Synthesis, Biological and Computational Evaluation of Novel 2,3-dihydro-2-aryl-4-(4- isobutylphenyl)-1,5-benzothiazepine Derivatives as Anticancer and Anti-EGFR Tyrosine Kinase Agents

Author(s): Afzal B. Shaik*, Yejella R. Prasad, Srinath Nissankararao, Shaik Shahanaaz

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 20 , Issue 9 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Despite the availability of a variety of chemotherapeutic agents, cancer is still one of the leading causes of death worldwide because of the problems with existing chemotherapeutic agents like objectionable side effects, lack of selectivity, and resistance. Hence, there is an urgent need for the development of novel anticancer agents with high usefulness, fewer side effects, devoid of resistance and superior selectivity.

Objective: The objective of this study is to synthesize a series of novel 1,5-benzothiazepine derivatives and evaluate their anticancer activity employing biological and computational methods.

Methods: Twenty new benzothiazepines (BT1-BT20) were prepared by condensing different 1-(4- isobutylphenyl)ethanone chalcones with 2-amiothiophenol and evaluated for their anticancer activity by MTT assay against three cell lines including HT-29 (colon cancer), MCF-7 (breast cancer) and DU-145 (prostate cancer). These compounds were also tested for their inhibitory action against EGFR (Epidermal Growth Factor Receptor) tyrosine kinase enzyme by taking into account of their excellent action against colon and breast cancer cell lines. Further, the structural features responsible for the activity were identified by Pharmacophorebased modelling using Schrodinger’s PHASETM software.

Results: Among the 20 benzothiazepine derivatives, three compounds viz., BT18, BT19 and BT20 exhibited promising activity against the cell lines tested and the activity of BT20 was more than the standard methotrexate. Again the above three compounds showed excellent inhibitory activity with the percentage inhibition of 64.5, 57.3 and 55.8 respectively against EGFR (Epidermal Growth Factor Receptor) tyrosine kinase. PHASE identified a five-point AHHRR model for the proposed activity and the computational studies provided insights into the structural requirements for the anticancer activity and the results were consistent with the observed in vitro activity data.

Conclusion: These novel benzothiazepines will be useful as lead molecules for the further development of new cancer therapies against colon and breast cancers.

Keywords: 1, 5-benzothiazepine, anticancer activity, MTT assay, EGFR tyrosine kinase, PHASETM, AHHRR model.

