Synthesis and biological evaluation of pyrido[3',2':4,5]furo [3,2-d]pyrimidine derivatives as novel PI3 kinase p110α inhibitors

Abstract 4-Morpholin-4-ylpyrido[3′,2′:4,5]thieno[3,2- d ]pyrimidine 2a was discovered in our chemical library as a novel p110α inhibitor with an IC 50 of 1.4 μM. By structural modification of 2a , the 2-aryl-4-morpholinopyrido[3′,2′:4,5]furo[3,2- d ]pyrimidine derivative 10e was discovered as a p110α inhibitor with approximately 400-fold greater potency than 2a . Evaluation of isoform selectivity showed that 10e is a potent inhibitor of p110β. Furthermore, 10e showed anti-proliferative activity in various cell lines, including multi-drug resistant MCF7/ADR-res cells, and was effective against HeLa human cervical tumor xenografts in nude mice.