3-Arylamino-quinoxaline-2-carboxamides inhibit the PI3K/Akt/mTOR signaling pathways to activate P53 and induce apoptosis

Thirty-eight new 3-arylaminoquinoxaline-2-carboxamide derivatives were in silico designed, synthesized and their cytotoxicity against five human cancer cell lines and one normal cells WI-38 were evaluated. Molecular mechanism studies indicated that N-(3-Aminopropyl)-3-(4-chlorophenyl) amino-quinoxaline-2-carboxamide (6be), the compound with the most potent anti-proliferation can inhibit the PI3K-Akt-mTOR pathway via down regulating the levels of PI3K, Akt, p-Akt, p-mTOR and simultaneously inhibit the phosphorylation of Thr308 and Ser473 residues in Akt kinase to servers as a dual inhibitor. Further investigation revealed that 6be activate the P53 signal pathway, modulated the downstream target gene of Akt kinase such p21, p27, Bax and Bcl-2, caused the fluctuation of intracellular ROS, Ca2+ and mitochondrial membrane potential to induce cell cycle arrest and apoptosis in MGC-803 cells. 6be also display moderate anti-tumor activity in vivo while displaying no obvious adverse signs during the drug administration. The results suggest that 3-arylaminoquinoxaline-2-carboxamide derivatives might server as new scaffold for development of PI3K-Akt-mTOR inhibitor.

Automated summary

The study synthesized thirty-eight new 3-arylaminoquinoxaline-2-carboxamide derivatives, with one compound (6be) showing the strongest anti-proliferative effect by inhibiting the PI3K-Akt-mTOR pathway to induce cell cycle arrest and apoptosis, while activating the P53 signaling pathway and modulating downstream target genes of Akt kinase. These compounds displayed moderate anti-tumor activity in vivo without showing obvious adverse reactions during drug administration, suggesting that 3-arylaminoquinoxaline-2-carboxamide derivatives could serve as a new scaffold for PI3K-Akt-mTOR inhibitors.