Novel 1,4-Dihydropyridines as Specific Binders and Activators of SIRT3 Impair Cell Viability and Clonogenicity and Downregulate Hypoxia-Induced Targets in Cancer Cells.
J Med Chem
; 66(14): 9622-9641, 2023 07 27.
Article
em En
| MEDLINE
| ID: mdl-37439550
ABSTRACT
The mitochondrial SIRT3 modulates several biological pathways such as cancer, metabolism, and hypoxia-related diseases. Recently, we discovered new 1,4-dihydropyridines, compounds 2 and 3, the latter being a SIRT3-specific activator. In the present work, a novel 2- and 3-related small series of compounds have been developed, with 3c displaying the strongest SIRT3 binding and activation, with a KD of 29 µM and 387% of enzyme activation. Differently, 3d was the best in enhancing glutamate dehydrogenase activity and deacetylating K68- and K122-acMnSOD in triple-negative MDA-MB-231 breast cancer cells. Tested in CAL-62 thyroid cancer and MDA-MB-231 cells, 3d displayed the strongest time- and dose-dependent reduction of cell viability and clonogenicity at a single-digit micromolar level, along with cell death, in both normoxia and hypoxia conditions. Moreover, 3d downregulated not only hypoxia-induced factors, such as HIF-1α, EPAS-1, and CA-IX, but also epithelial-mesenchymal transition master regulators and extracellular matrix components such as SNAIL1, ZEB1, SLUG, COL1A2, MMP2, and MMP9, markedly hampering MDA-MB-231 cell migration.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sirtuína 3
/
Neoplasias
Limite:
Humans
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Itália