Design, Synthesis, Anticancer Activity and Docking Studies of Thiazole Linked Phenylsulfone Moiety as Cyclin-Dependent Kinase 2 (CDK2) Inhibitors

Abstract

Inhibition of the cyclin dependent kinase 2 (CDK2) is a well-known cancer treatment approach. Based on the molecular docking simulation analysis, two new series of 2-(1-(4-methoxyphenyl)-2-(phenylsulfonyl)ethylidene)hydrazineylidene)-2,5-dihydrothiazole as CDK-2 inhibitors were designed. The lead compound IV (5-benzoyl-N2-phenyl-1,3-thiazole-2,4-diamine) was modified and optimized prior to this analysis. In contrast to Roniciclib (−8.6 kcal/mol), docking results of CDK2 hits showed high affinity and docking scores ranging from −9.1 to −10.3 kcal/mol. All of the compounds studied were evaluated in vitro for CDK2 inhibitory activity. In comparison to Roscovitine's IC50 of 0.432 µM, compound 11b had a maximum IC50 of 0.416 µM. Additionally, all hits were tested for antiproliferative activities against PC-3 human prostate cancer cells, HEPG-2 human hepatocellular carcinoma, and MCF-7 breast adenocarcinoma cell lines. The arylhydrazine moiety of the tested compounds 11a–e demonstrated high potency against HEPG-2, with 11b (IC50 = 0.11 µM) being more active than doxorubicin (IC50 = 0.12 µM). In addition, compound 11b (IC50 = 0.245 µM) was nearly as effective as doxorubicin (IC50 = 0.246 µM) against MCF-7 cancer cells. 11d showed superior antiproliferative activity against PC-3 cell line (IC50= 0.23 µM) relative to doxorubicin (IC50 = 0.29 µM).