ChemMedChem, 2021-07, Vol.16 (13), p.2130-2145
2021
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- Autor(en) / Beteiligte
- Titel
- Discovery of Antimetastatic Chiral Ionone Alkaloid Derivatives Targeting HIF‐1α/VEGF/VEGFR2 Pathway
- Ist Teil von
- ChemMedChem, 2021-07, Vol.16 (13), p.2130-2145
- Ort / Verlag
- Germany: Wiley Subscription Services, Inc
- Erscheinungsjahr
- 2021
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1860-7179eISSN: 1860-7187DOI: 10.1002/cmdc.202100072Titel-ID: cdi_proquest_miscellaneous_2504342923
- Format
- –
- Schlagworte
- Akt, AKT protein, AKT1 protein, AKT2 protein, Alkaloids, Alkaloids - chemical synthesis, Alkaloids - chemistry, Alkaloids - pharmacology, Anticancer properties, Antineoplastic Agents - chemical synthesis, Antineoplastic Agents - chemistry, Antineoplastic Agents - pharmacology, Antitumor activity, Antitumor effect, Breast cancer, Cell Line, Tumor, Cell migration, Cell Movement - drug effects, Cell Survival - drug effects, Chemotaxis, Chiral ionone alkaloid derivatives, Dose-Response Relationship, Drug, Drug Discovery, Drug Screening Assays, Antitumor, HIF-1α, Humans, Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors, Hypoxia-Inducible Factor 1, alpha Subunit - genetics, Hypoxia-Inducible Factor 1, alpha Subunit - metabolism, Ionone, Metastases, Metastasis, Molecular Structure, Norisoprenoids - chemical synthesis, Norisoprenoids - chemistry, Norisoprenoids - pharmacology, Protein kinase C, Structure-Activity Relationship, TOR protein, Vascular endothelial growth factor, Vascular Endothelial Growth Factor A - antagonists & inhibitors, Vascular Endothelial Growth Factor A - genetics, Vascular Endothelial Growth Factor A - metabolism, Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors, Vascular Endothelial Growth Factor Receptor-2 - genetics, Vascular Endothelial Growth Factor Receptor-2 - metabolism, VEGFR2