Li Hui, Hu Yan, Wang Xueyan, He Guangwei, Xu Yungen, Zhu Qihua
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 21009, China.
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 21009, China.
Bioorg Med Chem. 2016 Oct 1;24(19):4731-4740. doi: 10.1016/j.bmc.2016.08.016. Epub 2016 Aug 11.
8,9-Dihydro-2,4,7,9a-tetraazabenzo[cd]azulen-6(7H)-ones were designed and synthesized as a new class of PARP-1/2 inhibitors. The compounds displayed a variable pattern of PARP-1/2 enzymes inhibition profile that, in part, paralleled the antiproliferative activity in cell lines. Among them, compound 9e exhibited not only the significant IC50 value of 28nM in the PARP-1 and 7.7nM in PARP-2 enzyme assay, but also a profound synergic efficacy combined with temozolomide with PF50 values of 2.6, 2.5, and 6.5 against MDA-MB-468, SW-620 and A549 and cell line, respectively.
8,9-二氢-2,4,7,9a-四氮杂苯并[cd]薁-6(7H)-酮被设计并合成为一类新型的PARP-1/2抑制剂。这些化合物表现出不同的PARP-1/2酶抑制谱模式，部分与细胞系中的抗增殖活性平行。其中，化合物9e不仅在PARP-1酶分析中显示出28nM的显著IC50值，在PARP-2酶分析中显示出7.7nM的显著IC50值，而且与替莫唑胺联合使用时具有显著的协同功效，对MDA-MB-468、SW-620和A549细胞系的PF50值分别为2.6、2.5和6.5。
