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Current Drug Research Reviews

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ISSN (Print): 2589-9775
ISSN (Online): 2589-9783

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Research Article

Repurposing of Benzimidazole Scaffolds for HER2 Positive Breast Cancer Therapy: An In-Silico Approach

Author(s): Selvaraj Jubie, Uma Durai, Subbiah Latha, Selvaraj Ayyamperumal, Ashish Wadhwani and Thangavelu Prabha*

Volume 13, Issue 1, 2021

Published on: 21 August, 2020

Page: [73 - 83] Pages: 11

DOI: 10.2174/2589977512999200821170221

Price: $65

Abstract

Background: A newer trend has been seen recently to reuse the conventional drugs with distinct indications for the newer applications to speed up the drug discovery and development based on earlier records and safety data. Most of the non-cancerous agents could afford a little or tolerable side effects in individuals. However, the repositioning of these non-cancerous agents for successful anticancer therapy is an outstanding strategy for future anti-cancer drug development. Since more diverse and selective cancer drug targets are being discovered and developed, the approved drug collections are particularly useful to quickly identify clinically advanced anticancer drugs against those targets.

Objective: Antihelminthic drugs such as Mebendazole and Albendazole (Benzimidazole class) have been reported to exhibit cytotoxicity (or anticancer activities) against several types of cancer. Therefore, this study aims to repurpose the benzimidazole scaffold for breast cancer treatment.

Methods: In the present study, three hydrazone analogs having a benzimidazole motif in their structural frame were synthesized. Their in-silico binding studies against HER2 receptor (PDB ID: 4LQM) and ADMET studies were carried out using Accelrys drug discovery studio 4.1. Cytotoxicity of the synthesized compounds against HER2 overexpressed MCF-7 cell lines was determined by MTT assay.

Results: One of the compounds 2-[2-(2,4-dinitrophenyl)hydrazinylidene]-2,3-dihydro-1H-benzimidazole (U1) has shown good cytotoxicity when compared to the standard Lapatinib, which is a well known HER2 inhibitor.

Conclusions: Thus, the designed benzimidazole scaffold might serve as the best leads for treating breast cancer, which is additionally confirmed by performing their docking study via Accelrys discovery studio.

Keywords: Repurposing, benzimidazole, in-silico study, HER2, breast cancer, accelrys drug discovery studio 4.1.

