A series of novel bicyclic, substituted pyrimidinone compounds were designed, synthesized and characterized. In vitro antiproliferative 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 μM). 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 μM, 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.
DNA can fold into non-canonical structures such as Gquadruplexes (G4 s) in addition to adopting the double helical structure. Considering the relationship between stabilization of G4 structure and anticancer effects, development of G4 interactive compounds has been of significant interest. Past years have witnessed the discovery of scaffolds targeting G4 structures based on planar, multi-aromatic ring compounds.With an aim to engineer drug-like properties, we designed and synthesized pyridopyrimidinone based selective G4 DNA stabilizing agents 1-3, and further they were evaluated for G4 DNA recognition properties. CD melting studies revealed the preferential stabilization of parallel topology of promoter c-MYC and c-KIT G4 DNAs by the ligands, especially 2 and 3, over the different topologies of telomeric G4 DNA. UV melting experiments suggested that no significant stabilization was observed for duplex DNA. Further, the results from ITC experiments substantiated the preferential stabilization of parallel topology of c-MYC G4 DNA over telomeric and duplex DNA by the ligands 2. These data showed that ligand 2 has moderate binding affinity to the c-MYC G4 DNA and is~49-fold and~25fold selective over the telomeric G4 DNA and the duplex DNA respectively. The molecular modeling and dynamics studies of the ligand 2 in complex with c-MYC and c-KIT1 G4 DNAs showed that this ligand stacks on the 5'-quartet of c-MYC and 3'-quartet of c-KIT1 G4 DNA structures.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.