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Zwergel, Clemens ; Aventaggiato, Michele ; Garbo, Sabrina ; Di Bello, Elisabetta ; Fassari, Bruno ; Noce, Beatrice ; Castiello, Carola ; Lambona, Chiara ; Barreca, Federica ; Rotili, Dante ; Fioravanti, Rossella ; Schmalz, Thomas ; Weyand, Michael ; Niedermeier, Amelie ; Tripodi, Marco ; Colotti, Gianni ; Steegborn, Clemens ; Battistelli, Cecilia ; Tafani, Marco ; Valente, Sergio ; Mai, Antonello:
Novel 1,4-Dihydropyridines as Specific Binders and Activators of SIRT3 Impair Cell Viability and Clonogenicity and Downregulate Hypoxia-Induced Targets in Cancer Cells.
In: Journal of Medicinal Chemistry.
Bd. 66
(2023)
Heft 14
.
- S. 9622-9641.
ISSN 1520-4804
DOI: https://doi.org/10.1021/acs.jmedchem.3c00337
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.
Weitere Angaben
| Publikationsform: | Artikel in einer Zeitschrift |
|---|---|
| Begutachteter Beitrag: | Ja |
| Institutionen der Universität: | Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Chemie > Lehrstuhl Biochemie Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Chemie > Lehrstuhl Biochemie > Lehrstuhl Biochemie I - Proteinbiochemie der Signaltransduktion - Univ.-Prof. Dr. Clemens Steegborn |
| Titel an der UBT entstanden: | Ja |
| Themengebiete aus DDC: | 500 Naturwissenschaften und Mathematik > 540 Chemie |
| Eingestellt am: | 21 Aug 2023 05:51 |
| Letzte Änderung: | 21 Aug 2023 05:51 |
| URI: | https://eref.uni-bayreuth.de/id/eprint/86602 |