Exploring the antiproliferative and proapoptotic activities of new pyridopyrimidine derivatives and their analogs

This study investigates a series of newly synthesized compounds, including pyridopyrimidine derivatives (9a-g), tricyclic pyridotriazolopyrimidine analogs (18a-d), and dihydropyrimidinones (22a-i), as apoptotic inducers and inhibitors of phosphatidylinositol-3-kinase alpha (PI3K alpha), with potential anticancer activity. An initial in vitro screening of 60 cancer cell lines identified pyridopyrimidine derivatives 9a-g as promising broad-spectrum anticancer agents, with compound 9e demonstrating the strongest inhibitory activity, particularly against T47D breast cancer cells. Notably, the antitumor potency of compound 9e surpassed that of Pictilisib, inducing G2M phase cell cycle arrest and initiating apoptosis through the intrinsic apoptotic pathway. Molecular docking studies further indicated that compound 9e binds to PI3K alpha in a similar fashion to the co-crystallized ligand. Moreover, compound 9e exhibited favorable drug-like properties, including compliance with Lipinski's rule and Veber's rule, good solubility, acceptable TPSA, and high gastrointestinal absorption reinforcing its potential as a highly effective anticancer agent.