基于异羟肟酸的新型Zn2+螯合基团组蛋白去乙酰化酶抑制剂的设计、合成与抗肿瘤活性评价

doi:10.5246/jcps.2025.06.039

摘要/Abstract

摘要：

本研究旨在合成系列新型的含有不同锌离子螯合基团(羟乙胺酰基)的组蛋白去乙酰化酶抑制剂(HDACIs), 并通过对细胞HeLa、A549和HepG2进行了体外肿瘤细胞增殖抑制评价。结果表明对A549细胞株异常敏感, 尤其以化合物e8 (IC₅₀= 1.68 μmol/L) 的活性最好, 优于阳性对照物SAHA (IC₅₀= 4.85 μmol/L) 的抑制活性, 并且对正常细胞显示出低毒性 (IC₅₀= 415.93 vs IC₅₀= 9.09 μmol/L), 细胞周期与凋亡实验结果显示: 化合物e8对肿瘤细胞的G0/G1期阻滞作用较强; 同时具有一定的诱导肿瘤细胞凋亡能力。此外, 分子对接实验结果显示: 通过其在活性腔内与氨基酸残基产生的疏水性作用、氢键作用与锌离子发生的静电作用, 使得化合物e8能够稳定地对接到HDAC活性腔内。因此, 设计合成的化合物e8有进一步研究的潜力和价值, 有望进一步开发为新型HDAC抑制剂。

关键词: 组蛋白去乙酰化酶抑制剂, 抗肿瘤活性, Zn2+螯合部位, 异羟肟酸类化合物

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

吴争荣, 赵静思, 金鹏, 贺殿. 基于异羟肟酸的新型Zn²⁺螯合基团组蛋白去乙酰化酶抑制剂的设计、合成与抗肿瘤活性评价[J]. 中国药学(英文版), 2025, 34(6): 519-529.

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.

图/表 5

Scheme 1. General synthesis of the target compounds e8–e15. Reagents and conditions: (I) 1,4-dioxane, rt, 6 h; (II) NaHCO3, 50 ºC, 24 h; (III) THF, rt, 6 h; (IV) THF, rt, 16 h.

Table 1. Cytotoxicity of target compounds e1–e15 to different cells following 24 h of exposure.

Figure 1. Effects of compound e8 on A549 cells cycle progression. (A) Control; (B) treated with 50.0 μmol/L SAHA; (C) treated with 5.0 μmol/L SAHA; (D) treated with 50.0 μmol/L e8; (E) treated with 5.0 μmol/L e8.

Figure 2. Apoptosis in A549 cells were treated with compound e8. (A) Control; (B) treated with 50.0 μmol/L SAHA; (C) treated with 5.0 μmol/L SAHA; (D) treated with 50.0 μmol/L e8; (E) treated with 5.0 μmol/L e8.

Figure 3. Molecular binding mode of compound e8 to HDACs. (A) Control (SAHA); (B) compound e8.

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基于异羟肟酸的新型Zn²⁺螯合基团组蛋白去乙酰化酶抑制剂的设计、合成与抗肿瘤活性评价

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

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