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[1]
Gurova K. New hopes from old drugs: revisiting DNA-binding small molecules as anticancer agents. Future Oncol 2009; 5(10): 1685-704.
[http://dx.doi.org/10.2217/fon.09.127] [PMID: 20001804]
[2]
Ito T, Ando H, Suzuki T, et al. Identification of a primary target of thalidomide teratogenicity. Science 2010; 327(5971): 1345-50.
[http://dx.doi.org/10.1126/science.1177319] [PMID: 20223979]
[3]
de Thé H, Le Bras M, Lallemand-Breitenbach V. The cell biology of disease: Acute promyelocytic leukemia, arsenic, and PML bodies. J Cell Biol 2012; 198(1): 11-21.
[http://dx.doi.org/10.1083/jcb.201112044] [PMID: 22778276]
[4]
Chen H, Wu J, Gao Y, Chen H, Zhou J. Scaffold repurposing of old drugs towards new cancer drug discovery. Curr Top Med Chem 2016; 16(19): 2107-14.
[http://dx.doi.org/10.2174/1568026616666160216155556] [PMID: 26881709]
[5]
Kushida CA. Ropinirole for the treatment of restless legs syndrome. Neuropsychiatr Dis Treat 2006; 2(4): 407-19.
[http://dx.doi.org/10.2147/nedt.2006.2.4.407] [PMID: 19412490]
[6]
Julie HI, Charles EM, Michael AS, Barbara AG, Kirsten LJ. Gabapentin and pregabalin use and association with adverse outcomes among hemodialysis patients. J Am Soc Nephrol 2018; 29: 1970-8.
[http://dx.doi.org/10.1681/ASN.2018010096]
[7]
Xue H, Li J, Xie H, Wang Y. Review of drug repositioning approaches and resources. Int J Biol Sci 2018; 14(10): 1232-44.
[http://dx.doi.org/10.7150/ijbs.24612] [PMID: 30123072]
[8]
Truong M, Monahan LG, Carter DA, Charles IG. Repurposing drugs to fast-track therapeutic agents for the treatment of cryptococcosis. PeerJ 2018; 6: e4761.
[http://dx.doi.org/10.7717/peerj.4761] [PMID: 29740519]
[9]
Cruz MC, Bartlett MS, Edlind TD. In vitro susceptibility of the opportunistic fungus Cryptococcus neoformans to anthelmintic benzimidazoles. Antimicrob Agents Chemother 1994; 38(2): 378-80.
[http://dx.doi.org/10.1128/AAC.38.2.378] [PMID: 8192471]
[10]
Joffe LS, Schneider R, Lopes W, et al. The antihelminthic compound mebendazole has multiple antifungal effects against Cryptococcus neoformans. Front Microbiol 2017; 8: 535.
[http://dx.doi.org/10.3389/fmicb.2017.00535] [PMID: 28400768]
[11]
https://www.who.int/cancer/prevention/diagnosis-screening/breast-cancer/en/
[12]
Nygren P, Larsson R. Drug repositioning from bench to bedside: tumour remission by the antihelmintic drug mebendazole in refractory metastatic colon cancer. Acta Oncol 2014; 53(3): 427-8.
[http://dx.doi.org/10.3109/0284186X.2013.844359] [PMID: 24160353]
[13]
Martin RJ. Modes of action of anthelmintic drugs. Vet J 1997; 154(1): 11-34.
[http://dx.doi.org/10.1016/S1090-0233(05)80005-X] [PMID: 9265850]
[14]
Hu Y, Ellis BL, Yiu YY, et al. An extensive comparison of the effect of anthelmintic classes on diverse nematodes. PLoS One 2013; 8(7): e70702.
[http://dx.doi.org/10.1371/journal.pone.0070702] [PMID: 23869246]
[15]
Martarelli D, Pompei P, Baldi C, Mazzoni G. Mebendazole inhibits growth of human adrenocortical carcinoma cell lines implanted in nude mice. Cancer Chemother Pharmacol 2008; 61(5): 809-17.
[http://dx.doi.org/10.1007/s00280-007-0538-0] [PMID: 17581752]
[16]
Sasaki J, Ramesh R, Chada S, Gomyo Y, Roth JA, Mukhopadhyay T. The anthelmintic drug mebendazole induces mitotic arrest and apoptosis by depolymerizing tubulin in non-small cell lung cancer cells. Mol Cancer Ther 2002; 1(13): 1201-9.
[PMID: 12479701]
[17]
Mukhopadhyay T, Sasaki J, Ramesh R, Roth JA. Mebendazole elicits a potent antitumor effect on human cancer cell lines both in vitro and in vivo. Clin Cancer Res 2002; 8(9): 2963-9.
[PMID: 12231542]
[18]
Larsen AR, Bai RY, Chung JH, et al. Repurposing the antihelmintic mebendazole as a hedgehog inhibitor. Mol Cancer Ther 2015; 14(1): 3-13.
[http://dx.doi.org/10.1158/1535-7163.MCT-14-0755-T] [PMID: 25376612]
[19]
Upcroft P, Upcroft JA. Drug targets and mechanisms of resistance in the anaerobic protozoa. Clin Microbiol Rev 2001; 14(1): 150-64.
[http://dx.doi.org/10.1128/CMR.14.1.150-164.2001] [PMID: 11148007]
[20]
Bertram GK. Clinical pharmacology of the anthelmintic drugs. 1992.
[21]
Pourgholami MH, Woon L, Almajd R, Akhter J, Bowery P, Morris DL. in vitro and in vivo suppression of growth of hepatocellular carcinoma cells by albendazole. Cancer Lett 2001; 165(1): 43-9.
[http://dx.doi.org/10.1016/S0304-3835(01)00382-2] [PMID: 11248417]
[22]
