Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China; Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518057, PR China.
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.
Bioorg Chem. 2021 Sep;114:105026. doi: 10.1016/j.bioorg.2021.105026. Epub 2021 May 26.
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 (IC = 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.
在这项工作中，设计并合成了两个系列含环胺的苯并咪唑甲酰胺衍生物，作为有效的抗癌剂。PARP1/2 抑制活性测定表明，大多数化合物表现出显著的活性。对这些化合物进行了体外抗增殖活性研究，针对四种人癌细胞系（MDA-MB-436、MDA-MB-231、MCF-7 和 CAPAN-1），其中一些化合物对肿瘤细胞表现出强烈的细胞毒性。其中，2-(1-(4,4-二氟环己基)哌啶-4-基)-1H-苯并[d]咪唑-4-甲酰胺（17d）被发现是有效的 PARP1/2 抑制剂（IC50 值分别为 4.30 和 1.58 nM）。此外，17d 具有明显的选择性抗肿瘤活性和值得注意的微粒体代谢稳定性。更重要的是，进一步的研究表明，17d 具有优异的 ADME 特性。这些综合结果表明，17d 可能是治疗癌症的有前途的候选药物。