[1]
NCI Dictionary of Cancer Terms. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/cancer [Accessed March 13, 2019].
[2]
Hejmadi, M. Introduction to Cancer Biology, 2nd ed.; Book boon Ltd : London, 2009.
[3]
Cancer-World Health Organisation. http://www.who.int/topics/cancer/ [Accessed January 17, 2016]
[4]
Bian, T.; Chandagirikoppal Vijendra, K.; Wang, Y.; Meacham, A.; Hati, S.; Cogle, C.R.; Sun, H.; Xing, C. Exploring the structure-activity relationship and mechanism of a chromene scaffold (CXL Series) for its selective antiproliferative activity toward multidrug-resistant cancer cells. J. Med. Chem., 2018, 61(15), 6892-6903.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00813 ] [PMID: 29995404]
[5]
Mansoori, B.; Mohammadi, A.; Davudian, S.; Shirjang, S.; Baradaran, B. The different mechanisms of cancer drug resistance: A brief review. Adv. Pharm. Bull., 2017, 7(3), 339-348.
[http://dx.doi.org/10.15171/apb.2017.041 ] [PMID: 29071215]
[6]
David, E.T. Chemistry and Pharmacology of Anticancer Drugs, 1st ed; CRC Press: Florida, 2006.
[7]
Thomas, L.L.; David, A.W.; Victoria, F.R.; William, Z.S. Foye’s Principles of Medicinal Chemistry. In: Cancer and Chemotherapy; Victoria F Roche, 7th ed; Lippincott Williams & Wilkins: Philadelphia, 2013, pp. 1199-1266.
[8]
Graham, L.P. An Introduction to Medicinal Chemistry. In: Anticancer Agents; Graham L Patrick, 5th ed; Oxford University Press: Oxford, 2013, pp. 514-577.
[9]
Majumdar, P.; Bathula, C.; Basu, S.M.; Das, S.K.; Agarwal, R.; Hati, S.; Singh, A.; Sen, S.; Das, B.B. Design, synthesis and evaluation of thiohydantoin derivatives as potent topoisomerase I (Top1) inhibitors with anticancer activity. Eur. J. Med. Chem., 2015, 102, 540-551.
[http://dx.doi.org/10.1016/j.ejmech.2015.08.032 ] [PMID: 26312433]
[10]
Nagao, T.; Sato, M.; Iwasawa, Y.; Takada, T.; Ishida, R. Studies on a new 1,5-benzothiazepine derivative (CRD-401). 3. Effects of optical isomers of CRD-401 on smooth muscle and other pharmacological properties. Jpn. J. Pharmacol., 1972, 22(4), 467-478.
[http://dx.doi.org/10.1254/jjp.22.467 ] [PMID: 4405112]
[11]
Chaffman, M.; Brogden, R.N. Diltiazem. A review of its pharmacological properties and therapeutic efficacy. Drugs, 1985, 29(5), 387-454.
[http://dx.doi.org/10.2165/00003495-198529050-00001 ] [PMID: 3891302]
[12]
Kawakita, S.; Kinoshita, M.; Ishikawa, H.; Kagoshima, T.; Katori, R.; Ishikawa, K.; Hirota, Y. Efficacy and safety of clentiazem in patients with essential hypertension: Results of an early pilot test. Clin. Cardiol., 1991, 14(1), 53-60.
[http://dx.doi.org/10.1002/clc.4960140112 ] [PMID: 2019030]
[13]
Geyer, H.M., III; Watzman, N.; Buckley, J.P. Effects of a tranquilizer and two antidepressants on learned and unlearned behaviors. J. Pharm. Sci., 1970, 59(7), 964-968.
[http://dx.doi.org/10.1002/jps.2600590709 ] [PMID: 5428090]
[14]
Hopenwasser, J.; Mozayani, A.; Danielson, T.J.; Harbin, J.; Narula, H.S.; Posey, D.H.; Shrode, P.W.; Wilson, S.K.; Li, R.; Sanchez, L.A. Postmortem distribution of the novel antipsychotic drug quetiapine. J. Anal. Toxicol., 2004, 28(4), 264-267.
