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

化学 组合化学 立体化学
作者
Fang Liu,Shaohua Wen,Manli Liu,Yong Min,Zhigang Zhang,Liqiao Shi,Kaimei Wang,Yun‐Xia Deng,Ziwen Yang,Fei Yang,Shaoyong Ke
出处
期刊:Bioorganic Chemistry [Elsevier]
卷期号:153: 107847-107847
标识
DOI:10.1016/j.bioorg.2024.107847
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 β-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 μM, which induced cell death in A875 cells at least partly (initially), by apoptosis.
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