, Center of Excellence on Environmental Health and Toxicology (EHT), Ministry of Education, 906 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand cLaboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand *Corresponding author Satapanawat Sittihan: Program on Chemical Biology, Chulabhorn Graduate Institute, 906 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand; E-mail: [email protected] ABSTRACT A series of novel bis(arylsulfonyl)dihydroimidazolinones with different aryl substitution patterns were readily synthesized and evaluated for their antitumor activities. Some of the newly synthesized compounds exhibited cytotoxicity at micromolar range against multiple cancer cell lines, including A549, HepG2, HuCCA-1, and MOLT-3. The most potent analogue contained pentafluorobenzenesulfonyl groups, which could be chemically elaborated to serve as a potential pharmacophore. Keywords: Bis(arylsulfonyl)dihydroimidazolinones; Cytotoxicity; Antitumor Cancer is an alarming health problem that threatens both developing and developed countries regardless of differences in the population lifestyles [1]. Despite advances in chemotherapeutic development, a search for novel chemical agents with anticancer features has been a pressing issue [2, 3]. Furthermore, complication in treatment often arises from recurrent variability in responses as well as resistance to cancer chemotherapy from one patient to another [4-6]. Among a variety of candidate compounds with potential anticancer properties, diarylsulfonylureas have garnered much attention especially since the advent of sulofenur (LY186641, 1, Figure 1) [7]. In particular, 1 displayed a broad spectrum of activities in different human tumor xenografts and advanced into a clinical phase [7, 8]. However, further investigation of 1 was discontinued due to its high protein binding and limited dosing caused by the appearance of severe anemia, a side-effect likely from aniline-based metabolites [9]. Extensive structural modification led to the identification of less toxic ILX-295501 (2, formerly LY295501), which was principally metabolized by hydroxylation with negligible detection of aniline metabolites in animal models [9]. Effective against all tumor types tested in human tumor cloning assay, 2 set the maximum tolerated doses for subsequent clinical studies at 1,000 mg/m2/day for 3-4 weeks with no hematological toxicities commonly observed with 1 [10, 11]. The cytotoxic mechanism of diarylsulfonylureas is still unclear. Mitochondrial localization of these compounds with subsequent morphological changes and the uncoupling of mitochondrial oxidative phosphorylation, which resulted in low cellular ATP level, may be responsible for the observed antitumor activities [12, 13].
Figure 1. Examples of antitumor sulfonylureas (1-8) and novel bis(arylsulfonyl)dihydroimidazolinone derivatives (9). Continuous investigation into structural variation led to the discovery of cyclic arylsulfonylureas as a promising new class of antitumor agents. In particular, 4-phenyl-1-(5indanyl)sulfonylimidazolidinone (3) exhibited much more potency than 1 [14]. Perturbation in molecular structure revealed the importance of imidazolidinone core with regard to functional group, planarity, steric and conformational requirement. For instance, replacement of this motif with oxazoline, thiadiazolidine-1,1-dioxide, imidazolidinethione and imidazolidine oxime resulted in diminished or loss of cytotoxicity [15-17]. Additional substituents at either 4- or 5postion of the imidazolidinone core were deleterious to antitumor properties most likely due to unfavorable steric congestion [18, 19]. Replacement of 4-phenyl moiety in 3 with benzyl or naphthyl groups or conformational restriction on this phenyl ring significantly reduced the activity [20]. Rational design and tenacious effort led to the identification of 4-phenyl-1-[N-(4aminobenzoyl)indoline-5-sulfonyl]-4,5-dihydro-2-imidazolone (4) with better potency than doxorubicin [21]. Later, the (S)-isomer (5, DW2282) was identified as the reactive stereoisomer with lower toxicity profile including hypoglycemia [22]. Derivatives of 5 with conjugation of amino acids at the aniline amino group, particularly phenylalanine and leucine, displayed improved water solubility and bioavailability without loss of in vivo anticancer activity [23, 24]. Other decorated cyclic arylsulfonylureas also exhibited remarkable antitumor properties. Hydantoin-based derivatives such as 6 were reported to significantly inhibit ovarian and renal cancer cells [25]. Dimethoxyimidazolidinone core with one or two arylsulfonyl groups (7 and 8) possessed good inhibitory effect on lung and renal cancer cells and demonstrated potential as carbonic anhydrase inhibitors [26, 27]. However, dihydroimidazolone analogues are much less explored. This structural motif contains a planar cyclic sulfonylurea core indispensible for cytotoxicity. In the present study, a new series of bis(arylsulfonyl)dihydroimidazolinone have been synthesized (9). Modification was made through variation in arylsulfonyl groups. The synthesized compounds were evaluated against four cancer cell lines. To access bis(arylsulfonyl)dihydroimidazolinone derivatives, commercially available 1,3dihydroimidazolin-2-one (10) underwent deprotonation, followed by addition of arylsulfonyl electrophiles (Table 1). For optimization studies, para-toluenesulfonyl chloride (TsCl) was chosen as a model electrophile. A variety of bases and different solvents were evaluated. Different methods of addition were also examined. Initially, based on literature precedent, NaH and DMF were selected as the base and the solvent of choice, respectively [28]. Attempts to perform arylsulfonylation under Barbier-type reaction condition led to a low yield of 9a (entry
1). By switching to sequential deprotonation and addition of TsCl, we observed a significant improvement in the reaction yield (entry 2). Arylsulfonylation conducted at elevated temperature experienced slight erosion in yield (entry 3). Different bases such as KOt-Bu (entry 4) and NaHMDS (entry 5) were evaluated but proved less efficient than NaH. Finally, the reaction carried out in DMSO led to a significant decrease in yield (entry 6). Table 1. Optimization of the synthesis of 9a.