[http://dx.doi.org/10.1093/jat/28.4.264 ] [PMID: 15189678]
[15]
Bariwal, J.B.; Upadhyay, K.D.; Manvar, A.T.; Trivedi, J.C.; Singh, J.S.; Jain, K.S.; Shah, A.K. 1,5-Benzothiazepine, a versatile pharmacophore: a review. Eur. J. Med. Chem., 2008, 43(11), 2279-2290.
[http://dx.doi.org/10.1016/j.ejmech.2008.05.035 ] [PMID: 18639369]
[16]
Khairy, A.M. El-Bayouki. Synthesis, reactions, and biological activity of 1,4-thiazepines and their fused aryl and heteroaryl derivatives. a review. J. Sulfur Chem., 2011, 32, 623-690.
[http://dx.doi.org/10.1080/17415993.2011.607165]
[17]
Priyanka, R.; Kishore, D. An overview of 1,5-benzothiazepines. Int. J. Pharma Bio Sci., 2013, 4, 779-788.
[18]
Saha, D.; Jain, G.; Sharma, A. Benzothiazepines: Chemistry of a privileged scaffold. RSC Advances, 2015, 5, 70619-70639.
[http://dx.doi.org/10.1039/C5RA12422K]
[19]
El-Bayouki, K.A.M. Benzo[1,5]thiazepine: Synthesis, reactions, spectroscopy, and applications. Org. Chem. Int., 2013, 2013, , Article ID 210474.
[20]
Chandrasekhar, B. Fused 1,5-benzothiazepines from o-aminothiophenol and its derivatives as versatile synthons. Acta Chim. Slov., 2014, 61(4), 651-680.
[PMID: 25551705]
[21]
Wang, L.; Zhang, P.; Zhang, X.; Zhang, Y.; Li, Y.; Wang, Y. Synthesis and biological evaluation of a novel series of 1,5-benzothiazepine derivatives as potential antimicrobial agents. Eur. J. Med. Chem., 2009, 44(7), 2815-2821.
[http://dx.doi.org/10.1016/j.ejmech.2008.12.021 ] [PMID: 19144450]
[22]
Kendre, B.V.; Landge, M.G.; Bhusare, S.R. Synthesis and biological evaluation of some novel pyrazole, isoxazole, benzoxazepine, benzothiazepine and benzodiazepine derivatives bearing an aryl sulfonate moiety as antimicrobial and anti-inflammatory agents. Arab. J. Chem., 2019, 12(8), 2091-2097.
[23]
Kumar, M.; Sharma, K.; Fogla, A.K.; Sharma, K.; Rathore, M. Synthesis and antimicrobial activity of 2,4-diaryl-2,3-dihydrobenzo [b][1,4]thiazepines. Res. Chem. Intermed., 2013, 39, 2555-2564.
[http://dx.doi.org/10.1007/s11164-012-0782-8]
[24]
Dandia, A.; Upreti, M.; Saha, M.; Shivpuri, A. One-pot synthesis of a novel tetracyclic ring system: benzopyrano-1,2,4-trazol0[3,4-b][1,3,4] thiadiazepines and their antifungal activity. Phosphorus Sulfur Silicon Relat. Elem., 1998, 143, 115-124.
[http://dx.doi.org/10.1080/10426509808045490]
[25]
Bhasker, N.; Prashanthi, Y.; Reddy, B.V.S. Piperidine mediated synthesis of hetero chalcones and 8-Substituted-2,5-dihydro-2-(2-furanyl)-4-(2-thienyl)-1,5-benzothiazepines as antibacterial agents. Chem. Sci. Trans., 2014, 3, 11-18.
[26]
Dandia, A.; Singh, R.; Singh, D.; Laxkar, A.; Sivpuri, A. Regioselective synthesis of diltiazem analogue pyrazolo[4,3-c][1,5]benzothiazepines and antifungal activity. Phosphorus Sulfur Silicon Relat. Elem., 2010, 185, 2472-2479.
[http://dx.doi.org/10.1080/10426501003713064]
[27]
Inada, Y.; Itoh, K.; Kamiya, K.; Sugihara, H.; Nishikawa, K. (R)-3-[(S)-1-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5- tetrahydro-1,5-benzothiazepine-5-acetic acid (CV-5975): A new potent and long-lasting inhibitor of angiotensin converting enzyme. Jpn. J. Pharmacol., 1988, 47(2), 135-141.
