Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Synthesis of Some Benzimidazole-derived Molecules and their Effects on PARP-1 Activity and MDA-MB-231, MDA-MB-436, MDA-MB-468 Breast Cancer Cell Viability

Author(s): A. Selen Gurkan-Alp*, Mehmet Alp, Arzu Z. Karabay, Asli Koc and Erdem Buyukbingol

Volume 20, Issue 14, 2020

Page: [1728 - 1738] Pages: 11

DOI: 10.2174/1871520620666200502001953

Price: $65

Abstract

Background: Poly (ADP-ribosyl) polymerase-1 (PARP-1) inhibitors are compounds that are used to treat cancers, which are defective in DNA-repair and DNA Damage-Response (DDR) pathways.

Objective: In this study, a series of potential PARP-1 inhibitor substituted (piperazine-1-carbonyl)phenyl)-1Hbenzo[ d]imidazole-4-carboxamide compounds were synthesised and tested for their PARP-1 inhibitory and anticancer activities.

Methods: Compounds were tested by cell-free colorimetric PARP-1 activity and MTT assay in MDA-MB-231, MDA-MB-436, MDA-MB-468 breast cancer, and L929 fibroblast cell lines.

Results: Our results showed that compound 6a inhibited viability in MDA-MB-231 and MDA-MB-468 cells whereas 8a inhibited viability in MDA-MB-468 cells. Compound 6b significantly inhibited cell viability in tested cancer cells. However, 6b exhibited toxicity in L929 cells, whereas 6a and 8a were found to be non-toxic for L929 cells. Compounds 6a, 6b and 8a exhibited significant inhibition of PARP-1 activity.

Conclusion: These three compounds exhibited PARP-1 inhibitory activities and anticancer effects on breast cancer cells, and further research will enlighten the underlying mechanisms of their effects.

Keywords: Benzimidazole, breast cancer, cancer, docking, PARP-1 inhibitors, olaparib.