entry 1 2 3 4 5 6
base NaH (300 mol%) NaH (300 mol%) NaH (300 mol%) KOt-Bu (300 mol%) NaHMDS (300 mol%) NaH (300 mol%)
solvent DMF DMF DMF DMF DMF DMSO
addition condition Barbier-type. 0 °C to rt, 12 h Deprotonation: 0 °C to rt, 30 min, then 0 °C, TsCl addition, 0 °C to rt, 12 h Deprotonation: 0 °C to rt, 30 min, then 0 °C, TsCl addition, 0 to 60 °C, 12 h Deprotonation: 0 °C to rt, 30 min, then 0 °C, TsCl addition, 0 °C to rt, 12 h Deprotonation: 0 °C to rt, 30 min, then 0 °C, TsCl addition, 0 °C to rt, 12 h Deprotonation: 0 °C to rt, 30 min, then 0 °C, TsCl addition, 0 °C to rt, 12 h
yield of 9a (%) 22 59 54 35 27 21
With the optimized condition in hand, we commenced the synthesis of an array of bis(arylsulfonyl)dihydroimidazolinone analogues (Table 2). Compounds containing different Me and OMe substitution patterns on the phenyl rings were synthesized (9a-9d). Naphthalene, quinoline and isoxazole were incorporated through the use of different arylsulfonyl chloride sources (9e-9g). Our next group of target molecules was fluoride derivatives since we were interested in the effects of fluorine substitution on cytotoxicity [29]. To this end, arenes with mono- and bis(trifluoromethyl) substituents (9i-9m) and mono(trifluoromethoxy) groups (9n-9p) were synthesized. A variety of substitution patterns of mono-, di- and trifluorobenzenes were included (9q-9ab). Finally, we also obtained pentafluorobenzene derivative 9ac. The isolated yields ranged from 44% to 65%. Table 2. Synthesis of bis(arylsulfonyl)dihydroimidazolinone derivatives (9a-9ac)
To evaluate the bioactivity of bis(arylsulfonyl)dihydroimidazolinone derivatives and the effect of modification of the aryl ring, the synthesized compounds were assessed for cytotoxicity against non-small-cell lung carcinoma A-549, hepatocellular carcinoma HepG2, human cholangiocarcinoma HuCCA-1, and T-lymphoblast MOLT-3. The selectivity indices (SI) of these compounds were determined against cytotoxicity in normal human embryonic lung cell MRC-5. Doxorubicin was used as a positive control. Selected inhibitory results are shown in Table 3. Derivatives with p-tolyl and phenyl groups suppressed MOLT-3 at 41.3 and 46.8 μM, respectively, but were inefficient in inhibiting the growth of other cancer cell lines and MRC-5 (entry 1 and 2). Inclusion of mesityl group having additional methyl groups at ortho positions enhanced activity of the compound, leading to growth suppression of A549 (75.1 μM), HepG2 (77.3 μM), HuCCA-1 (45.9 μM), MOLT-3 (38.5 μM), and MRC-5 (96.2 μM) (entry 3). Compounds containing extended aryl systems such as 1- and 2-naphalene were effective against only MOLT-3 at 22.8 and 40.5 μM, respectively (entry 4 and 5).
Table 3. Selected IC50 values of bis(arylsulfonyl)dihydroimidazolinones against different cancer cell lines and human embryonic lung cells. entry
Compound
A549a HepG2a HuCCA-1b MOLT-3a MRC-5a c c c c IC50 (μM) SI IC50 (μM) SI IC50 (μM) SI IC50 (μM) SI IC50 (μM) 1 9a 41.3±3.9 2 9b 46.8±4.3 3 9c 75.1±8.8 1.28 77.3±5.1 1.24 45.9±4.7 2.10 38.5±12.9 2.50 96.2±4.7 4 9e 22.8±2.0 5 9f 40.5±3.7 6 9i 36.9±3.1 1.52 68.9±7.1 0.82 62.9±10.8 0.89 56.2±10.8 7 9j 57.1±9.2 8 9k 82.8±6.6 1.07 53.9±9.4 1.64 79.2±15.4 1.12 88.4±5.2 9 9n 84.5±2.6 0.99 53.4±0.85 1.57 84.0±0.88 10 9o 54.3±12.4 11 9p 84.5±8.0 1.06 76.6±8.2 1.17 45.4±2.9 1.97 40.6±3.7 2.21 89.6±5.6 12 9d 34.6±7.4 13 9q 107.0±15.8 14 9r 68.5±26.4 15 9s 43.2±4.6 16 9t 31.7±4.8 17 9u 93.5±4.7 29.2±3.5 18 9x 93.3±1.2 0.99 24.8±0.52 3.74 45.4±6.7 2.04 92.7±0.069 19 9y 57.8±4.1 1.18 69.4±7.3 0.99 38.5±0.31 1.78 4.70±0.87 14.55 68.4±22.0 20 9ac 16.0±0.32 3.10 13.9±2.3 3.57 17.4±3.6 2.85 3.75±0.55 13.23 49.6±3.3 21 doxorubicin 0.47±0.036 6.19 0.55±0.069 5.29 1.13±0.37 2.58 0.051±0.0051 57.06 2.91±0.47 -: At the maximum concentration of 50 μg/mL, less than 50% inhibition was observed; aMTT assay; bXTT assay; cSelectivity index = cytotoxicity in MRC-5/cytotoxicity in cancer cell line.
Bis(arylsulfonyl)dihydroimidazolinone derivatives with fluorinated substituents showed interesting bioactivities. Compound bearing a trifluoromethyl group at ortho position exhibited cytotoxicity against several cell lines, including A549 (36.9 μM), HepG2 (68.9 μM), HuCCA-1 (62.9 μM) and MRC-5 (56.2 μM) (entry 6). While a trifluoromethyl substituent at meta position suppressed only growth of MOLT-3 at IC50 of 57.1 μM (entry 7), analogue with paratrifluoromethyl group was effective against HepG2 (82.8 μM), HuCCA-1 (53.9 μM), MOLT-3 (79.2 μM) and MRC-5 (88.4 μM) (entry 8). A similar trend was observed with trifluoromethoxy substituents. Compound with substituent at ortho position could suppress A549 (84.5 μM), HuCCA-1 (53.4 μM) and MRC-5 (84.0 μM) (entry 9) while analogue with meta-trifluoromethoxy group was effective against only MOLT-3 at IC50 of 54.3 μM (entry 10). Substitution at para position led to cytotoxicity against all cell lines tested, including A549 (84.5 μM), HepG2 (76.6 μM), HuCCA-1 (45.4 μM), MOLT3 (40.6 μM), and MRC-5 (89.6 μM) (entry 11). With trifluoromethyl and trifluoromethoxy groups, substitution at meta position seemed to be effective specifically against MOLT-3. In contrast, compounds bearing either ortho or para substituents exhibited broader activity against several cell lines. The importance of fluorine atoms was demonstrated by comparing entry 11 and 12. Bis(arylsulfonyl)dihydroimidazolinone derivative with para-methoxyphenyl group loss its activity against several cell lines except MOLT-3 (34.6 μM, entry 12) whereas its fluorinated counterpart could suppress the growth of all cancer cell lines studied. The effect of replacing hydrogen with fluorine atoms on the benzene ring was striking. Monofluorinated arenes displayed moderate activity against MOLT-3. Compounds with ortho-, meta- and para-fluorobenzene gave IC50 at 107.0, 68.5 and 43.2 μM, respectively (entry 13, 14 and 15) while ineffective against other cell lines. The introduction of two fluorine atoms led to improved inhibition. In other words, derivative containing 2,5-difluorobenzene showed enhanced
activity with IC50 of 31.7 μM for MOLT-3 (entry 16). Analogue with 2,5-difluorobenzene exhibited growth suppression in different cell lines, including HepG2 (93.5 μM) and HuCCA-1 (29.2 μM) (entry 17) while analogue with 3,4-difluorobenzene displayed even broader activity against HepG2 (93.3 μM), HuCCA-1 (24.8 μM), MOLT-3 (45.4 μM) and MRC-5 (92.7 μM) (entry 18). The addition of more fluorine atoms on the benzene ring led to significant improvement in activity. Compound with 3,4,5-trifluorobenzene was ten times more potent against MOLT-3 at IC50 of 4.70 μM (entry 19) than compound with 3,4-difluorobenzene (45.4 μM, entry 18). This analogue bearing 3,4,5-trifluorobenzene was also effective against A549, HepG2, HuCCA-1 and MRC-5 (57.8, 69.4, 38.5 and 68.4 μM, respectively). Finally, derivative with pentafluorobenzene displayed the best inhibitory activity (entry 20). This compound inhibited A549, HepG2, HuCCA-1 and MOLT-3 at 16.0, 13.9, 17.4 and 3.75 μM, respectively, while the compound affected MRC-5 at IC50 of 49.6 μM. Some of the selectivity indices of 9ac were comparable to those of doxorubicin. However, as a control, doxorubicin still displayed superior cytotoxicity against all cell lines examined (entry 21). The observed cytotoxicity of 9ac may stem from cytoskeletal dysfunction. Fluorinated sulfonamides have been reported to inhibit the growth of a variety of tumor cells, including those with multidrug resistance phenotype [30]. The efficacy of these compounds correlated with their ability to undergo nucleophilic aromatic substitution reaction, which suggested that irreversible binding to β-tubulin was their mechanism of inhibition [31]. In particular, T138067 (11) was shown to covalently and selectively modify the β1, β2 and β4 isozymes of β-tubulin at a conserved cysteine-239 residue [32]. This tubulin covalent modification disrupted microtubule polymerization, triggering a collapse of the cytoskeleton and subsequent apoptosis [32]. Based on the observed improved activities with respect to increasing number of fluorine substituents on the benzene ring (entry 13-20, Table 3), we speculated that 9ac may exert their inhibitory effect through covalent binding of tubulin, similar to the mechanism of 11.
