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

Abstract

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, androst-1,4-diene-3,17-dione, dienedione and 9α-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 μM, which induced cell death in A875 cells at least partly (initially), by apoptosis.

Keywords

• Steroidal thiazolidin-4-ones
• Structural diversity
• Antiproliferative activity
• Enzyme inhibitors
• Molecular docking