Novel Pyrimidinone Derivatives Show Anticancer Activity and Induce Apoptosis: Synthesis, SAR and Putative Binding Mode

A series of novel bicyclic, substituted pyrimidinone compounds were designed, synthesized and characterized. In vitro anti-proliferative activity of the synthesized compounds was evaluated against six different human cancer cell lines using MTT assay. Among all twenty four compounds tested, compound 22 (N-([1,1 '-biphenyl]-4-yl)-2-((3-methyl-4-oxo-6,7,8,9-tetrahydro-4Hpyrido[1,2-a]pyrimidin-2-yl)oxy)acetamide) exhibited significant cell growth inhibition of human liver cancer cells HepG2 with GIC(50) (50% growth inhibitory concentration) value of 120+10 nM and was found to be selective over healthy human embryonic kidney (HEK) cell line (33.1% inhibition at 20 mu M). Further studies demonstrated that compound 22 induced cell apoptosis in HepG2 cells and resulted in similar effect to Staurosporine, a well known proapoptopic compound widely used to induce apoptosis in various cancer cell lines. Compound 22 also rendered acceptable aqueous solubility (3.5+0.37 mu M, at pH 7.4) and attractive metabolic stability against human liver microsomes with a half-life of 34.63+0.33 minutes. Based on the similarity observed between the known tankyrase-1 inhibitors available in literature and compound 22, in silico docking study was performed and the results suggested that the compound interacted with the key amino acid residues present in the tankyrase-1 enzyme active site.