新型5-氟-1H-苯并咪唑-4-甲酰胺衍生物作为高效PARP-1抑制剂的设计、合成及生物学评价
Design, synthesis and biological evaluation of novel 5-fluoro-1H-benzimidazole-4-carboxamide derivatives as potent PARP-1 inhibitors.
作者信息
Wang Junwei, Wang Xuyan, Li Hui, Ji Dezhong, Li Yuyan, Xu Yungen, Zhu Qihua
机构信息
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
出版信息
Bioorg Med Chem Lett. 2016 Aug 15;26(16):4127-32. doi: 10.1016/j.bmcl.2016.06.045. Epub 2016 Jun 16.
A series of novel 5-fluorine-benzimidazole-4-carboxamide analogs were designed and synthesized. All target compounds were evaluated for their PARP-1 inhibitory activity. Compounds possessed high intrinsic PARP-1 inhibitory potency have been evaluated in vitro cellular assays to measure the potentiation effect of cytotoxic agents against cancer cell line. These efforts led to the identification of compound 10f, which displayed strong inhibition against the PARP-1 enzyme with an IC50 of 43.7nM, excellent cell inhibitory activity in HCT116 cells (IC50=7.4μM) and potentiation of temozolomide cytotoxicity in cancer cell line A549 (PF50=1.6).
设计并合成了一系列新型5-氟苯并咪唑-4-甲酰胺类似物。对所有目标化合物进行了PARP-1抑制活性评估。对具有高内在PARP-1抑制效力的化合物进行了体外细胞试验，以测定细胞毒性剂对癌细胞系的增效作用。这些研究工作导致鉴定出化合物10f，其对PARP-1酶表现出强抑制作用，IC50为43.7nM，在HCT116细胞中具有优异的细胞抑制活性（IC50 = 7.4μM），并且在癌细胞系A549中增强了替莫唑胺的细胞毒性（PF50 = 1.6）。
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