Zhang Zixue, Zhang Qingwei, Zhang Hao, Jiao Minru, Guo Zheng, Peng Xinyan, Fu Lei, Li Jianqi
School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai 201203, China.
Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai 201203, China.
Bioorg Chem. 2021 Dec;117:105407. doi: 10.1016/j.bioorg.2021.105407. Epub 2021 Oct 6.
A series of quinazolinyl-containing benzamide derivatives were designed, synthesized and evaluated for their in vitro histone deacetylase 1 (HDAC1) inhibitory activities. Compounds 11a surpassed the known class I selective HDAC inhibitor MS-275 in both HDAC1 enzymatic inhibitory activity and cellular anti-proliferative activity against a selected set of cancer cell types (Hut78, K562, Hep3B and HCT116 cells) with no observed effects on human normal cells. In particular, compound 11a inhibited HDAC1 over the other tested HDACs isoforms (HDAC2, HDAC6 and HDAC8) with acceptable safety profiles. Moreover, compound 11a displayed favorable oral pharmacokinetic properties and showed significant antitumor activity in the A549 tumor xenograft model in vivo.
设计、合成了一系列含喹唑啉基的苯甲酰胺衍生物，并对其体外组蛋白去乙酰化酶1（HDAC1）抑制活性进行了评估。化合物11a在HDAC1酶抑制活性和对一组选定癌细胞类型（Hut78、K562、Hep3B和HCT116细胞）的细胞抗增殖活性方面均超过了已知的I类选择性HDAC抑制剂MS-275，且对人正常细胞无明显影响。特别是，化合物11a对其他测试的HDAC异构体（HDAC2、HDAC6和HDAC8）具有HDAC1抑制作用，且安全性良好。此外，化合物11a具有良好的口服药代动力学性质，并在体内A549肿瘤异种移植模型中显示出显著的抗肿瘤活性。