Khalilzadeh A, Wangoo KT, Morris DL, Pourgholami MH. Epothilone-paclitaxel resistant leukemic cells CEM/dEpoB300 are sensitive to albendazole: Involvement of apoptotic pathways. Biochem Pharmacol 2007; 74(3): 407-14.
[http://dx.doi.org/10.1016/j.bcp.2007.05.006] [PMID: 17560963]
[23]
Chu SW, Badar S, Morris DL, Pourgholami MH. Potent inhibition of tubulin polymerisation and proliferation of paclitaxel-resistant 1A9PTX22 human ovarian cancer cells by albendazole. Anticancer Res 2009; 29(10): 3791-6.
[PMID: 19846910]
[24]
Patel K, Doudican NA, Schiff PB, Orlow SJ. Albendazole sensitizes cancer cells to ionizing radiation. Radiat Oncol 2011; 6: 160.
[http://dx.doi.org/10.1186/1748-717X-6-160] [PMID: 22094106]
[25]
Kaushik NK, Kaushik N, Park D, Choi EH. Altered antioxidant system stimulates dielectric barrier discharge plasma-induced cell death for solid tumor cell treatment. PLoS One 2014; 9(7): e103349.
[http://dx.doi.org/10.1371/journal.pone.0103349] [PMID: 25068311]
[26]
Jubie S, Selvaraj A, Neethu Y, et al. Early stage repurposing of benzimidazole scaffolds towards breast cancer through in-silico tools. J Pharm Sci 2018; 10(10): 2419-23.
[27]
Zahi M, Tina C. the her2 receptor in breast cancer: pathophysiology, clinical use, and new advances in therapy. Chemother Res Pract 2012; 2012: 743193.
[28]
Swain SM, Baselga J, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 2015; 372(8): 724-34.
[http://dx.doi.org/10.1056/NEJMoa1413513] [PMID: 25693012]
[29]
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER2/neu oncogene. Science 1987; 235(4785): 177-82.
[http://dx.doi.org/10.1126/science.3798106] [PMID: 3798106]
[30]
Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344(11): 783-92.
[http://dx.doi.org/10.1056/NEJM200103153441101] [PMID: 11248153]
[31]
Davoli A, Hocevar BA, Brown TL. Progression and treatment of HER2-positive breast cancer. Cancer Chemother Pharmacol 2010; 65(4): 611-23.
[http://dx.doi.org/10.1007/s00280-009-1208-1] [PMID: 20087739]
[32]
Freudenberg JA, Wang Q, Katsumata M, Drebin J, Nagatomo I, Greene MI. The role of HER2 in early breast cancer metastasis and the origins of resistance to HER2-targeted therapies. Exp Mol Pathol 2009; 87(1): 1-11.
[http://dx.doi.org/10.1016/j.yexmp.2009.05.001] [PMID: 19450579]
[33]
Ayaz MD, Shafia M. Molecular docking approaches, types application and basic challenges. J Anal Bioanal Tech 2017; 8(02): 356-8.
[34]
Jubie S, Pawan KY, Chandrasekar MJN, Gomathi PJ, Chaitanya MVNL, Dhanabal SP. Novel fatty acid analogues as fatty acid synthase-thio esterase domain inhibitors; Synthesis and their cytotoxicity screening. Lett Drug Des Discov 2015; 12(6): 495.
[http://dx.doi.org/10.2174/1570180812666141216210751]
[35]
Blaise KN, Pierre T, Alex N, Jubie S, Selvaraj A, Chandrasekar MJN. Identification of human nmprtase inhibitors from adenocarpus mannii; an in-silico approach. J Pharm Sci. 2017; 9(2): 95-9.
[36]
Bkhaitan MM, Mirza AZ, Shamshad H, Ali HI. Identification of potent virtual leads and ADME prediction of isoxazolidine podophyllotoxin derivatives as topoisomerase II and tubulin inhibitors. J Mol Graph Model 2017; 73: 74-93.
[http://dx.doi.org/10.1016/j.jmgm.2017.01.015] [PMID: 28242581]
[37]
Prival MJ. Evaluation of the TOPKAT system for predicting the carcinogenicity of chemicals. Environ Mol Mutagen 2001; 37(1): 55-69.
[http://dx.doi.org/10.1002/1098-2280(2001)37:1<55::AID-EM1006>3.0.CO;2-5] [PMID: 11170242]
[38]
Qu Q, Qu J, Han L, et al. Inhibitory effects of phytochemicals on metabolic capabilities of CYP2D6(*)1 and CYP2D6(*)10 using cell-based models in vitro. Acta Pharmacol Sin 2014; 35(5): 685-96.
[http://dx.doi.org/10.1038/aps.2013.202] [PMID: 24786236]
[39]
McMasters DR, Torres RA, Crathern SJ, et al. Inhibition of recombinant cytochrome P450 isoforms 2D6 and 2C9 by diverse drug-like molecules. J Med Chem 2007; 50(14): 3205-13.
[http://dx.doi.org/10.1021/jm0700060] [PMID: 17559204]
[40]
Poulin P, Burczynski FJ, Haddad S. The role of extracellular binding proteins in the cellular uptake of drugs: Impact on quantitative in vitro-to-in vivo extrapolations of toxicity and efficacy in physiologically based pharmacokinetic-pharmacodynamic research. J Pharm Sci 2016; 105(2): 497-508.
[http://dx.doi.org/10.1002/jps.24571] [PMID: 26173749]
[41]
Venkanna A, Pavan ChK, Poornima B, Bandi S, Nishant J. Suresh Babu K. Design, synthesis and anti-proliferative activities of novel-7′- o-substituted schisantherin a derivatives. MedChemComm 2016; 7: 1159-70.
[http://dx.doi.org/10.1039/C6MD00097E]

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