Abstract
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•Novel one- pot synthesis of new thiopyrimidine analogues were designed using aromatic aldehydes, cyano ethyl acetate and thiourea.•New synthetic thiopyrimidine analogue, 8a is able to induce cell apoptosis and cell cycle arrest in MCF-7 cancer cell line in micromolar concentration.•The antiproliferative activity of potent synthetic thiopyrimidine analogue is suggested to bind in the active site of phosphodiesterase 4B and 4D and this may help in future screening of inhibition consequences of cAMP or cGMP based biological events.
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 6-amino-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 antiproliferative activity to MCF-7 cells with sensitivity and minimal cytotoxic effect (IC50 53.3 µM- HepG2, 12.9 µM- MCF-7 and >100 µM- WI-38). Compound 8a was able to induce 40% of total antioxidants and 60% following treatment with 50 µM 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.