[http://dx.doi.org/10.1254/jjp.47.135 ] [PMID: 3199591]
[28]
Inoue, H.; Konda, M.; Hashiyama, T.; Otsuka, H.; Watanabe, A.; Gaino, M.; Takahashi, K.; Date, T.; Okamura, K.; Takeda, M.; Narita, H.; Murata, S.; Odawara, A.; Sasaki, H.; Nagao, T. Synthesis biological evaluation of alkyl, alkoxy, alkylthio, or amino-substituted 2,3-dihydro-1,5-benzothiazepin-4(5H)-ones. Chem. Pharm. Bull. (Tokyo), 1997, 45(6), 1008-1026.
[http://dx.doi.org/10.1248/cpb.45.1008 ] [PMID: 9214707]
[29]
Fiorini, I.; Nacci, V.; Ciani, S.M.; Garofalo, A.; Campiani, G.; Savini, L.; Novellino, E.; Greco, G.; Bernasconi, P.; Mennini, T. Novel ligands specific for mitochondrial benzodiazepine receptors: 6-arylpyrrolo[2,1-d][1,5]benzothiazepine derivatives. Synthesis, structure-activity relationships, and molecular modeling studies. J. Med. Chem., 1994, 37(10), 1427-1438.
[http://dx.doi.org/10.1021/jm00036a007 ] [PMID: 8182701]
[30]
Amblard, M.; Daffix, I.; Bedos, P.; Bergé, G.; Pruneau, D.; Paquet, J.L.; Luccarini, J.M.; Bélichard, P.; Dodey, P.; Martinez, J. Design and synthesis of potent bradykinin agonists containing a benzothiazepine moiety. J. Med. Chem., 1999, 42(20), 4185-4192.
[http://dx.doi.org/10.1021/jm9901529 ] [PMID: 10514288]
[31]
Di Santo, R.; Costi, R. 2H-Pyrrolo[3,4-b] [1,5]benzothiazepine derivatives as potential inhibitors of HIV-1 reverse transcriptase. Farmaco, 2005, 60(5), 385-392.
[http://dx.doi.org/10.1016/j.farmac.2005.03.006 ] [PMID: 15910811]
[32]
Suzuki, T.; Ohashi, M.; Takaiti, O.; Harigaya, S. Calmodulin antagonistic action of new 1,5-benzothiazepines derived from diltiazem. Arzneimittelforschung, 1994, 44(1), 3-6.
[PMID: 8135875]
[33]
Gudisela, M.R.; Srinivasu, N.; Mulakayala, C.; Bommu, P.; Rao, M.V.B.; Mulakayala, N. Design, synthesis and anticancer activity of N-(1-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-1-oxo-3-phenylpropan-2-yl derivatives. Bioorg. Med. Chem. Lett., 2017, 27(17), 4140-4145.
[http://dx.doi.org/10.1016/j.bmcl.2017.07.029 ] [PMID: 28756024]
[34]
Xiang, J.; Zhang, Z.; Mu, Y.; Xu, X.; Guo, S.; Liu, Y.; Russo, D.P.; Zhu, H.; Yan, B.; Bai, X. Discovery of novel tricyclic thiazepine derivatives as anti-drug-resistant cancer agents by combining diversity-oriented synthesis and converging screening approach. ACS Comb. Sci., 2016, 18(5), 230-235.
[http://dx.doi.org/10.1021/acscombsci.6b00010 ] [PMID: 27082930]
[35]
Wu, L.; Yang, X.; Peng, Q.; Sun, G. Synthesis and antiproliferative activity evaluation of novel benzo[d][1,3] dioxolesfused 1,4-thiazepines. Eur. J. Med. Chem., 2017, 127, 599-605.
[http://dx.doi.org/10.1016/j.ejmech.2017.01.021 ] [PMID: 28119200]
[36]
Ameta, K.L.; Rathore, N.S.; Kumar, B. Synthesis and in vitro anti-breast cancer activity of some novel 1, 5-benzothiazepine derivatives. J. Serb. Chem. Soc., 2012, 77, 725-731.
[http://dx.doi.org/10.2298/JSC110715219A]
[37]
Martinez, W.R.; Gardenia, C.G.M.; Silva, T.G.D.; Silva, R.O.; Menezes, P.H. Synthesis of novel[3,1]-benzothiazepine and[3,1]-benzoxazepine derivatives with antitumoral activity. RSC Advances, 2014, 4, 14715-14718.