Figure 2. Structure of T138067 (11) The utility of bis(pentafluorosulfonyl)dihydroimidazolinone (9ac) as a potential pharmacophore was illustrated by chemical elaboration into a more complex molecular framework. To this end, 9ac served as a dienophile in a Diels–Alder cycloaddition reaction with cyclopentadiene to furnish cycloadduct 12 (Scheme 1). The transformation was highly selective for the endo product as confirmed by NOE experiments, similar to literature precedent of related systems [33]. Scheme 1. Derivatization of 9ac by Diels–Alder cycloaddition reaction and relative stereochemistry assignment of cycloadduct 12
In conclusion, we have synthesized a new family of bis(arylsulfonyl)dihydroimidazolinones and evaluated their antitumor activities against A549, HepG2, HuCCA-1, and MOLT-3 cancer cell lines. An increase in the number fluorine substituents on the benzene rings enhanced the inhibitory activity of 9. The most potent analogue, bis(pentafluorosulfonyl)dihydroimidazolinone (9ac), exhibited cytotoxicity at micromolar range against all cell lines tested. We speculated that the inhibitory mechanism of 9ac involved covalent modification of β-tubulin. Further investigation into the structure-toxicity relationship and elucidation of mechanism of these compounds will be reported elsewhere. Acknowledgments This research work was supported by Chulabhorn Graduate Institute, the Center of Excellence on Environmental Health and Toxicology, Science & Technology Postgraduate Education and Research Development Office (PERDO), Ministry of Education, and Thailand Research Fund (MRG6280082). We are grateful for Chulabhorn Research Institute for evaluating the cytotoxicity of these compounds. Appendix A. Supplementary Material Supplementary Material to this article can be found online at References [1] F. Bray, J. Ferlay, I. Soerjomataram, R. L. Siegel, L. A. Torre, A. Jemal, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA Cancer J. Clin., 68 (2018) 394-424. [2] K. Ferrante, B. Winograd, R. Canetta, Promising new developments in cancer chemotherapy, Cancer Chemother. Pharmacol., 43 (1999) S61-S68. [3] V. T. DeVita, Jr., E. Chu, A history of cancer chemotherapy, Cancer Res., 68 (2008) 86436653. [4] R. Yang, M. Niepel, T. K. Mitchison, P. K. Sorger, Dissecting variability in responses to cancer chemotherapy through systems pharmacology, Clin. Pharmacol. Ther., 88 (2010) 34-38. [5] L. J. Goldstein, H. Galski, A. Fojo, M. Willingham, S.-U. Lai, A. Gazdar, R. Pirker, A. Green, W. Crist, G. M. Brodeur, M. Lieber, J. Cossman, M. M. Gottesman, I. Paston, Expression of a multidrug resistance gene in human cancers, J. Natl. Cancer Inst., 81 (1989) 116-124. [6] D. A. Kessler, R. H. Austin, H. Levine, Resistance to chemotherapy: Patient variability and cellular heterogeneity, Cancer Res., 74 (2014) 4663-4670. [7] J. J. Howbert, C. S. Grossman, T. A. Crowell, B. J. Rieder, R. W. Harper, K. E. Kramer, E. V. Tao, J. Aikins, G. A. Poore, S. M. Rinzel, G. B. Grindley, W. N. Shaw, G. C. Todd, Novel agents effective against solid tumors: The diarylsulfonylureas. Synthesis, activities, and analysis of quantitative structure-activity relationships, J. Med. Chem., 33 (1990) 2393-2407. [8] C. W. Taylor, D. S. Alberts, M. A. Ketcham, W. G. Satterlee, M. T. Holdsworth, P. M. PLezia, Y.-M. Peng, T. M. McCloskey, D. J. Roe, M. Hamilton, S. E. Salmon, Clinical pharmacology of a novel diarylsulfonylurea anticancer agent, J. Clin. Oncol., 7 (1989) 17331740. [9] P. J. Houghton, J. A. Houghton, Antitumor diarylsulfonylureas: novel agents with unfulfilled promise, Invest. New Drug, 14 (1996) 271-280. [10] S. G. Diab, S. G. Hilsenbeck, E. Izbicka, S. D. Weitman, D. D. Von Hoff, Significant activity of a novel cytotoxic agent, LY295501, against a wide range of tumors in the human tumor cloning system, Anticancer Drug, 10 (1999) 303-307.
