Design, Synthesis, and Biological Evaluation of Novel Thienopyrimidine Derivatives as PI3Kα Inhibitors

Three series of novel thienopyrimidine derivatives 9a-l, 15a-l, and 18a-h were designed and synthesized, and their IC50 values against four cancer cell lines HepG-2, A549, PC-3, and MCF-7 were evaluated. Most compounds show moderate cytotoxicity against the tested cancer cell lines. The most promising compound 9a showed moderate activity with IC50 values of 12.32 +/- 0.96, 11.30 +/- 1.19, 14.69 +/- 1.32, and 9.80 +/- 0.93 mu M, respectively. The inhibitory activities of compounds 9a and 15a against PI3K alpha and mTOR kinase were further evaluated. Compound 9a exhibited PI3K alpha kinase inhibitory activity with IC50 of 9.47 +/- 0.63 mu M. In addition, docking studies of compounds 9a and 15a were also investigated.