[http://dx.doi.org/10.1039/c3ra44937h]
[38]
Deshmukh, R.N.; Dengle, R.V. Synthesis, characterization and in vitro anticancer evaluation of bis-[1,5]-benzothiazepines against human breast cancer cell line MCF-7. Int. J. Pharm. Sci. Res., 2016, 7, 5024-5029.
[39]
Yang, J.; Yang, S.; Zhou, S.; Lu, D.; Ji, L.; Li, Z.; Yu, S.; Meng, X. Synthesis, anti-cancer evaluation of benzenesulfonamide derivatives as potent tubulin-targeting agents. Eur. J. Med. Chem., 2016, 122, 488-496.
[http://dx.doi.org/10.1016/j.ejmech.2016.07.002 ] [PMID: 27423028]
[40]
Shaik, A.B.; Prasad, Y.R.; Shahanaaz, S. Design, facile synthesis, characterization and computational evaluation of novel isobutylchalcones as cytotoxic agents: Part-A. Fabad Jour. of Pharma. Sci., 2015, 40(1), 1-16.
[41]
Sharma, A.K.; Singh, G.; Yadav, A.K.; Prakash, L. Improved method for the synthesis of new 1,5-benzothiazepine derivatives as analogues of anticancer drugs. Molecules, 1997, 2(9), 129-134.
[http://dx.doi.org/10.3390/20900129]
[42]
Schenone, M.; Dančík, V.; Wagner, B.K.; Clemons, P.A. Target identification and mechanism of action in chemical biology and drug discovery. Nat. Chem. Biol., 2013, 9(4), 232-240.
[http://dx.doi.org/10.1038/nchembio.1199 ] [PMID: 23508189]
[43]
Jung, H.J.; Kwon, H.J. Target deconvolution of bioactive small molecules: the heart of chemical biology and drug discovery. Arch. Pharm. Res., 2015, 38(9), 1627-1641.
[http://dx.doi.org/10.1007/s12272-015-0618-3 ] [PMID: 26040984]
[44]
Lee, H.; Lee, J.W. Target identification for biologically active small molecules using chemical biology approaches. Arch. Pharm. Res., 2016, 39(9), 1193-1201.
[http://dx.doi.org/10.1007/s12272-016-0791-z ] [PMID: 27387321]
[45]
Hati, S.; Tripathy, S.; Dutta, P.K.; Agarwal, R.; Srinivasan, R.; Singh, A.; Singh, S.; Sen, S. Spiro[pyrrolidine-3, 3´-oxindole] as potent anti-breast cancer compounds: Their design, synthesis, biological evaluation and cellular target identification. Sci. Rep., 2016, 6, 32213.
[http://dx.doi.org/10.1038/srep32213 ] [PMID: 27573798]
[46]
Kumar, N.; Hati, S.; Munshi, P.; Sen, S.; Sehrawat, S.; Singh, S. A novel spiroindoline targets cell cycle and migration via modulation of microtubule cytoskeleton. Mol. Cell. Biochem., 2017, 429(1-2), 11-21.
[http://dx.doi.org/10.1007/s11010-016-2932-6 ] [PMID: 28213771]
[47]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4 ] [PMID: 6606682]
[48]
Alyssa, M. Krasinskas. EGFR signaling in colorectal carcinoma. Patholog. Res. Int., 2011, 2011 Article ID 932932.
[49]
Carmi, C.; Cavazzoni, A.; Zuliani, V.; Lodola, A.; Bordi, F.; Plazzi, P.V.; Alfieri, R.R.; Petronini, P.G.; Mor, M. 5-benzylidene-hydantoins as new EGFR inhibitors with antiproliferative activity. Bioorg. Med. Chem. Lett., 2006, 16(15), 4021-4025.
[http://dx.doi.org/10.1016/j.bmcl.2006.05.010 ] [PMID: 16713265]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 20
ISSUE: 9
Year: 2020
Published on: 20 August, 2020
Page: [1115 - 1128]
Pages: 14
DOI: 10.2174/1871520620666200130091142
Price: $65

Article Metrics

PDF: 23
HTML: 1