Heterocycle-functional steroidal derivatives: Design, synthesis, bioevaluation and SARs of steroidal pyrazolo[1,5-a]pyrimidines as potential ALK inhibitors

文献类型： 外文期刊

第一作者： Liu, Fang

作者： Liu, Fang;Wen, Shaohua;Liu, Manli;Min, Yong;Zhang, Zhigang;Shi, Liqiao;Wang, Kaimei;Yang, Ziwen;Yang, Fei;Ke, Shaoyong;Deng, Yunxia;Yang, Fei;Yang, Ziwen;Yang, Fei

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关键词： Dehydroepiandrosterone; Epiandrosterone; Steroidal pyrazolo[1; a ]pyrimidine; Antiproliferation; Anaplastic lymphoma kinase; Structure-activity relationships

期刊名称：BIOORGANIC CHEMISTRY （ 影响因子：4.7； 五年影响因子：4.9 ）

ISSN： 0045-2068

年卷期： 2024 年 153 卷

页码：

收录情况： SCI

摘要： Two series of heterocyclic steroidal pyrazolo[1,5-a]pyrimidines derived from dehydroepiandrosterone (DHEA) and epiandrosterone (EPIA) were designed and synthesized, and these compounds were screened for their potential antiproliferation activities. The preliminary bioassay indicated that some of target compounds exhibited significantly good antiproliferation activities against human melanoma cell line (A875) and human hepatocellular carcinoma (Huh-7) cell lines compared with 5-fluorouracil (5-FU), and some of which present good antiproliferative activities as potential ALK inhibitors. The detailed analysis of structure-activity relationships (SARs) based on the inhibition activities, kinase assay, and molecular docking demonstrated that the antiproliferation activities of these steroidal pyrazolo[1,5-a]pyrimidine might be affected by the beta-hydroxyl group of steroidal scaffold and the N atom of pyridine heterocycle. Especially, compound 4c has certain inhibitory effects on the tyrosine protein kinases ALK, CDK2/CyclinE1, FAK, CDK5/P35, CDK9/CyclinT1, CDK5/P25, PIM2, CDK2/ CyclinA2, CDK1/CyclinB1, etc., and which displayed highest inhibitory effect on the kinases of ALK with inhibition rate 40.63 % at the concentration of 10 mu M, which induced cell death in A875 cells at least partly (initially), by apoptosis.

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