2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel HDAC inhibitors with a 3-(benzazol-2-yl)quinoxaline framework

Design, synthesis, and biological evaluation of novel HDAC inhibitors with a 3-(benzazol-2-yl)quinoxaline framework

  • Bioorg Med Chem Lett. 2023 May 15:88:129305. doi: 10.1016/j.bmcl.2023.129305.
Yawen Yang 1,  Qingqing Liu 2,  Xinyi Wang 1,  Shaohua Gou 3
Affiliations

Affiliations

  • 1 Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China.
  • 2 Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; School of Pharmacy, Jilin Medical University, Jilin City 132013, Jilin Province, China.
  • 3 Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China. Electronic address: sgou@seu.edu.cn.
PMID: 37116762 DOI: 10.1016/j.bmcl.2023.129305
Abstract

A series of novel histone deacetylase (HDAC) inhibitors derived from 3-(benzazol-2-yl)quinoxaline derivatives were designed and synthesized by a pharmacophore fusion strategy. In vitro results showed that most of the synthesized compounds exhibited good anti-proliferative activity. Among them, compound 10c showed the most potent cytotoxicity, especially in HCT-116 cells with an IC50 value of 0.91 μM much superior to Vorinostat (5.66 μM). 10c was also found to induce cell Apoptosis, arrest the cell cycle at G2/M phase, induce the generation of Reactive Oxygen Species and inhibit cell invasion and migration in HCT-116 cells. Further studies revealed that 10c could up-regulate the acetylation levels of H3 and α-tubulin, exhibit significant Topo I inhibition and induce the release of related apoptotic biomarkers. These results highlight the great potential of 10c to become a promising anti-cancer HDAC Inhibitor.

Keywords

Antitumor; Epigenetics; Histone deacetylase; Inhibitors; Topoisomerase I.

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