[11] B. Forouzesh, C. H. Takimoto, A. Goetz, S. Diab, L. A. Hammond, L. Smetzer, G. Schwartz, R. Gazak, J. T. Callaghan, D. D. Von Hoff, E. K. Rowinsky, A phase I and pharmacokinetics study of ILX-295501, an oral diarylsulfonylurea, on a weekly for 3 weeks every 4-week schedule in patients with advanced solid malignancies, Clin. Cancer Res., 9 (2003) 5540-5549. [12] P. J. Houghton, F. C. Bailey, J. A. Houghton, K. G. Murti, J. J. Howbert, G. B. Grindley, Evidences for mitochondrial localization of N-(4-methylphenylsulfonyl)-N'-(4-chlorophenyl)urea in human colon adenocarcinoma cells, Cancer Res., 50 (1990) 664-668. [13] J. H. Thakar, C. Chapin, R. H. Berg, R. A. Ashmun, P. J. Houghton, Effect of antitumor diarylsulfonylureas on in vio and in vitro mitochondrial structure and functions, Cancer Res., 51 (1991) 6286-6291. [14] S.-H. Jung, J.-S. Song, H.-S. Lee, S.-U. Choi, C.-O. Lee, Synthesis and evaluation of cytotoxicity of novel arylsulfonylimidazolidinones containing sulfonylurea pharmacophore, Arch. Pharm. Res., 19 (1996) 570-580. [15] S.-H. Jung, K.-L. Park, H.-S. Lee, J.-S. Whang, Evaluation of the role of imidazolidinone motif of antineoplastic 4-phenyl-1-arylsulfonylimidazolidinones using 4-phenyl-2arylsulfonyloxazolines, Arch. Pharm. Res. 24 (2001) 499-502. [16] I.-W. Kim, S.-H. Jung, Recognition of the importance of imidazolidinone motif for cytotoxicity of 4-phenyl-1-arylsulfonylimidazolidinones using thiadiazolidine-1,1-dioxide analogs, Arch. Pharm. Res., 25 (2002) 421-427. [17] V. K. Sharma, K.C. Lee, C. Joo, N. Sharma, S.-H. Jung, Importance of imidazolidinone motif in 4-phenyl-N-arylsulfonylimidazolidinone for their anticancer activity, Bull. Korean Chem. Soc., 32 (2011) 3009-3016. [18] S. Subramanian, N.-S. Kim, P. Thanigaimalai, V. K. Sharma, K.-C. Lee, J. S. Kang, H.-M. Kim, S.-H. Jung, Structure-activity relationship studies of novel arylsulfonylimidazolidinones for their anticancer activity, Eur. J. Med. Chem., 46 (2011) 3258-3264. [19] V. K. Sharma, K.-C. Lee, E. Venkateswararao, C. Joo, M.-S. Kim, N. Sharma, S.-H. Jung, Structure-activity relationship study of arylsulfonylimidazolidinones as anticancer agents, Bioorg. Med. Chem. Lett., 21 (2011) 6829-6832. [20] S.-H. Jung, S.-J. Kwak, N.-D. Kim, S.-U. Lee, C.-O. Lee, Stereochemical requirement at 4position of 4-phenyl-1-arylsulfonylimidazolidinones for their cytotoxicities, Arch. Pharm. Res., 23 (2000) 35-41. [21] S.-H. Jung, H.-S. Lee, N.-S. Kim, H.-M. Kim, M. Lee, D.-R. Choi, J.-A. Lee, Y.-H. Chung, E.-Y. Moon, H.-S. Hwang, S.-K. Seong, D.-K. Lee, Synthesis and cytotoxic activity of 1-(1benzoylindoline-5-sulfonyl)-4-phenylimidazolidinones, Arch. Pharm. Res., 27 (2004) 478-484. [22] C.-W. Lee, D. H. Hong, S. B. Han, S.-H. Jung, H. C. Kim, R. L. Fine, S.-H. Lee, H. M. Kim, A novel stereo-selective sulfonylurea. 1-[1-(4-aminobenzoyl)-2,3-dihydro-1H-indol-6sulfonyl]-4-phenyl-imidazolidin-2-one, has antitumor efficacy in in vitro and in vivo tumor models, Biochem. Pharmacol., 64 (2002) 473-480. [23] S.-C. Bang, K.-C. Lee, V. K. Sharma, N. Sharmam H.-S. Yang, S.-H. Jung, Synthesis of water soluble analogs of arylsulfonylimidazolidinone (JSAH-2282), Bull. Korean Chem. Soc., 34 (2013) 2011-2015. [24] K.-C. Lee, E. Venkateswararao, V. K. Sharma, S.-H. Jung, Investigation of amino acid conjugates of (S)-1-[1-(4-aminobenzoyl)-2,3-dihydro-1H-indol-6-sulfonyl]-4-phenylimidazolidin-2-one (DW2282) as water soluble anticancer prodrugs, Eur. J. Med. Chem., 80 (2014) 439-446.
[25] I. M. El-Deeb, S. M. Bayoumi, M. A. El-Sherbeny, A. A.-M. Abdel-Aziz, Synthesis and antitumor evaluation of novel cyclic arylsulfonylureas: ADME-T and pharmacophore prediction, Eur. J. Med. Chem., 45 (2010) 2516-2530. [26] A. A.-M. Abdel-Aziz, A. S. El-Azab, H. I. El-Subbagh, A. M. Al-Obaid, A. M. Alanazi, M. A. Al-Omar, Design, synthesis, single-crystal and preliminary antitumor activity of novel arenesulfonylimidazolidin-2-ones, Bioorg. Med. Chem. Lett., 22 (2012) 2008-2014. [27] A. A.-M. Abdel-Aziz, A. S. El-Azab, D. Ekinci, M. Şentürk, C. T. Supuran, Investigation of arenesulfonyl-2-imidazolidinones as potent carbonic anhydrase inhibitors, J. Enzyme Inhib. Med. Chem., 30 (2015) 81-84. [28] P.J. Dransfield, A.S. Dilley, S. Wang, D. Romo, A unified synthetic strategy toward oroidin-derived alkaloids premised on a biosynthetic proposal, Tetrahedron, 62 (2006) 52235247. [29] B. Kevin Park, N.R. Kitteringham, Effects of fluorine substitution on drug metabolism: Pharmacological and toxicological implications, Drug Metab. Rev., 26 (1994) 605-643. [30] J. C. Medina, B. Shan, H. Beckmann, R. P. Farrell, D. L. Clark, R. M. Learned, D. Roche, A. Li, V. Baichwal, C. Case, P. A. Baeuerle, T. Rosen, J. C. Jaen, Novel antineoplastic agents with efficacy against multidrug resistant tumor cells, Bioorg. Med. Chem. Lett., 8 (1998) 26532656. [31] J. C. Medina, D. Roche, B. Shan, R. M. Learned, W. P. Frankmoelle, D. L. Clark, T. Rosen, J. C. Jaen, Novel halogenated sulfonamides inhibit the growth of multidrug resistant MCF7/ADR cancer cells, Bioorg. Med. Chem. Lett., 9 (1999) 1843-1846. [32] B. Shan, J. C. Medina, E. Santha, W. P. Frankmoelle, T.-C. Chou, R. M. Learned, M. R. Narbut, D. Stott, P. Wu, J. C. Jaen, T. Rosen, P. B. M. W. M. Timmermans, H. Beckmann, Selective, covalent modification of β-tubulin residue Cys-239 by T138067, an antitumor agent with in vivo efficacy against multidrug-resistant tumors, Proc. Natl. Acad. Sci. USA, 96 (1999) 5686-5691. [33] R.A. Whitney, Cycloaddition reactions of 1,3-diacetylimidazolin-2-one, Tetrahedron Lett., 22 (1981) 2063-2066.
Synthesis and Antitumor Activity of Bis(arylsulfonyl)dihydroimidazolinone Derivatives Satapanawat Sittihan*, Watthanachai Jumpathong, Pattarawut Sopha, Somsak Ruchirawat
Highlights
Synthesis of novel bis(arylsulfonyl)dihydroimidazolinones and antitumor activities. Increase in cytotoxicity with increased number of fluorine atoms on benzene ring. Compound 9ac exhibiting cytotoxicity at micromolar range against all cancer cells.
S0960-894X(19)30741-3 https://doi.org/10.1016/j.bmcl.2019.126776 BMCL 126776
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date: Revised Date: Accepted Date:
12 September 2019 20 October 2019 23 October 2019
Please cite this article as: Sittihan, S., Jumpathong, W., Sopha, P., Ruchirawat, S., Synthesis and Antitumor Activity of Bis(arylsulfonyl)dihydroimidazolinone Derivatives, Bioorganic & Medicinal Chemistry Letters (2019), doi: https://doi.org/10.1016/j.bmcl.2019.126776
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Elsevier Ltd. All rights reserved.
