Design, synthesis and biological evaluation of substituted 2-(thiophen-2-yl)-1,3,5-triazine derivatives as potential dual PI3Kα/mTOR inhibitors.

Abstract

The phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) have been regarded as promising targets for the treatment of cancer. Herein, we synthesized a new series of substituted 2-(thiophen-2-yl)-1,3,5-triazine derivatives as novel PI3Kα/mTOR dual inhibitors for cancer therapy. All compounds were evaluated for the IC50 values against three cancer cell lines (A549, MCF-7 and Hela). Most of the target compounds exhibited moderate to excellent anti-tumor activities against these three tested cancer cell lines especially against A549 and Hela cancer cell lines. Among them, the most promising compound 13g showed excellent anti-tumor potency for A549, MCF-7 and Hela cell lines with IC50 values of 0.20\xa0±\xa00.05\xa0µM, 1.25\xa0±\xa00.11\xa0µM and 1.03\xa0±\xa00.24\xa0µM, respectively. Notably, according to the result of enzymatic activity assay, compound 13g was identified as a novel PI3Kα/mTOR dual inhibitor, which had an approximately 10-fold improvement in mTOR inhibition, compared to the class I PI3K inhibitor 1 (pictilisib, GDC-0941), with IC50 values of 525\xa0nM to 48\xa0nM. And western blot analysis indicated compound 13g could efficiently suppress the phosphorylation of AKT at the dose of 0.1\xa0µM, which further demonstrated compound 13g had significant inhibitory effect on the PI3K/Akt/mTOR pathway. Furthermore, compound 13g could stimulate A549 cells arrest at G0/G1 phase in a dose-dependent manner, and induced apoptosis at a low concentration.