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 IC(50) for compound 11 g was as low as 0.035+/-0.004 muM. 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-1alpha/VEGF/VEGFR2/Akt pathway, which suppressed the downstream signaling molecules, including Akt1/mTOR/p70S6K and Akt2/PKCzeta/integrin beta1 pathways. Taken together, chiral ionone alkaloid derivative 11 g has the potential to be developed into an antitumor metastatic agent for breast cancer. CI - (c) 2021 Wiley-VCH GmbH.