Abstract：
Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors have been successfully applied in the clinical treatment of various cancer. Side effects and drug resistant cases were reported, and more effective PARP-1 inhibitors were required. However, studies on the AD site of PARP-1 inhibitors are currently incomplete. Therefore, to synthesize more potential candidate PARP-1 inhibitors and disclose some AD site SAR of the PARP-1 inhibitors, herein, a series of 2-phenyl-benzimidazole-4-carboxamide derivatives using different saturated nitrogen-contained heterocycles as linker group (6a-6t) have been designed, synthesized, and evaluated PARP-1 inhibitory activity and proliferation inhibitory against BRCA-1 mutant MDA-MB-436 cell line in vitro. The results showed 6b (IC50 = 8.65 nM) exhibited the most PARP-1 enzyme inhibitory activity comparable with Veliparib (IC50 = 15.54 nM) and Olaparib (IC50 = 2.77 nM); 6m exhibited the strongest MDA-MB-436 cell anti-proliferation activity (IC50 = 25.36 ± 6.06 μM) comparable with Olaparib (IC50 = 23.89 ± 3.81 μM). The compounds 6b, 6r, and 6m could be potential candidates for effective PARP-1 inhibitors and valuable for further optimization. The analysis of activity data also showed that the holistically anti-proliferation activity of the 1,4-diazepane group was about~twofold than that of the piperazine group. Meanwhile, the terminal 3-methyl-furanyl group exhibited the most robust PARP-1 inhibitory and anti-proliferation activity. It is hoped that the results could benefitable for further optimization of PARP-1 inhibitors. Furthermore, we note that some compounds (6d,6g,6n,6p,6s) showed poor PARP-1 inhibitory (>500 nM) but relatively good anti-proliferation activity, which indicates the proliferation inhibitory mechanism against MDA-MB-436 cell line was worth investigating in-depth.
摘要：
聚(ADP-核糖)聚合酶-1(PARP-1)抑制剂已成功应用于多种肿瘤的临床治疗。报告了副作用和耐药病例，需要更有效的PARP-1抑制剂。然而,关于PARP-1抑制剂的AD位点的研究目前还不完全。因此,合成更多潜在的候选PARP-1抑制剂，并揭示PARP-1抑制剂的一些AD位点SAR，在这里，设计了一系列2-苯基-苯并咪唑-4-甲酰胺衍生物，使用不同的饱和含氮杂环作为连接基团（6a-6t），合成，并在体外评价了PARP-1对BRCA-1突变型MDA-MB-436细胞的抑制活性和增殖抑制作用。结果显示6b（IC50=8.65nM）表现出与Veliparib（IC50=15.54nM）和Olaparib（IC50=2.77nM）相当的最大PARP-1酶抑制活性；6m表现出最强的MDA-MB-436细胞抗增殖活性（IC50=25.36±6.06μM），与Olaparib（IC50=23.89±3.81μM）相当。化合物6b，6r,和6m可能是有效PARP-1抑制剂的潜在候选者，对进一步优化有价值。活性数据分析还表明，1，4-二氮杂环庚烷组的整体抗增殖活性约为哌嗪组的〜两倍。同时,末端3-甲基呋喃基表现出最强大的PARP-1抑制和抗增殖活性。希望该结果有利于PARP-1抑制剂的进一步优化。此外，我们注意到一些化合物(6d，6g,6n,6p,6s）显示较差的PARP-1抑制（>500nM），但相对良好的抗增殖活性，这表明对MDA-MB-436细胞系的增殖抑制机制值得深入研究。
