Discovery of Antimetastatic Chiral Ionone Alkaloid Derivatives Targeting HIF‐1α/VEGF/VEGFR2 Pathway

Novel chiral ionone alkaloid derivatives were synthesized and their antimetastatic effects were evaluated in human breast cancer cells using chemotaxis assay. Compared with positive control LY294002, a PI3 K inhibitor, derivatives 10 a, 11 a, 11 c, 11 g, 11 j, 11 k and 11 w exhibited significant inhibitory effects against cancer cell migration. Especially, the IC50 for compound 11 g was as low as 0.035±0.004 μM. Further investigations on compound 11 g revealed that it could exert inhibitory effects on the adhesion, migration and invasion of MDA‐MB‐231 cells. The mechanisms for the antitumor metastatic effects of 11 g might be through the inhibition of HIF‐1α/VEGF/VEGFR2/Akt pathway, which suppressed the downstream signaling molecules, including Akt1/mTOR/p70S6K and Akt2/PKCζ/integrin β1 pathways. Taken together, chiral ionone alkaloid derivative 11 g has the potential to be developed into an antitumor metastatic agent for breast cancer. Novel chiral ionone alkaloid derivatives were synthesized, and compound 11 g with higher antichemotactic migration activity than the lead compound was screened. Compound 11 g exerted inhibitory effects on the adhesion, migration and invasion of MDA‐MB‐231 cells. The mechanisms for the antitumor metastatic effects of 11 g might be that it inhibited HIF‐1α expression to down regulate the secretion of VEGF and the phosphorylation of VEGFR2, and then suppressed the downstream pathways, including Akt1/mTOR/p70S6K and Akt2/PKCζ/integrin β1.