Department of Medicinal Chemistry, School of Pharmacy, Qingdao University Medical College, Qingdao University, Qingdao, Shandong, China.
State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 211198 Nanjing, China.
Bioorg Med Chem Lett. 2022 Sep 1;71:128821. doi: 10.1016/j.bmcl.2022.128821. Epub 2022 May 25.
Both poly(ADP-ribose)polymerase-1 (PARP-1) and histone deacetylase (HDAC) are important antitumor targets and have attracted extensive attention. In this work, a total of fourteen PARP-1/HDAC dual targeting inhibitors were designed and synthesized using either benzopyrazole or benzimidazole as core structures. Two leading compounds 1-8-6 and 1-8-7 were proven to be dual targeting inhibitors of PARP-1 and HDAC6, and showed high antiproliferative activities against six human cancer cell lines with IC values in micromole range. Moreover, compounds 1-8-6 and 1-8-7 could impair tumor cell proliferation in 48 h and 72 h with much higher potency than co-treatment of Olaparib and Tubastatin A. 1-8-6 displayed remarkable anti-migration and anti-angiogenesis activities. Meanwhile, western blot experiment result showed that 1-8-6 was able to heighten expression level of acetylated α-tubulin with marginal effects to acetylated histones H3 and H4. Finally, docking simulation work showed that 1-8-6 could fit into the active sites of PARP-1 and HDAC6. All results indicated that 1-8-6 is a promising candidate for further preclinical studies.
聚（ADP-核糖）聚合酶-1（PARP-1）和组蛋白去乙酰化酶（HDAC）都是重要的抗肿瘤靶点，引起了广泛关注。在这项工作中，我们设计并合成了 14 种以苯并吡唑或苯并咪唑为核心结构的 PARP-1/HDAC 双重靶向抑制剂。两个先导化合物 1-8-6 和 1-8-7 被证明是 PARP-1 和 HDAC6 的双重靶向抑制剂，对六种人癌细胞系具有高的抗增殖活性，IC 值在微摩尔范围内。此外，化合物 1-8-6 和 1-8-7 在 48 小时和 72 小时内可显著抑制肿瘤细胞增殖，其活性明显高于奥拉帕尼和他拉唑胺的联合处理。1-8-6 显示出显著的抗迁移和抗血管生成活性。同时，Western blot 实验结果表明，1-8-6 能够提高乙酰化微管蛋白的表达水平，对乙酰化组蛋白 H3 和 H4 的影响较小。最后，对接模拟工作表明，1-8-6 能够与 PARP-1 和 HDAC6 的活性位点结合。所有结果表明，1-8-6 是进一步进行临床前研究的有前途的候选药物。
