Author : Asmaa Mandour
CoAuthors : Nour E. A. Abd El-Sattar, Eman H. K. Badawy,aWafaa H. AbdEl-Hady,Mohamed I. Abo-Alkasem and Nasser S. M. Ismail
Source : Chemical and Pharmaceutical Bulletin
Date of Publication : 01/2021
Abstract :
Cyclin dependent kinase 2 (CDK2) inhibition is a well-established strategy for treating cancer. Differentseries of novel thiazolone (1, 7–9) together with fused thiazolthione (2–6, and 10) derivatives were designed,then synthesized and evaluated for their biological inhibitory activity against CDK2. Additionally, the cytotoxicityof the new compounds was explored against breast and colon cancer cell lines. The novel thiazoloneand the fused thiazolthione derivatives exhibited potent CDK2/cyclin A2 inhibitory effect of an IC50 valuesranging 105.39–742.78 nM. Amongst them compounds 4 and 6 revealed highest IC50 of 105.39 and 139.27 nM,respectively. Most compounds showed significant inhibition on both breast cancer and colon cancer cell lineswith IC50 range 0.54–5.26 and 0.83–278 μM, respectively. Further investigations involved flow cytometryanalysis on MCF-7 cancer cell line for compounds 5 and 7 which resulted in arrest cell-cycle at two phasesPre G1/G2-M and re-enforced apoptosis via activation of caspase-7. Molecular modeling simulation of thedesigned compounds revealed that they were well fitted into CDK2 active site and their complexes were stabilizedthrough the essential hydrogen bonding. Three dimensional quantitative structure activity relationship(3D QSAR) pharmacophore, and absorption, distribution, metabolism, excretion, and toxicity (ADMET)studies were also carried out showing proper pharmacokinetic and drug-likeness which aided in the predictionof the structure requirements responsible for the observed antitumor activity.
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