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Discovery of Antimetastatic Chiral Ionone Alkaloid Derivatives Targeting HIF-1α/VEGF/VEGFR2 Pathway.
- Source :
-
ChemMedChem [ChemMedChem] 2021 Jul 06; Vol. 16 (13), pp. 2130-2145. Date of Electronic Publication: 2021 Apr 29. - Publication Year :
- 2021
-
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 IC <subscript>50</subscript> 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.<br /> (© 2021 Wiley-VCH GmbH.)
- Subjects :
- Alkaloids chemical synthesis
Alkaloids chemistry
Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Cell Line, Tumor
Cell Movement drug effects
Cell Survival drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Hypoxia-Inducible Factor 1, alpha Subunit genetics
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Molecular Structure
Norisoprenoids chemical synthesis
Norisoprenoids chemistry
Structure-Activity Relationship
Vascular Endothelial Growth Factor A genetics
Vascular Endothelial Growth Factor A metabolism
Vascular Endothelial Growth Factor Receptor-2 genetics
Vascular Endothelial Growth Factor Receptor-2 metabolism
Alkaloids pharmacology
Antineoplastic Agents pharmacology
Drug Discovery
Hypoxia-Inducible Factor 1, alpha Subunit antagonists & inhibitors
Norisoprenoids pharmacology
Vascular Endothelial Growth Factor A antagonists & inhibitors
Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1860-7187
- Volume :
- 16
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- ChemMedChem
- Publication Type :
- Academic Journal
- Accession number :
- 33755334
- Full Text :
- https://doi.org/10.1002/cmdc.202100072