Design, synthesis and bioactivity evaluations of 8-substituted-quinoline-2-carboxamide derivatives as novel histone deacetylase (HDAC) inhibitors

  • Bioorg Med Chem. 2023 May 1:85:117242. doi: 10.1016/j.bmc.2023.117242.
Yunpeng Zhao  1 ,  Zefu Yao  1 ,  Wandi Ren  2 ,  Xinying Yang  2 ,  Xuben Hou  1 ,  Shengda Cao  3 ,  Hao Fang  4
Affiliations
  • 1. Department of Medicinal Chemistry and Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 250012 Jinan, Shandong, PR China.
  • 2. Department of Pharmaceutical Analysis and Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 250012 Jinan, Shandong, PR China.
  • 3. Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012 Jinan, Shandong, PR China; Department of Medicinal Chemistry and Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 250012 Jinan, Shandong, PR China. Electronic address: [email protected].
  • 4. Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012 Jinan, Shandong, PR China; Department of Medicinal Chemistry and Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 250012 Jinan, Shandong, PR China. Electronic address: [email protected].
PMID: 37079967 DOI: 10.1016/j.bmc.2023.117242
Abstract

The inhibition of histone deacetylases (HDACs) has been considered a promising therapeutic strategy for treatment of many diseases, especially Cancer. In the current study, a series of 8-substituted quinoline-2-carboxamide derivatives were designed and synthesized as potent HDAC inhibitors. The most potent compound 21 g (IC50 = 0.050 µM) exhibited 3-fold greater HDAC inhibitory activity compared to the known HDAC Inhibitor Vorinostat (IC50 = 0.137 µM). Additionally, compound 21g exhibited low toxicity against normal cells(IC50 in HUVEC cell > 50 µM) and showed good liver microsomal stability, therefore, may serve as a new lead compound for further development.

Keywords
Anti-cancer; HDAC inhibitor; Quinoline derivativve.