Discovery of the PARP (poly ADP-ribose polymerase) inhibitor 2-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-1H-benzo[d]imidazole-4-carboxamide for the treatment of cancer.
Bioorg Chem. 2021 09; 114:105026.BC

Abstract

In this work, two series of cyclic amine-containing benzimidazole carboxamide derivatives were designed and synthesized as potent anticancer agents. PARP1/2 inhibitory activity assays indicated that most of the compounds showed significant activity. The in vitro antiproliferative activity of these compounds was investigated against four human cancer cell lines (MDA-MB-436, MDA-MB-231, MCF-7 and CAPAN-1), and several compounds exhibited strong cytotoxicity to tumor cells. Among them, 2-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-1H-benzo[d]imidazole-4-carboxamide (17d) was found to be effective PARP1/2 inhibitors (IC50 = 4.30 and 1.58 nM, respectively). In addition, 17d possessed obvious selective antineoplastic activity and noteworthy microsomal metabolic stability. What's more, further studies revealed that 17d was endowed with an excellent ADME profile. These combined results indicated that 17d could be a promising candidate for the treatment of cancer.

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Authors+Show Affiliations

Tang L

Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China; Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518057, PR China.

Wu W

Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518057, PR China; National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.

Zhang C

Shi Z

Department of Chemistry, Tsinghua University, Beijing 100084, PR China.

Chen D

Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518057, PR China.

Zhai X

Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China. Electronic address: zhaixin_syphu@126.com.

Jiang Y

Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China; Joint Key State Laboratory of Tumor Chemogenomics, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, PR China; School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, PR China. Electronic address: jiangyy@sz.tsinghua.edu.cn.

MeSH

AnimalsAntineoplastic AgentsBenzimidazolesCell Line, TumorDrug Screening Assays, AntitumorHumansMaleMicrosomes, LiverMolecular Docking SimulationMolecular Dynamics SimulationPoly (ADP-Ribose) Polymerase-1Poly(ADP-ribose) Polymerase InhibitorsPoly(ADP-ribose) PolymerasesRats, Sprague-Dawley

Pub Type(s)

Journal Article

Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

34186467

Citation

Tang, Lin, et al. "Discovery of the PARP (poly ADP-ribose Polymerase) Inhibitor 2-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-1H-benzo[d]imidazole-4-carboxamide for the Treatment of Cancer." Bioorganic Chemistry, vol. 114, 2021, p. 105026.

Tang L, Wu W, Zhang C, et al. Discovery of the PARP (poly ADP-ribose polymerase) inhibitor 2-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-1H-benzo[d]imidazole-4-carboxamide for the treatment of cancer. Bioorg Chem. 2021;114:105026.

Tang, L., Wu, W., Zhang, C., Shi, Z., Chen, D., Zhai, X., & Jiang, Y. (2021). Discovery of the PARP (poly ADP-ribose polymerase) inhibitor 2-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-1H-benzo[d]imidazole-4-carboxamide for the treatment of cancer. Bioorganic Chemistry, 114, 105026. https://doi.org/10.1016/j.bioorg.2021.105026

Tang L, et al. Discovery of the PARP (poly ADP-ribose Polymerase) Inhibitor 2-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-1H-benzo[d]imidazole-4-carboxamide for the Treatment of Cancer. Bioorg Chem. 2021;114:105026. PubMed PMID: 34186467.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Discovery of the PARP (poly ADP-ribose polymerase) inhibitor 2-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-1H-benzo[d]imidazole-4-carboxamide for the treatment of cancer. AU - Tang,Lin, AU - Wu,Weibin, AU - Zhang,Cunlong, AU - Shi,Zhichao, AU - Chen,Dawei, AU - Zhai,Xin, AU - Jiang,Yuyang, Y1 - 2021/05/26/ PY - 2020/10/09/received PY - 2021/05/06/revised PY - 2021/05/24/accepted PY - 2021/6/30/pubmed PY - 2021/12/16/medline PY - 2021/6/29/entrez KW - ADME properties KW - Anti-cancer KW - Drug design KW - PARP inhibitors SP - 105026 EP - 105026 JF - Bioorganic chemistry JO - Bioorg Chem VL - 114 N2 - In this work, two series of cyclic amine-containing benzimidazole carboxamide derivatives were designed and synthesized as potent anticancer agents. PARP1/2 inhibitory activity assays indicated that most of the compounds showed significant activity. The in vitro antiproliferative activity of these compounds was investigated against four human cancer cell lines (MDA-MB-436, MDA-MB-231, MCF-7 and CAPAN-1), and several compounds exhibited strong cytotoxicity to tumor cells. Among them, 2-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-1H-benzo[d]imidazole-4-carboxamide (17d) was found to be effective PARP1/2 inhibitors (IC50 = 4.30 and 1.58 nM, respectively). In addition, 17d possessed obvious selective antineoplastic activity and noteworthy microsomal metabolic stability. What's more, further studies revealed that 17d was endowed with an excellent ADME profile. These combined results indicated that 17d could be a promising candidate for the treatment of cancer. SN - 1090-2120 UR - https://www.unboundmedicine.com/medline/citation/34186467/Discovery_of_the_PARP__poly_ADP_ribose_polymerase__inhibitor_2__1__44_difluorocyclohexyl_piperidin_4_yl__1H_benzo[d]imidazole_4_carboxamide_for_the_treatment_of_cancer_ DB - PRIME DP - Unbound Medicine ER -

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Discovery of the PARP (poly ADP-ribose polymerase) inhibitor 2-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-1H-benzo[d]imidazole-4-carboxamide for the treatment of cancer.Bioorg Chem. 2021 09; 114:105026.BC