Synthesis and Antitumor Activity of Bis(arylsulfonyl)dihydroimidazolinone Derivatives Satapanawat Sittihana,*, Watthanachai Jumpathonga, Pattarawut Sophab, Somsak Ruchirawata,c aProgram
on Chemical Biology, Chulabhorn Graduate Institute, Center of Excellence on Environmental Health and Toxicology (EHT), Ministry of Education, 906 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand bProgram on Applied Biological Sciences, Chulabhorn Graduate Institute, Center of Excellence on Environmental Health and Toxicology (EHT), Ministry of Education, 906 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand cLaboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand *Corresponding author Satapanawat Sittihan: Program on Chemical Biology, Chulabhorn Graduate Institute, 906 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand; E-mail: [email protected] ABSTRACT A series of novel bis(arylsulfonyl)dihydroimidazolinones with different aryl substitution patterns were readily synthesized and evaluated for their antitumor activities. Some of the newly synthesized compounds exhibited cytotoxicity at micromolar range against multiple cancer cell lines, including A549, HepG2, HuCCA-1, and MOLT-3. The most potent analogue contained pentafluorobenzenesulfonyl groups, which could be chemically elaborated to serve as a potential pharmacophore. Keywords: Bis(arylsulfonyl)dihydroimidazolinones; Cytotoxicity; Antitumor Cancer is an alarming health problem that threatens both developing and developed countries regardless of differences in the population lifestyles [1]. Despite advances in chemotherapeutic development, a search for novel chemical agents with anticancer features has been a pressing issue [2, 3]. Furthermore, complication in treatment often arises from recurrent variability in responses as well as resistance to cancer chemotherapy from one patient to another [4-6]. Among a variety of candidate compounds with potential anticancer properties, diarylsulfonylureas have garnered much attention especially since the advent of sulofenur (LY186641, 1, Figure 1) [7]. In particular, 1 displayed a broad spectrum of activities in different human tumor xenografts and advanced into a clinical phase [7, 8]. However, further investigation of 1 was discontinued due to its high protein binding and limited dosing caused by the appearance of severe anemia, a side-effect likely from aniline-based metabolites [9]. Extensive structural modification led to the identification of less toxic ILX-295501 (2, formerly LY295501), which was principally metabolized by hydroxylation with negligible detection of aniline metabolites in animal models [9]. Effective against all tumor types tested in human tumor cloning assay, 2 set the maximum tolerated doses for subsequent clinical studies at 1,000 mg/m2/day for 3-4 weeks with no hematological toxicities commonly observed with 1 [10, 11]. The cytotoxic mechanism of diarylsulfonylureas is still unclear. Mitochondrial localization of these compounds with subsequent morphological changes and the uncoupling of mitochondrial oxidative phosphorylation, which resulted in low cellular ATP level, may be responsible for the observed antitumor activities [12, 13].
Figure 1. Examples of antitumor sulfonylureas (1-8) and novel bis(arylsulfonyl)dihydroimidazolinone derivatives (9). Continuous investigation into structural variation led to the discovery of cyclic arylsulfonylureas as a promising new class of antitumor agents. In particular, 4-phenyl-1-(5indanyl)sulfonylimidazolidinone (3) exhibited much more potency than 1 [14]. Perturbation in molecular structure revealed the importance of imidazolidinone core with regard to functional group, planarity, steric and conformational requirement. For instance, replacement of this motif with oxazoline, thiadiazolidine-1,1-dioxide, imidazolidinethione and imidazolidine oxime resulted in diminished or loss of cytotoxicity [15-17]. Additional substituents at either 4- or 5postion of the imidazolidinone core were deleterious to antitumor properties most likely due to unfavorable steric congestion [18, 19]. Replacement of 4-phenyl moiety in 3 with benzyl or naphthyl groups or conformational restriction on this phenyl ring significantly reduced the activity [20]. Rational design and tenacious effort led to the identification of 4-phenyl-1-[N-(4aminobenzoyl)indoline-5-sulfonyl]-4,5-dihydro-2-imidazolone (4) with better potency than doxorubicin [21]. Later, the (S)-isomer (5, DW2282) was identified as the reactive stereoisomer with lower toxicity profile including hypoglycemia [22]. Derivatives of 5 with conjugation of amino acids at the aniline amino group, particularly phenylalanine and leucine, displayed improved water solubility and bioavailability without loss of in vivo anticancer activity [23, 24]. Other decorated cyclic arylsulfonylureas also exhibited remarkable antitumor properties. Hydantoin-based derivatives such as 6 were reported to significantly inhibit ovarian and renal cancer cells [25]. Dimethoxyimidazolidinone core with one or two arylsulfonyl groups (7 and 8) possessed good inhibitory effect on lung and renal cancer cells and demonstrated potential as carbonic anhydrase inhibitors [26, 27]. However, dihydroimidazolone analogues are much less explored. This structural motif contains a planar cyclic sulfonylurea core indispensible for cytotoxicity. In the present study, a new series of bis(arylsulfonyl)dihydroimidazolinone have been synthesized (9). Modification was made through variation in arylsulfonyl groups. The synthesized compounds were evaluated against four cancer cell lines. To access bis(arylsulfonyl)dihydroimidazolinone derivatives, commercially available 1,3dihydroimidazolin-2-one (10) underwent deprotonation, followed by addition of arylsulfonyl electrophiles (Table 1). For optimization studies, para-toluenesulfonyl chloride (TsCl) was chosen as a model electrophile. A variety of bases and different solvents were evaluated. Different methods of addition were also examined. Initially, based on literature precedent, NaH and DMF were selected as the base and the solvent of choice, respectively [28]. Attempts to perform arylsulfonylation under Barbier-type reaction condition led to a low yield of 9a (entry
1). By switching to sequential deprotonation and addition of TsCl, we observed a significant improvement in the reaction yield (entry 2). Arylsulfonylation conducted at elevated temperature experienced slight erosion in yield (entry 3). Different bases such as KOt-Bu (entry 4) and NaHMDS (entry 5) were evaluated but proved less efficient than NaH. Finally, the reaction carried out in DMSO led to a significant decrease in yield (entry 6). Table 1. Optimization of the synthesis of 9a.
