Discovery of structural diversity guided steroidal thiazolidin-4-one derivatives as potential cytotoxic agents targeting CDK1

文献类型： 外文期刊

第一作者： Yang, Fei

作者： Yang, Fei;Min, Yong;Li, Kui;Yang, Ziwen;Wang, Kaimei;Gong, Yan;Liu, Manli;Ke, Shaoyong;Yang, Fei;Yang, Ziwen;Liu, Changli

作者机构：

关键词： Steroidal thiazolidin-4-ones; Structural diversity; Antiproliferative activity; Enzyme inhibitors; Molecular docking

期刊名称：JOURNAL OF SAUDI CHEMICAL SOCIETY （ 影响因子：5.6； 五年影响因子：4.6 ）

ISSN： 1319-6103

年卷期： 2024 年 28 卷 3 期

页码：

收录情况： SCI

摘要： Structural diversity guided steroidal thiazolidin-4-one conjugates were designed and synthesized based on six steroid skeletons mainly including androst-4-ene-3,17-dione, dehydroepiandrosterone, epiandrosterone, androst1,4-diene-3,17-dione, dienedione and 9 alpha-hydroxy-androst-4-ene-3,17-dione. Their in vitro inhibition activities against cell proliferation were fully investigated, and some of which exhibited good antiproliferative activities as potential CDK1 inhibitor. The detailed analysis of structure-activity relationships (SARs) based on the inhibition activities, kinase assay, and molecular docking model demonstrated that the structure of different steroidal core ring skeleton as well as the N substituents of the thiazolidin-4-one ring influenced the inhibitory activity on cancer cell lines. Especially, compounds 15c and 16c have certain inhibitory effects on the tyrosine protein kinases CDK1/CyclinA2, ALK, CDK6/CyclinD1, FGFR1 and PIM2. Compounds 16c displayed highest inhibitory effect on the kinases of CDK1/CyclinA2 with inhibition rate 56.38 % at the concentration of 10 mu M, which induced cell death in A875 cells at least partly (initially), by apoptosis.

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