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Discovery of 2-(1-(3-(4-Chloroxyphenyl)-3-oxo- propyl)pyrrolidine-3-yl)-1H-benzo[d]imidazole-4-carboxamide: A Potent Poly(ADP-ribose) Polymerase (PARP) Inhibitor for Treatment of Cancer

1
Department of Chemistry, Tsinghua University, Beijing 100084, China
2
The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China
3
Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518055, China
4
Shenzhen Ruikang Pharmaceutical Technology Co. Ltd., Shenzhen 518055, China
5
Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Simona Collina and Mariarosaria Miloso
Molecules 2019, 24(10), 1901; https://doi.org/10.3390/molecules24101901
Received: 14 March 2019 / Revised: 29 April 2019 / Accepted: 2 May 2019 / Published: 17 May 2019
(This article belongs to the Special Issue Recent Advances in Anticancer Drugs)
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Abstract

A series of benzimidazole carboxamide derivatives have been synthesized and characterized by 1H-NMR, 13C-NMR and HRMS. PARP inhibition assays and cellular proliferation assays have also been carried out. Compounds 5cj and 5cp exhibited potential anticancer activities with IC50 values of about 4 nM against both PARP-1 and PARP-2, similar to the reference drug veliparib. The two compounds also displayed slightly better in vitro cytotoxicities against MDA-MB-436 and CAPAN-1 cell lines than veliparib and olaparib, with values of 17.4 µM and 11.4 µM, 19.8 µM and 15.5 µM, respectively. The structure-activity relationship based on molecular docking was discussed as well. View Full-Text
Keywords: poly(ADP-ribose) polymerase; PARP enzyme inhibition; benzimidazole carboxamide poly(ADP-ribose) polymerase; PARP enzyme inhibition; benzimidazole carboxamide
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Min, R.; Wu, W.; Wang, M.; Tang, L.; Chen, D.; Zhao, H.; Zhang, C.; Jiang, Y. Discovery of 2-(1-(3-(4-Chloroxyphenyl)-3-oxo- propyl)pyrrolidine-3-yl)-1H-benzo[d]imidazole-4-carboxamide: A Potent Poly(ADP-ribose) Polymerase (PARP) Inhibitor for Treatment of Cancer. Molecules 2019, 24, 1901.

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