« Previous Next »
Graphical Abstract

[1]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
Geenen, J.J.J.; Linn, S.C.; Beijnen, J.H.; Schellens, J.H.M. PARP inhibitors in the treatment of triple-negative breast cancer. Clin. Pharmacokinet., 2018, 57(4), 427-437.
[http://dx.doi.org/10.1007/s40262-017-0587-4] [PMID: 29063517]
[3]
Wang, X.; Shi, Y.; Huang, D.; Guan, X. Emerging therapeutic modalities of PARP inhibitors in breast cancer. Cancer Treat. Rev., 2018, 68, 62-68.
[http://dx.doi.org/10.1016/j.ctrv.2018.05.014] [PMID: 29870916]
[4]
De Vos, M.; Schreiber, V.; Dantzer, F. The diverse roles and clinical relevance of PARPs in DNA damage repair: Current state of the art. Biochem. Pharmacol., 2012, 84(2), 137-146.
[http://dx.doi.org/10.1016/j.bcp.2012.03.018] [PMID: 22469522]
[5]
Eustermann, S.; Wu, W.F.; Langelier, M.F.; Yang, J.C.; Easton, L.E.; Riccio, A.A.; Pascal, J.M.; Neuhaus, D. Structural basis of detection and signaling of DNA single-strand breaks by human PARP-1. Mol. Cell, 2015, 60(5), 742-754.
[http://dx.doi.org/10.1016/j.molcel.2015.10.032] [PMID: 26626479]
[6]
Cao, M.; Sun, X.; Zhou, Y.; Huang, W.; Meng, L.; Wei, J.F. Poly (ADP-Ribosyl) polymerase 1 inhibitors: A patent review. Rec. Pat. Anticancer Drug Discov., 2017, 12(3), 208-220.
[http://dx.doi.org/10.2174/1574892812666170508124932] [PMID: 28482792]
[7]
Anwar, M.; Aslam, H.M.; Anwar, S. PARP inhibitors. Hered. Cancer Clin. Pract., 2015, 13(1), 4.
[http://dx.doi.org/10.1186/s13053-014-0024-8] [PMID: 25606064]
[8]
Fu, L.; Wang, S.; Wang, X.; Wang, P.; Zheng, Y.; Yao, D.; Guo, M.; Zhang, L.; Ouyang, L. Crystal structure-based discovery of a novel synthesized PARP1 inhibitor (OL-1) with apoptosis-inducing mechanisms in triple-negative breast cancer. Sci. Rep., 2016, 6(1), 3.
[http://dx.doi.org/10.1038/s41598-016-0007-2] [PMID: 28442756]
[9]
U.S. Food and Drug Administration. FDA approves olaparib tablets for maintenance treatment in ovarian cancer., https://www.fda. gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm572143.htm
[10]
Frampton, J.E. Olaparib: A review of its use as maintenance therapy in patients with ovarian cancer. BioDrugs, 2015, 29(2), 143-150.
[http://dx.doi.org/10.1007/s40259-015-0125-6] [PMID: 25899311]
[11]
U.S. Food and Drug Administration. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm533891.htm
[12]
Dockery, L.E.; Gunderson, C.C.; Moore, K.N. Rucaparib: The past, present, and future of a newly approved PARP inhibitor for ovarian cancer. OncoTargets Ther., 2017, 10, 3029-3037.
[http://dx.doi.org/10.2147/OTT.S114714] [PMID: 28790837]
[13]
U.S. Food and Drug Administration. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm548487.htm
[14]
Shi, Y.; Jin, J.; Ji, W.; Guan, X. Therapeutic landscape in mutational triple negative breast cancer. Mol. Cancer, 2018, 17(1), 99.
[http://dx.doi.org/10.1186/s12943-018-0850-9] [PMID: 30007403]
[15]
Ha, K.; Fiskus, W.; Choi, D.S.; Bhaskara, S.; Cerchietti, L.; Devaraj, S.G.; Shah, B.; Sharma, S.; Chang, J.C.; Melnick, A.M.; Hiebert, S.; Bhalla, K.N. Histone deacetylase inhibitor treatment induces ‘BRCAness’ and synergistic lethality with PARP inhibitor and cisplatin against human triple negative breast cancer cells. Oncotarget, 2014, 5(14), 5637-5650.
[http://dx.doi.org/10.18632/oncotarget.2154] [PMID: 25026298]
[16]
Lord, C.J.; Ashworth, A. The DNA damage response and cancer therapy. Nature, 2012, 481(7381), 287-294.
[http://dx.doi.org/10.1038/nature10760] [PMID: 22258607]
[17]
Alp, M.; Gurkan-Alp, A.S.; Ozkan, T.; Sunguroglu, A. Synthesis and antiproliferative evaluation of novel 5-(4-methylpiperazin-1-yl)-2-phenyl- 1H-benzimidazole derivatives. Z. Natforsch. C J. Biosci., 2015, 70(3-4), 79-85.
[http://dx.doi.org/10.1515/znc-2014-4189] [PMID: 26020557]
[18]
Wang, B.; Chu, D. . Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP) activity. GB Patent 2,462,361A, 2010.
[19]
Qiu, J.; Liuzhao, M.; Yunxia, Y.; Xin, C.; Ji, C.; Yong, Z. One type of benzimidazole derivatives and application thereof. CN Patent 10,2627,610, 2012.
