The mitochondrialSIRT3 modulates several biologicalpathways suchas cancer, metabolism, and hypoxia-related diseases. Recently, wediscovered new 1,4-dihydropyridines, compounds 2 and 3, the latter being a SIRT3-specific activator. In the presentwork, a novel 2- and 3-related small seriesof compounds have been developed, with 3c displayingthe strongest SIRT3 binding and activation, with a K (D) of 29 & mu;M and 387% of enzyme activation. Differently, 3d was the best in enhancing glutamate dehydrogenase activityand deacetylating K68- and K122-acMnSOD in triple-negative MDA-MB-231breast cancer cells. Tested in CAL-62 thyroid cancer and MDA-MB-231cells, 3d displayed the strongest time- and dose-dependentreduction of cell viability and clonogenicity at a single-digit micromolarlevel, along with cell death, in both normoxia and hypoxia conditions.Moreover, 3d downregulated not only hypoxia-induced factors,such as HIF-1 & alpha;, EPAS-1, and CA-IX, but also epithelial-mesenchymaltransition master regulators and extracellular matrix components suchas SNAIL1, ZEB1, SLUG, COL1A2, MMP2, and MMP9, markedly hamperingMDA-MB-231 cell migration.
Zwergel, C., Aventaggiato, M., Garbo, S., Di Bello, E., Fassari, B., Noce, B., et al. (2023). Novel 1,4-Dihydropyridines as Specific Binders and Activators of SIRT3 Impair Cell Viability and Clonogenicity and Downregulate Hypoxia-Induced Targets in Cancer Cells. JOURNAL OF MEDICINAL CHEMISTRY, 66(14), 9622-9641 [10.1021/acs.jmedchem.3c00337].
Novel 1,4-Dihydropyridines as Specific Binders and Activators of SIRT3 Impair Cell Viability and Clonogenicity and Downregulate Hypoxia-Induced Targets in Cancer Cells
Rotili, Dante;
2023-01-01
Abstract
The mitochondrialSIRT3 modulates several biologicalpathways suchas cancer, metabolism, and hypoxia-related diseases. Recently, wediscovered new 1,4-dihydropyridines, compounds 2 and 3, the latter being a SIRT3-specific activator. In the presentwork, a novel 2- and 3-related small seriesof compounds have been developed, with 3c displayingthe strongest SIRT3 binding and activation, with a K (D) of 29 & mu;M and 387% of enzyme activation. Differently, 3d was the best in enhancing glutamate dehydrogenase activityand deacetylating K68- and K122-acMnSOD in triple-negative MDA-MB-231breast cancer cells. Tested in CAL-62 thyroid cancer and MDA-MB-231cells, 3d displayed the strongest time- and dose-dependentreduction of cell viability and clonogenicity at a single-digit micromolarlevel, along with cell death, in both normoxia and hypoxia conditions.Moreover, 3d downregulated not only hypoxia-induced factors,such as HIF-1 & alpha;, EPAS-1, and CA-IX, but also epithelial-mesenchymaltransition master regulators and extracellular matrix components suchas SNAIL1, ZEB1, SLUG, COL1A2, MMP2, and MMP9, markedly hamperingMDA-MB-231 cell migration.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
