Innovative hydroxamic acid-derived HDAC inhibitors: design, synthesis, and anticancer evaluation with diverse Zn2+-binding groups

doi:10.5246/jcps.2025.06.039

Abstract

Abstract:

A series of potential HDACIs containing diverse Zn²⁺-chelating hydroxamate moieties were synthesized and evaluated for their anticancer activity in vitro on HeLa, A549, and HepG2 cell lines. The A549 cell line was the most sensitive, and the most active compound, e8, exhibited an IC₅₀ value of 1.68 μmol/L, surpassing the positive control, SAHA (IC₅₀ = 4.85 μmol/L). Additionally, compound e8 demonstrated lower toxicity to normal WI-38 cells compared to SAHA (IC₅₀ = 415.93 μmol/L vs. 9.09 μmol/L). Furthermore, e8 efficiently induced G0/G1 phase cell cycle arrest and apoptosis in A549 cells. Molecular docking studies showed that compound e8 coordinated the Zn²⁺ cation at the enzyme’s active site and formed hydrophobic and hydrogen bonds within the hydrophobic pocket of the enzyme, resulting in stable docking with the HDAC enzyme. These studies suggested that compound e8 has the potential to be developed as a promising lead for further optimization and development of HDACIs.

Key words: Histone deacetylase inhibitors, Antitumor activity, Zn2+ binding domain, Hydroxamic acid analogues

Supporting: /attached/file/20250704/20250704010718_379.pdf

Zhengrong Wu, Jingsi Zhao, Peng Jing, Dian He. Innovative hydroxamic acid-derived HDAC inhibitors: design, synthesis, and anticancer evaluation with diverse Zn²⁺-binding groups[J]. Journal of Chinese Pharmaceutical Sciences, 2025, 34(6): 519-529.

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References 33

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Innovative hydroxamic acid-derived HDAC inhibitors: design, synthesis, and anticancer evaluation with diverse Zn²⁺-binding groups

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