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

Yawen Yang; Qingqing Liu; Xinyi Wang; Shaohua Gou

doi:10.1016/j.bmcl.2023.129305

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. Epub 2023 Apr 26.

Authors

Yawen Yang¹, Qingqing Liu², Xinyi Wang¹, Shaohua Gou³

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / pharmacology
Apoptosis
Cell Line, Tumor
Cell Proliferation
Drug Design
Drug Screening Assays, Antitumor
Histone Deacetylase Inhibitors* / pharmacology
Humans
Quinoxalines / pharmacology
Structure-Activity Relationship
Vorinostat / pharmacology

Substances

Histone Deacetylase Inhibitors
Antineoplastic Agents
Quinoxalines
Vorinostat