New quinoline/chalcone hybrids as anti-cancer agents: Design, synthesis, and evaluations of cytotoxicity and PI3K inhibitory activity.

ABSTRACT: A series of quinoline-chalcone hybrids was designed as potential anti-cancer agents, synthesized and evaluated. Different cytotoxic assays revealed that compounds experienced promising activity. Compounds 9i and 9j were the most potent against all the cell lines tested with IC50?=?1.91-5.29?µM against A549 and K-562 cells. Mechanistically, 9i and 9j induced G2/M cell cycle arrest and apoptosis in both A549 and K562 cells. Moreover, all PI3K isoforms were inhibited non selectively with IC50s of 52-473?nM when tested against the two mentioned compounds with 9i being most potent against PI3K-? (IC50?=?52?nM). Docking of 9i and 9j showed a possible formation of H-bonding with essential valine residues in the active site of PI3K-? isoform. Meanwhile, Western blotting analysis revealed that 9i and 9j inhibited the phosphorylation of PI3K, Akt, mTOR, as well as GSK-3? in both A549 and K562 cells, suggesting the correlation of blocking PI3K/Akt/mTOR pathway with the above antitumor activities. Together, our findings support the antitumor potential of quinoline-chalcone derivatives for NSCLC and CML by inhibiting the PI3K/Akt/mTOR pathway.

SUBMITTER: Abbas SH 

PROVIDER: S-EPMC6931042 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature