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

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.