entry 1 2 3 4 5 6
base NaH (300 mol%) NaH (300 mol%) NaH (300 mol%) KOt-Bu (300 mol%) NaHMDS (300 mol%) NaH (300 mol%)
solvent DMF DMF DMF DMF DMF DMSO
addition condition Barbier-type. 0 °C to rt, 12 h Deprotonation: 0 °C to rt, 30 min, then 0 °C, TsCl addition, 0 °C to rt, 12 h Deprotonation: 0 °C to rt, 30 min, then 0 °C, TsCl addition, 0 to 60 °C, 12 h Deprotonation: 0 °C to rt, 30 min, then 0 °C, TsCl addition, 0 °C to rt, 12 h Deprotonation: 0 °C to rt, 30 min, then 0 °C, TsCl addition, 0 °C to rt, 12 h Deprotonation: 0 °C to rt, 30 min, then 0 °C, TsCl addition, 0 °C to rt, 12 h
yield of 9a (%) 22 59 54 35 27 21
With the optimized condition in hand, we commenced the synthesis of an array of bis(arylsulfonyl)dihydroimidazolinone analogues (Table 2). Compounds containing different Me and OMe substitution patterns on the phenyl rings were synthesized (9a-9d). Naphthalene, quinoline and isoxazole were incorporated through the use of different arylsulfonyl chloride sources (9e-9g). Our next group of target molecules was fluoride derivatives since we were interested in the effects of fluorine substitution on cytotoxicity [29]. To this end, arenes with mono- and bis(trifluoromethyl) substituents (9i-9m) and mono(trifluoromethoxy) groups (9n-9p) were synthesized. A variety of substitution patterns of mono-, di- and trifluorobenzenes were included (9q-9ab). Finally, we also obtained pentafluorobenzene derivative 9ac. The isolated yields ranged from 44% to 65%. Table 2. Synthesis of bis(arylsulfonyl)dihydroimidazolinone derivatives (9a-9ac)
To evaluate the bioactivity of bis(arylsulfonyl)dihydroimidazolinone derivatives and the effect of modification of the aryl ring, the synthesized compounds were assessed for cytotoxicity against non-small-cell lung carcinoma A-549, hepatocellular carcinoma HepG2, human cholangiocarcinoma HuCCA-1, and T-lymphoblast MOLT-3. The selectivity indices (SI) of these compounds were determined against cytotoxicity in normal human embryonic lung cell MRC-5. Doxorubicin was used as a positive control. Selected inhibitory results are shown in Table 3. Derivatives with p-tolyl and phenyl groups suppressed MOLT-3 at 41.3 and 46.8 μM, respectively, but were inefficient in inhibiting the growth of other cancer cell lines and MRC-5 (entry 1 and 2). Inclusion of mesityl group having additional methyl groups at ortho positions enhanced activity of the compound, leading to growth suppression of A549 (75.1 μM), HepG2 (77.3 μM), HuCCA-1 (45.9 μM), MOLT-3 (38.5 μM), and MRC-5 (96.2 μM) (entry 3). Compounds containing extended aryl systems such as 1- and 2-naphalene were effective against only MOLT-3 at 22.8 and 40.5 μM, respectively (entry 4 and 5).
Table 3. Selected IC50 values of bis(arylsulfonyl)dihydroimidazolinones against different cancer cell lines and human embryonic lung cells. entry
Compound
A549a HepG2a HuCCA-1b MOLT-3a MRC-5a c c c c IC50 (μM) SI IC50 (μM) SI IC50 (μM) SI IC50 (μM) SI IC50 (μM) 1 9a 41.3±3.9 2 9b 46.8±4.3 3 9c 75.1±8.8 1.28 77.3±5.1 1.24 45.9±4.7 2.10 38.5±12.9 2.50 96.2±4.7 4 9e 22.8±2.0 5 9f 40.5±3.7 6 9i 36.9±3.1 1.52 68.9±7.1 0.82 62.9±10.8 0.89 56.2±10.8 7 9j 57.1±9.2 8 9k 82.8±6.6 1.07 53.9±9.4 1.64 79.2±15.4 1.12 88.4±5.2 9 9n 84.5±2.6 0.99 53.4±0.85 1.57 84.0±0.88 10 9o 54.3±12.4 11 9p 84.5±8.0 1.06 76.6±8.2 1.17 45.4±2.9 1.97 40.6±3.7 2.21 89.6±5.6 12 9d 34.6±7.4 13 9q 107.0±15.8 14 9r 68.5±26.4 15 9s 43.2±4.6 16 9t 31.7±4.8 17 9u 93.5±4.7 29.2±3.5 18 9x 93.3±1.2 0.99 24.8±0.52 3.74 45.4±6.7 2.04 92.7±0.069 19 9y 57.8±4.1 1.18 69.4±7.3 0.99 38.5±0.31 1.78 4.70±0.87 14.55 68.4±22.0 20 9ac 16.0±0.32 3.10 13.9±2.3 3.57 17.4±3.6 2.85 3.75±0.55 13.23 49.6±3.3 21 doxorubicin 0.47±0.036 6.19 0.55±0.069 5.29 1.13±0.37 2.58 0.051±0.0051 57.06 2.91±0.47 -: At the maximum concentration of 50 μg/mL, less than 50% inhibition was observed; aMTT assay; bXTT assay; cSelectivity index = cytotoxicity in MRC-5/cytotoxicity in cancer cell line.
Bis(arylsulfonyl)dihydroimidazolinone derivatives with fluorinated substituents showed interesting bioactivities. Compound bearing a trifluoromethyl group at ortho position exhibited cytotoxicity against several cell lines, including A549 (36.9 μM), HepG2 (68.9 μM), HuCCA-1 (62.9 μM) and MRC-5 (56.2 μM) (entry 6). While a trifluoromethyl substituent at meta position suppressed only growth of MOLT-3 at IC50 of 57.1 μM (entry 7), analogue with paratrifluoromethyl group was effective against HepG2 (82.8 μM), HuCCA-1 (53.9 μM), MOLT-3 (79.2 μM) and MRC-5 (88.4 μM) (entry 8). A similar trend was observed with trifluoromethoxy substituents. Compound with substituent at ortho position could suppress A549 (84.5 μM), HuCCA-1 (53.4 μM) and MRC-5 (84.0 μM) (entry 9) while analogue with meta-trifluoromethoxy group was effective against only MOLT-3 at IC50 of 54.3 μM (entry 10). Substitution at para position led to cytotoxicity against all cell lines tested, including A549 (84.5 μM), HepG2 (76.6 μM), HuCCA-1 (45.4 μM), MOLT3 (40.6 μM), and MRC-5 (89.6 μM) (entry 11). With trifluoromethyl and trifluoromethoxy groups, substitution at meta position seemed to be effective specifically against MOLT-3. In contrast, compounds bearing either ortho or para substituents exhibited broader activity against several cell lines. The importance of fluorine atoms was demonstrated by comparing entry 11 and 12. Bis(arylsulfonyl)dihydroimidazolinone derivative with para-methoxyphenyl group loss its activity against several cell lines except MOLT-3 (34.6 μM, entry 12) whereas its fluorinated counterpart could suppress the growth of all cancer cell lines studied. The effect of replacing hydrogen with fluorine atoms on the benzene ring was striking. Monofluorinated arenes displayed moderate activity against MOLT-3. Compounds with ortho-, meta- and para-fluorobenzene gave IC50 at 107.0, 68.5 and 43.2 μM, respectively (entry 13, 14 and 15) while ineffective against other cell lines. The introduction of two fluorine atoms led to improved inhibition. In other words, derivative containing 2,5-difluorobenzene showed enhanced
activity with IC50 of 31.7 μM for MOLT-3 (entry 16). Analogue with 2,5-difluorobenzene exhibited growth suppression in different cell lines, including HepG2 (93.5 μM) and HuCCA-1 (29.2 μM) (entry 17) while analogue with 3,4-difluorobenzene displayed even broader activity against HepG2 (93.3 μM), HuCCA-1 (24.8 μM), MOLT-3 (45.4 μM) and MRC-5 (92.7 μM) (entry 18). The addition of more fluorine atoms on the benzene ring led to significant improvement in activity. Compound with 3,4,5-trifluorobenzene was ten times more potent against MOLT-3 at IC50 of 4.70 μM (entry 19) than compound with 3,4-difluorobenzene (45.4 μM, entry 18). This analogue bearing 3,4,5-trifluorobenzene was also effective against A549, HepG2, HuCCA-1 and MRC-5 (57.8, 69.4, 38.5 and 68.4 μM, respectively). Finally, derivative with pentafluorobenzene displayed the best inhibitory activity (entry 20). This compound inhibited A549, HepG2, HuCCA-1 and MOLT-3 at 16.0, 13.9, 17.4 and 3.75 μM, respectively, while the compound affected MRC-5 at IC50 of 49.6 μM. Some of the selectivity indices of 9ac were comparable to those of doxorubicin. However, as a control, doxorubicin still displayed superior cytotoxicity against all cell lines examined (entry 21). The observed cytotoxicity of 9ac may stem from cytoskeletal dysfunction. Fluorinated sulfonamides have been reported to inhibit the growth of a variety of tumor cells, including those with multidrug resistance phenotype [30]. The efficacy of these compounds correlated with their ability to undergo nucleophilic aromatic substitution reaction, which suggested that irreversible binding to β-tubulin was their mechanism of inhibition [31]. In particular, T138067 (11) was shown to covalently and selectively modify the β1, β2 and β4 isozymes of β-tubulin at a conserved cysteine-239 residue [32]. This tubulin covalent modification disrupted microtubule polymerization, triggering a collapse of the cytoskeleton and subsequent apoptosis [32]. Based on the observed improved activities with respect to increasing number of fluorine substituents on the benzene ring (entry 13-20, Table 3), we speculated that 9ac may exert their inhibitory effect through covalent binding of tubulin, similar to the mechanism of 11.
