Discovery of novel dihydroartemisinin-cinnamic hybrids inducing lung cancer cells apoptosis via inhibition of Akt/Bad signal pathway.

Abstract

A series of dihydroartemisinin-cinnamic acid hybrids were designed, synthesized and evaluated. Most of the tested compounds showed enhanced anti-proliferative activities than artemisinin and dihydroartemisinin, among which 16\xa0g had the superior potency with IC50 values ranging from 5.07\xa0μM to 7.88\xa0μM against four tested cancer cell lines. The cell cycle arrest revealed that 16\xa0g induced A549 cell cycle arrest at G0/G1 phase via regulation of G1-related protein expression (Cdk4). Further mechanism studies reveal that 16\xa0g induced A549 cells apoptosis via inhibiting Akt/Bad pathway. Moreover, 16\xa0g depolarized the mitochondria membrane potentials and induced ROS generation in A549. Additionally, 16\xa0g blocked migration of A549 cells in a concentration-dependent manner. What s more, 16\xa0g is barely nontoxic to zebrafish embryos. Overall, the cell cycle arrest, inhibition of Akt/Bad signal pathway, ROS generation and migration blocked might explain the potent anti-proliferative activities of these compounds.