[20]
Gurkan-Alp, A.S.; Göker, H.; Alp, M.; Ozkan, T.; Sunguroglu, A. Synthesis and anticancer effects of some novel 2-(4-phenoxyphenyl)-1H-benzimidazole derivatives on K562 cell line. Arch. Pharm. Res., 2015, 38(5), 650-658.
[http://dx.doi.org/10.1007/s12272-014-0438-x] [PMID: 25030856]
[21]
Trott, O.; Olson, A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[PMID: 19499576]
[22]
Dawicki-McKenna, J.M.; Langelier, M.F.; DeNizio, J.E.; Riccio, A.A.; Cao, C.D.; Karch, K.R.; McCauley, M.; Steffen, J.D.; Black, B.E.; Pascal, J.M. PARP-1 activation requires local unfolding of an autoinhibitory domain. Mol. Cell, 2015, 60(5), 755-768.
[http://dx.doi.org/10.1016/j.molcel.2015.10.013] [PMID: 26626480]
[23]
Sanner, M.F. Python: A programming language for software integration and development. J. Mol. Graph. Model., 1999, 17(1), 57-61.
[PMID: 10660911]
[24]
Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera--a visualization system for exploratory research and analysis. J. Comput. Chem., 2004, 25(13), 1605-1612.
[http://dx.doi.org/10.1002/jcc.20084] [PMID: 15264254]
[25]
Koc, A.; Ozkan, T.; Hekmatshoar, Y.; Gurkan-Alp, A.S.; Aktan, F.; Buyukbingol, Z.; Sunguroglu, A.; Buyukbingol, E.; Karabay, A.Z. Apoptotic effects of some tetrahydronaphthalene derivatives on K562 human chronic myelogenous leukemia cell line. Anticancer. Agents Med. Chem., 2018, 17(14), 1924-1930.
[http://dx.doi.org/10.2174/1871521409666170412122811] [PMID: 28403785]
[26]
Sugimoto, M.; Honna, K.; Kurisaki, K.; Sugahara, H.; Watanable, K.; Fujimoto, Y.; Ryu, S. Adamantane-Piperazine Derivatives. US Patent 4,001,223. 1977.
[27]
Arienti, K.L.; Brunmark, A.; Axe, F.U.; McClure, K.; Lee, A.; Blevitt, J.; Neff, D.K.; Huang, L.; Crawford, S.; Pandit, C.R.; Karlsson, L.; Breitenbucher, J.G. Checkpoint kinase inhibitors: SAR and radioprotective properties of a series of 2-arylbenzimidazoles. J. Med. Chem., 2005, 48(6), 1873-1885.
[http://dx.doi.org/10.1021/jm0495935] [PMID: 15771432]
[28]
Hideg, K Sümegi, B New alicyclic-amine-substituted 4- carboxamido-benzimidazoles as parp-inhibitors and antioxidants. WO Patent 2,004,096,793A1,. 2004.
[29]
Liu, L.; Kong, M.; Gassman, N.R.; Freudenthal, B.D.; Prasad, R.; Zhen, S.; Watkins, S.C.; Wilson, S.H.; Van Houten, B. PARP1 changes from three-dimensional DNA damage searching to one-dimensional diffusion after auto-PARylation or in the presence of APE1. Nucleic Acids Res., 2017, 45(22), 12834-12847.
[http://dx.doi.org/10.1093/nar/gkx1047] [PMID: 29121337]
[30]
Ali, M.G.; Silvano, D.A.E.; Barros, D.A.P.L. Diamondoid molecules: With Applications in Biomedicine, Materials Science, Nanotechnology & Petroleum Science; World Scientific Publishing Company: USA, 2012.
[31]
Riganas, S.; Papanastasiou, I.; Foscolos, G.B.; Tsotinis, A.; Dimas, K.; Kourafalos, V.N.; Eleutheriades, A.; Moutsos, V.I.; Khan, H.; Margarita, P.; Georgakopoulou, S.; Zaniou, A.; Theodoropoulou, M.; Mantelas, A.; Pondiki, S.; Vamvakides, A. New adamantane derivatives with sigma affinity and antiproliferative activity. Med. Chem., 2012, 8(4), 569-586.
[http://dx.doi.org/10.2174/157340612801216201] [PMID: 22530894]
[32]
Hu, H.; Lin, C.; Ao, M.; Ji, Y.; Tang, B.; Zhou, X.; Fang, M.; Zeng, J.; Wu, Z. Synthesis and biological evaluation of 1-(2-(adamantane-1-yl)-1H-indol-5-yl)-3-substituted urea/thiourea derivatives as anticancer agents. RSC Adv., 2017, 7(81), 51640-51651.
[http://dx.doi.org/10.1039/C7RA08149A]
[33]
Arun, B.; Akar, U.; Gutierrez-Barrera, A.M.; Hortobagyi, G.N.; Ozpolat, B. The PARP inhibitor AZD2281 (Olaparib) induces autophagy/mitophagy in BRCA1 and BRCA2 mutant breast cancer cells. Int. J. Oncol., 2015, 47(1), 262-268.
[http://dx.doi.org/10.3892/ijo.2015.3003] [PMID: 25975349]
[34]
Ryu, H.; Ahn, J.; Choi, H.K. Novel benzamide derivatives: Synthesis and bioactivity as potent PARP-1 inhibitors. Bull. Korean Chem. Soc., 2017, 38(8), 935-943.
[http://dx.doi.org/10.1002/bkcs.11207]

Rights & Permissions Print Cite
Article Metrics
82
10
© 2024 Bentham Science Publishers | Privacy Policy