{"title":"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。","authors":"Wendeng Li, Chunhong Ma, Changchun Ye, Xiaoya Chen, Shiyuan Liu, Zilu Chen, Xin Chen, Zhengshui Xu","doi":"10.1002/cmdc.202500322","DOIUrl":null,"url":null,"abstract":"<p><p>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 IC<sub>50</sub> 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 IC<sub>50</sub> 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.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500322"},"PeriodicalIF":3.4000,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Discovery of Pyrazolo[1, 5-a]pyrimidine-Based Selective HDAC6 Inhibitors with Broad-Spectrum Antiproliferative Activity.\",\"authors\":\"Wendeng Li, Chunhong Ma, Changchun Ye, Xiaoya Chen, Shiyuan Liu, Zilu Chen, Xin Chen, Zhengshui Xu\",\"doi\":\"10.1002/cmdc.202500322\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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 IC<sub>50</sub> 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 IC<sub>50</sub> 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.</p>\",\"PeriodicalId\":147,\"journal\":{\"name\":\"ChemMedChem\",\"volume\":\" \",\"pages\":\"e202500322\"},\"PeriodicalIF\":3.4000,\"publicationDate\":\"2025-08-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ChemMedChem\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/cmdc.202500322\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ChemMedChem","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/cmdc.202500322","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Discovery of Pyrazolo[1, 5-a]pyrimidine-Based Selective HDAC6 Inhibitors with Broad-Spectrum Antiproliferative Activity.
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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