Discovery of Pyrazolo[1, 5-a]pyrimidine-Based Selective HDAC6 Inhibitors with Broad-Spectrum Antiproliferative Activity.

IF 3.4 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem Pub Date : 2025-08-29 DOI:10.1002/cmdc.202500322

Wendeng Li, Chunhong Ma, Changchun Ye, Xiaoya Chen, Shiyuan Liu, Zilu Chen, Xin Chen, Zhengshui Xu

引用次数: 0

Abstract

Selective histone deacetylase 6 inhibitors show distinctive advantages for cancer treatment. In this paper, phenylhydroxamic acid group, a key pharmacophore of histone deacetylase 6 inhibitor, is introduced on common active pyrazolo[1,5-a]pyrimidine scaffold. Among all thirteen analogs, N-hydroxy-4-(((7-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)benzamide (8e) emerged as the most potent compound. Enzymatic assay showed that it potently inhibited histone deacetylase 6 with IC₅₀ of 3.84 nM, and demonstrated a 412-fold selectivity relative to the inhibition of histone deacetylase 1. In antiproliferative study, 8e also exhibited good antiproliferative activity against HL-60 and SK-MEL-2 cell lines with IC₅₀ of 0.2 and 0.35 nM, respectively. Molecular docking simulation indicated the binding site of histone deacetylase 6 could well accommodate pyrazolo[1,5-a]pyrimidine core, yielding a variety of interactions.

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具有广谱抗增殖活性的吡唑啉[1,5 -a]嘧啶选择性HDAC6抑制剂的发现。

选择性组蛋白去乙酰化酶6抑制剂在癌症治疗中显示出独特的优势。本文将组蛋白去乙酰化酶6抑制剂的关键药效团苯基羟肟酸基团引入到常见的活性吡唑[1,5-a]嘧啶支架上。在13种类似物中，n-羟基-4-（（（7-（4-甲氧基苯基）吡唑[1,5-a]嘧啶-5-基）氨基）甲基）苯酰胺（8e）是最有效的化合物。酶测结果表明，该化合物对组蛋白去乙酰化酶6有较强的抑制作用，IC50值为3.84 nM，对组蛋白去乙酰化酶1的选择性为412倍。在抗增殖研究中，8e对HL-60和SK-MEL-2细胞株也表现出良好的抗增殖活性，IC50分别为0.2和0.35 nM。分子对接模拟表明，组蛋白去乙酰化酶6的结合位点可以很好地容纳吡唑[1,5-a]嘧啶核，产生多种相互作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ChemMedChem 医学-药学

CiteScore

6.70

自引率

2.90%

发文量

280

审稿时长

1 months

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