Synthesis, biological evaluation and molecular docking studies of novel thiopyrimidine analogue as apoptotic agent with potential anticancer activity

This study synthesizes novel 6-amino-5-cyano-4-aryl-2-mercapto pyrimidines and condensed pyrimidines analogues in order to investigate their potential activity as anticancer agents. The compounds were synthesized via one-pot condensation of p-nitrobenzaldehyde or p-anisaldehyde with malononitrile and thiourea to prepare 6amino-5-cyano-4-aryl-2-mercaptopyrimidines series (1-9a,b). The pyrimidine analogues were biologically screened In-vitro in HepG2 and MCF-7 compared to normal WI-38. Compound 8a showed higher anti proliferative activity to MCF-7 cells with sensitivity and minimal cytotoxic effect (IC50 53.3 mu MHepG2, 12.9 mu MMCF-7 and > 100 mu MWI-38). Compound 8a was able to induce 40% of total antioxidants and 60% following treatment with 50 mu M of H2O2 for 3hrs as external source of oxidative stress in MCF-7. 8a was able to significantly induce early stage apoptosis of 74.37% MCF-7 and cell cycle arrest with cells accumulation in subG0-G1 phase to 69.42% and reduction of cells in G2M phase to 3.6% and high apoptotic index. Compound 8a induced over-expression of Fas receptor and Cyto C genes. Molecular docking studies suggested that 8a can bind to both phosphodiesterase 4B and 4D binding pockets and inhibit their action through network of hydrophobic interactions in Q-P pockets with preferential selectivity to PDE4B through invariant Glu443. The chemical profile and the biological results suggest that 8a can be a promising anticancer agent.