Medizinische Chemie

Novel series of pyrimidine derivatives (9a-o) were synthesized and evaluated for their antiproliferative activity against human colorectal carcinoma HCT-116, cervical carcinoma HeLa and breast carcinoma MCF-7 cell lines. Compounds 9b, 9k and 9h were the most active ones against HCT-116, HeLa and MCF-7 cell lines (IC50=2.46 ± 0.21,1.81 ± 0.11and3.83 ± 0.27 µM, respectively) compared to doxorubicin (IC50=2.39 ± 0.16,3.02 ± 0.18and5.56 ± 0.3 µM, respectively). Cell cycle analysis showed arrest at G1/S phase upon treatment of HCT-116, HeLa cells with compounds 9b and 9k, respectively, and at G2/M phase upon treatment of MCF-7 with 9h. Apoptotic effect of compounds 9b, 9k and 9h was showed through their pre G1 early and late apoptotic effects. Besides, compounds 9h and 9e displayed promising CDK2 and CDK9 inhibitory activities (IC50 values; 0.299 ± 0.02 and 0.396 ± 0.02, respectively). Molecular docking study showed similar binding modes of the studied compounds to that attained by the native ligands either for CDK2 and or for CDK9 isoform. These findings recognized compound 9h as potent antiproliferative agents against MCF-7 cancer cells with pronounced CDK2 inhibition activity.