School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui 230009, PR China.
School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui 230009, PR China.
Bioorg Med Chem Lett. 2020 Apr 15;30(8):127036. doi: 10.1016/j.bmcl.2020.127036. Epub 2020 Feb 14.
Currently, synergistic inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) and histone deacetylases (HDACs) has been a potential effective strategy for cancer treatment. Herein, by combining critical pharmacophores in approved drugs olaparib and chidamide, a series of novel 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid derivatives were designed and synthesized. All efforts led to a good dual PARP-1/HDAC-1 inhibitor, compound 4, with IC values of 4.2 and 340 nM against PARP-1 and HDAC-1, which were as potent as olaparib and chidamide respectively. The MTT assay further demonstrated that compound 4 had potent inhibitory activities against BRCA1/2-proficient K562 and MDA-MB-231 cells with GI values of 5.6 and 4.3 μM, respectively. Therefore, our results suggested that compound 4 could be a promising dual PARP-1/HDAC-1 inhibitor for further studies. In addition, a few excellent PARP-1 inhibitors such as 7-9 and HDAC-1 inhibitors such as 12 were serendipitously discovered, which also could be further studied in our next work.
目前，聚（ADP-核糖）聚合酶-1（PARP-1）和组蛋白去乙酰化酶（HDACs）的协同抑制已成为癌症治疗的一种潜在有效策略。在此，通过将已批准药物奥拉帕利和西达本胺中的关键药效团结合在一起，设计并合成了一系列新型 2-氟-5-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯甲酸衍生物。所有的努力都得到了一个良好的双重 PARP-1/HDAC-1 抑制剂，化合物 4，对 PARP-1 和 HDAC-1 的 IC 值分别为 4.2 和 340 nM，分别与奥拉帕利和西达本胺相当。MTT 测定进一步表明，化合物 4 对 BRCA1/2 有效的 K562 和 MDA-MB-231 细胞具有很强的抑制活性，GI 值分别为 5.6 和 4.3 μM。因此，我们的结果表明，化合物 4 可能是一种有前途的双重 PARP-1/HDAC-1 抑制剂，值得进一步研究。此外，还意外地发现了一些优秀的 PARP-1 抑制剂，如 7-9，以及一些优秀的 HDAC-1 抑制剂，如 12，它们也可以在我们的下一步工作中进一步研究。