Figure 2. Structure of T138067 (11) The utility of bis(pentafluorosulfonyl)dihydroimidazolinone (9ac) as a potential pharmacophore was illustrated by chemical elaboration into a more complex molecular framework. To this end, 9ac served as a dienophile in a Diels–Alder cycloaddition reaction with cyclopentadiene to furnish cycloadduct 12 (Scheme 1). The transformation was highly selective for the endo product as confirmed by NOE experiments, similar to literature precedent of related systems [33]. Scheme 1. Derivatization of 9ac by Diels–Alder cycloaddition reaction and relative stereochemistry assignment of cycloadduct 12
In conclusion, we have synthesized a new family of bis(arylsulfonyl)dihydroimidazolinones and evaluated their antitumor activities against A549, HepG2, HuCCA-1, and MOLT-3 cancer cell lines. An increase in the number fluorine substituents on the benzene rings enhanced the inhibitory activity of 9. The most potent analogue, bis(pentafluorosulfonyl)dihydroimidazolinone (9ac), exhibited cytotoxicity at micromolar range against all cell lines tested. We speculated that the inhibitory mechanism of 9ac involved covalent modification of β-tubulin. Further investigation into the structure-toxicity relationship and elucidation of mechanism of these compounds will be reported elsewhere. Acknowledgments This research work was supported by Chulabhorn Graduate Institute, the Center of Excellence on Environmental Health and Toxicology, Science & Technology Postgraduate Education and Research Development Office (PERDO), Ministry of Education, and Thailand Research Fund (MRG6280082). We are grateful for Chulabhorn Research Institute for evaluating the cytotoxicity of these compounds. Appendix A. Supplementary Material Supplementary Material to this article can be found online at References [1] F. Bray, J. Ferlay, I. Soerjomataram, R. L. Siegel, L. A. Torre, A. Jemal, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA Cancer J. Clin., 68 (2018) 394-424. [2] K. Ferrante, B. Winograd, R. Canetta, Promising new developments in cancer chemotherapy, Cancer Chemother. Pharmacol., 43 (1999) S61-S68. [3] V. T. DeVita, Jr., E. Chu, A history of cancer chemotherapy, Cancer Res., 68 (2008) 86436653. [4] R. Yang, M. Niepel, T. K. Mitchison, P. K. Sorger, Dissecting variability in responses to cancer chemotherapy through systems pharmacology, Clin. Pharmacol. Ther., 88 (2010) 34-38. [5] L. J. Goldstein, H. Galski, A. Fojo, M. Willingham, S.-U. Lai, A. Gazdar, R. Pirker, A. Green, W. Crist, G. M. Brodeur, M. Lieber, J. Cossman, M. M. Gottesman, I. Paston, Expression of a multidrug resistance gene in human cancers, J. Natl. Cancer Inst., 81 (1989) 116-124. [6] D. A. Kessler, R. H. Austin, H. Levine, Resistance to chemotherapy: Patient variability and cellular heterogeneity, Cancer Res., 74 (2014) 4663-4670. [7] J. J. Howbert, C. S. Grossman, T. A. Crowell, B. J. Rieder, R. W. Harper, K. E. Kramer, E. V. Tao, J. Aikins, G. A. Poore, S. M. Rinzel, G. B. Grindley, W. N. Shaw, G. C. Todd, Novel agents effective against solid tumors: The diarylsulfonylureas. Synthesis, activities, and analysis of quantitative structure-activity relationships, J. Med. Chem., 33 (1990) 2393-2407. [8] C. W. Taylor, D. S. Alberts, M. A. Ketcham, W. G. Satterlee, M. T. Holdsworth, P. M. PLezia, Y.-M. Peng, T. M. McCloskey, D. J. Roe, M. Hamilton, S. E. Salmon, Clinical pharmacology of a novel diarylsulfonylurea anticancer agent, J. Clin. Oncol., 7 (1989) 17331740. [9] P. J. Houghton, J. A. Houghton, Antitumor diarylsulfonylureas: novel agents with unfulfilled promise, Invest. New Drug, 14 (1996) 271-280. [10] S. G. Diab, S. G. Hilsenbeck, E. Izbicka, S. D. Weitman, D. D. Von Hoff, Significant activity of a novel cytotoxic agent, LY295501, against a wide range of tumors in the human tumor cloning system, Anticancer Drug, 10 (1999) 303-307.
