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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.
Molecules. 2019 May 17; 24(10)M

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.

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Authors+Show Affiliations

Min R
Department of Chemistry, Tsinghua University, Beijing 100084, China. mr16@mails.tsinghua.edu.cn. 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. mr16@mails.tsinghua.edu.cn.
Wu W
Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518055, China. weibin.wu@szkivita.com.
Wang M
Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518055, China. mzwang2000@163.com.
Tang L
Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518055, China. adamtl@126.com.
Chen D
Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518055, China. dawei-ba@163.com.
Zhao H
Shenzhen Ruikang Pharmaceutical Technology Co. Ltd., Shenzhen 518055, China. zhaohuan8650@126.com.
Zhang C
Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518055, China. zhcunl@126.com.
Jiang Y
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. Jiangyy@sz.tsinghua.edu.cn. Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China. Jiangyy@sz.tsinghua.edu.cn.

MeSH

Cell Line, TumorCell ProliferationCell SurvivalDrug DiscoveryDrug Screening Assays, AntitumorHumansImidazolesModels, MolecularMolecular Docking SimulationNeoplasmsPoly (ADP-Ribose) Polymerase-1Poly(ADP-ribose) Polymerase InhibitorsPoly(ADP-ribose) PolymerasesStructure-Activity Relationship

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31108884

Citation

Min, Rui, et al. "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 (Basel, Switzerland), vol. 24, no. 10, 2019.
Min R, Wu W, Wang M, et al. 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(10).
Min, R., Wu, W., Wang, M., Tang, L., Chen, D., Zhao, H., Zhang, C., & Jiang, Y. (2019). 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 (Basel, Switzerland), 24(10). https://doi.org/10.3390/molecules24101901
Min R, et al. 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 May 17;24(10) PubMed PMID: 31108884.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Min,Rui, AU - Wu,Weibin, AU - Wang,Mingzhong, AU - Tang,Lin, AU - Chen,Dawei, AU - Zhao,Huan, AU - Zhang,Cunlong, AU - Jiang,Yuyang, Y1 - 2019/05/17/ PY - 2019/03/14/received PY - 2019/04/29/revised PY - 2019/05/02/accepted PY - 2019/5/22/entrez PY - 2019/5/22/pubmed PY - 2019/11/16/medline KW - PARP enzyme inhibition KW - benzimidazole carboxamide KW - poly(ADP-ribose) polymerase JF - Molecules (Basel, Switzerland) JO - Molecules VL - 24 IS - 10 N2 - 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. SN - 1420-3049 UR - https://www.unboundmedicine.com/medline/citation/31108884/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_ DB - PRIME DP - Unbound Medicine ER -