化学
组蛋白脱乙酰基酶
自噬
伏立诺他
细胞凋亡
恶唑
乙酰化
组蛋白脱乙酰酶抑制剂
细胞周期检查点
组蛋白H3
细胞周期
去肽
组蛋白H4
癌症研究
组蛋白
生物化学
生物
基因
作者
Hualong Mo,Ruiqiang Zhang,Yajun Chen,ShuTing Li,Yao Wang,Wei Zou,Qiman Lin,Deng-Gao Zhao,Yarong Du,Kun Zhang,Yanyan Ma
标识
DOI:10.1016/j.ejmech.2022.114705
摘要
The combination of histone deacetylase (HDAC) and autophagy inhibitor has been considered as a novel cancer therapeutic strategy. To find novel HDAC inhibitors that can inhibit autophagy, several new series of oxazole- and thiazole-based HDAC inhibitors were designed and synthesized by replacing the phenyl cap in SAHA with 5-phenyloxazoles and 5-phenylthiazoles. The representative oxazole derivative, compound 21, showed better enzymatic inhibitory activity than SAHA (vorinostat). Compound 21 induced G2/M cell cycle arrest and its antiproliferative activity is 10-fold better than SAHA in multiple tumor cell lines. Western blot analysis showed that compound 21 can markedly increase the acetylation levels of tubulin, histone H3, and histone H4. Contrary to SAHA, compound 21 was found to inhibit autophagy. Additionally, compound 21 induced cell apoptosis via the Bax/Bcl-2 and caspase-3 pathways. Ultimately, compound 21 exhibited higher oral antitumor potency than SAHA in a A549 xenograft model. Our results indicated that compound 21 may be further developed as a promising anticancer agent.
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