[11] B. Forouzesh, C. H. Takimoto, A. Goetz, S. Diab, L. A. Hammond, L. Smetzer, G. Schwartz, R. Gazak, J. T. Callaghan, D. D. Von Hoff, E. K. Rowinsky, A phase I and pharmacokinetics study of ILX-295501, an oral diarylsulfonylurea, on a weekly for 3 weeks every 4-week schedule in patients with advanced solid malignancies, Clin. Cancer Res., 9 (2003) 5540-5549. [12] P. J. Houghton, F. C. Bailey, J. A. Houghton, K. G. Murti, J. J. Howbert, G. B. Grindley, Evidences for mitochondrial localization of N-(4-methylphenylsulfonyl)-N'-(4-chlorophenyl)urea in human colon adenocarcinoma cells, Cancer Res., 50 (1990) 664-668. [13] J. H. Thakar, C. Chapin, R. H. Berg, R. A. Ashmun, P. J. Houghton, Effect of antitumor diarylsulfonylureas on in vio and in vitro mitochondrial structure and functions, Cancer Res., 51 (1991) 6286-6291. [14] S.-H. Jung, J.-S. Song, H.-S. Lee, S.-U. Choi, C.-O. Lee, Synthesis and evaluation of cytotoxicity of novel arylsulfonylimidazolidinones containing sulfonylurea pharmacophore, Arch. Pharm. Res., 19 (1996) 570-580. [15] S.-H. Jung, K.-L. Park, H.-S. Lee, J.-S. Whang, Evaluation of the role of imidazolidinone motif of antineoplastic 4-phenyl-1-arylsulfonylimidazolidinones using 4-phenyl-2arylsulfonyloxazolines, Arch. Pharm. Res. 24 (2001) 499-502. [16] I.-W. Kim, S.-H. Jung, Recognition of the importance of imidazolidinone motif for cytotoxicity of 4-phenyl-1-arylsulfonylimidazolidinones using thiadiazolidine-1,1-dioxide analogs, Arch. Pharm. Res., 25 (2002) 421-427. [17] V. K. Sharma, K.C. Lee, C. Joo, N. Sharma, S.-H. Jung, Importance of imidazolidinone motif in 4-phenyl-N-arylsulfonylimidazolidinone for their anticancer activity, Bull. Korean Chem. Soc., 32 (2011) 3009-3016. [18] S. Subramanian, N.-S. Kim, P. Thanigaimalai, V. K. Sharma, K.-C. Lee, J. S. Kang, H.-M. Kim, S.-H. Jung, Structure-activity relationship studies of novel arylsulfonylimidazolidinones for their anticancer activity, Eur. J. Med. Chem., 46 (2011) 3258-3264. [19] V. K. Sharma, K.-C. Lee, E. Venkateswararao, C. Joo, M.-S. Kim, N. Sharma, S.-H. Jung, Structure-activity relationship study of arylsulfonylimidazolidinones as anticancer agents, Bioorg. Med. Chem. Lett., 21 (2011) 6829-6832. [20] S.-H. Jung, S.-J. Kwak, N.-D. Kim, S.-U. Lee, C.-O. Lee, Stereochemical requirement at 4position of 4-phenyl-1-arylsulfonylimidazolidinones for their cytotoxicities, Arch. Pharm. Res., 23 (2000) 35-41. [21] S.-H. Jung, H.-S. Lee, N.-S. Kim, H.-M. Kim, M. Lee, D.-R. Choi, J.-A. Lee, Y.-H. Chung, E.-Y. Moon, H.-S. Hwang, S.-K. Seong, D.-K. Lee, Synthesis and cytotoxic activity of 1-(1benzoylindoline-5-sulfonyl)-4-phenylimidazolidinones, Arch. Pharm. Res., 27 (2004) 478-484. [22] C.-W. Lee, D. H. Hong, S. B. Han, S.-H. Jung, H. C. Kim, R. L. Fine, S.-H. Lee, H. M. Kim, A novel stereo-selective sulfonylurea. 1-[1-(4-aminobenzoyl)-2,3-dihydro-1H-indol-6sulfonyl]-4-phenyl-imidazolidin-2-one, has antitumor efficacy in in vitro and in vivo tumor models, Biochem. Pharmacol., 64 (2002) 473-480. [23] S.-C. Bang, K.-C. Lee, V. K. Sharma, N. Sharmam H.-S. Yang, S.-H. Jung, Synthesis of water soluble analogs of arylsulfonylimidazolidinone (JSAH-2282), Bull. Korean Chem. Soc., 34 (2013) 2011-2015. [24] K.-C. Lee, E. Venkateswararao, V. K. Sharma, S.-H. Jung, Investigation of amino acid conjugates of (S)-1-[1-(4-aminobenzoyl)-2,3-dihydro-1H-indol-6-sulfonyl]-4-phenylimidazolidin-2-one (DW2282) as water soluble anticancer prodrugs, Eur. J. Med. Chem., 80 (2014) 439-446.
[25] I. M. El-Deeb, S. M. Bayoumi, M. A. El-Sherbeny, A. A.-M. Abdel-Aziz, Synthesis and antitumor evaluation of novel cyclic arylsulfonylureas: ADME-T and pharmacophore prediction, Eur. J. Med. Chem., 45 (2010) 2516-2530. [26] A. A.-M. Abdel-Aziz, A. S. El-Azab, H. I. El-Subbagh, A. M. Al-Obaid, A. M. Alanazi, M. A. Al-Omar, Design, synthesis, single-crystal and preliminary antitumor activity of novel arenesulfonylimidazolidin-2-ones, Bioorg. Med. Chem. Lett., 22 (2012) 2008-2014. [27] A. A.-M. Abdel-Aziz, A. S. El-Azab, D. Ekinci, M. Şentürk, C. T. Supuran, Investigation of arenesulfonyl-2-imidazolidinones as potent carbonic anhydrase inhibitors, J. Enzyme Inhib. Med. Chem., 30 (2015) 81-84. [28] P.J. Dransfield, A.S. Dilley, S. Wang, D. Romo, A unified synthetic strategy toward oroidin-derived alkaloids premised on a biosynthetic proposal, Tetrahedron, 62 (2006) 52235247. [29] B. Kevin Park, N.R. Kitteringham, Effects of fluorine substitution on drug metabolism: Pharmacological and toxicological implications, Drug Metab. Rev., 26 (1994) 605-643. [30] J. C. Medina, B. Shan, H. Beckmann, R. P. Farrell, D. L. Clark, R. M. Learned, D. Roche, A. Li, V. Baichwal, C. Case, P. A. Baeuerle, T. Rosen, J. C. Jaen, Novel antineoplastic agents with efficacy against multidrug resistant tumor cells, Bioorg. Med. Chem. Lett., 8 (1998) 26532656. [31] J. C. Medina, D. Roche, B. Shan, R. M. Learned, W. P. Frankmoelle, D. L. Clark, T. Rosen, J. C. Jaen, Novel halogenated sulfonamides inhibit the growth of multidrug resistant MCF7/ADR cancer cells, Bioorg. Med. Chem. Lett., 9 (1999) 1843-1846. [32] B. Shan, J. C. Medina, E. Santha, W. P. Frankmoelle, T.-C. Chou, R. M. Learned, M. R. Narbut, D. Stott, P. Wu, J. C. Jaen, T. Rosen, P. B. M. W. M. Timmermans, H. Beckmann, Selective, covalent modification of β-tubulin residue Cys-239 by T138067, an antitumor agent with in vivo efficacy against multidrug-resistant tumors, Proc. Natl. Acad. Sci. USA, 96 (1999) 5686-5691. [33] R.A. Whitney, Cycloaddition reactions of 1,3-diacetylimidazolin-2-one, Tetrahedron Lett., 22 (1981) 2063-2066.
Synthesis and Antitumor Activity of Bis(arylsulfonyl)dihydroimidazolinone Derivatives Satapanawat Sittihan*, Watthanachai Jumpathong, Pattarawut Sopha, Somsak Ruchirawat
Highlights
Synthesis of novel bis(arylsulfonyl)dihydroimidazolinones and antitumor activities. Increase in cytotoxicity with increased number of fluorine atoms on benzene ring. Compound 9ac exhibiting cytotoxicity at micromolar range against all cancer cells.