Synthesis and anticancer activity of novel histone deacetylase inhibitors that inhibit autophagy and induce apoptosis

Eur J Med Chem. 2022 Dec 5:243:114705. doi: 10.1016/j.ejmech.2022.114705.

Hualong Mo ¹, Ruiqiang Zhang ¹, Yajun Chen ¹, ShuTing Li ¹, Yao Wang ², Wenbo Zou ¹, Qiman Lin ¹, Deng-Gao Zhao ³, Yarong Du ⁴, Kun Zhang ⁵, Yan-Yan Ma ⁶

Affiliations

1 School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, 529020, China.
2 School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, 529020, China; International Healthcare Innovation Institute (Jiangmen), Jiangmen, 529040, China; Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, Jiangmen, China.
3 School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, 529020, China; International Healthcare Innovation Institute (Jiangmen), Jiangmen, 529040, China. Electronic address: zhaodenggao@wyu.edu.cn.
4 Key Laboratory of Space Radiobiology of Gansu Province & CAS Key Laboratory of Heavy Ion Radiation Biology and Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China. Electronic address: duyrlive@impcas.ac.cn.
5 School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, 529020, China; International Healthcare Innovation Institute (Jiangmen), Jiangmen, 529040, China.
6 School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, 529020, China. Electronic address: mayanyan@wyu.edu.cn.

PMID: 36215854 DOI: 10.1016/j.ejmech.2022.114705

Abstract

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.

Keywords

Antitumor; Apoptosis; Autophagy; Histone deacetylase inhibitor; Vorinostat.

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