Abstract
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.
Keywords:
Akt; Antitumor effect; Chiral ionone alkaloid derivatives; HIF-1α; VEGFR2.
© 2021 Wiley-VCH GmbH.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alkaloids / chemical synthesis
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Alkaloids / chemistry
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Alkaloids / pharmacology*
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Survival / drug effects
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Dose-Response Relationship, Drug
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Drug Discovery*
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Drug Screening Assays, Antitumor
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors*
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Molecular Structure
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Norisoprenoids / chemical synthesis
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Norisoprenoids / chemistry
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Norisoprenoids / pharmacology*
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Structure-Activity Relationship
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Vascular Endothelial Growth Factor A / antagonists & inhibitors*
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
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Vascular Endothelial Growth Factor Receptor-2 / genetics
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
Substances
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Alkaloids
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Antineoplastic Agents
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Norisoprenoids
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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KDR protein, human
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Vascular Endothelial Growth Factor Receptor-2