Novel 1,4-Dihydropyridines as Specific Binders and Activators of SIRT3 Impair Cell Viability and Clonogenicity and Downregulate Hypoxia-Induced Targets in Cancer Cells
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:66 |
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| Enthalten in: |
Journal of medicinal chemistry - 66(2023), 14 vom: 27. Juli, Seite 9622-9641 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zwergel, Clemens [VerfasserIn] |
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| Links: |
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| Themen: |
Collagen Type I, alpha2 Subunit |
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| Anmerkungen: |
Date Completed 28.07.2023 Date Revised 02.08.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.3c00337 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM359403441 |
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| 100 | 1 | |a Zwergel, Clemens |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Novel 1,4-Dihydropyridines as Specific Binders and Activators of SIRT3 Impair Cell Viability and Clonogenicity and Downregulate Hypoxia-Induced Targets in Cancer Cells |
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| 500 | |a Date Revised 02.08.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 700 | 1 | |a Aventaggiato, Michele |e verfasserin |4 aut | |
| 700 | 1 | |a Garbo, Sabrina |e verfasserin |4 aut | |
| 700 | 1 | |a Di Bello, Elisabetta |e verfasserin |4 aut | |
| 700 | 1 | |a Fassari, Bruno |e verfasserin |4 aut | |
| 700 | 1 | |a Noce, Beatrice |e verfasserin |4 aut | |
| 700 | 1 | |a Castiello, Carola |e verfasserin |4 aut | |
| 700 | 1 | |a Lambona, Chiara |e verfasserin |4 aut | |
| 700 | 1 | |a Barreca, Federica |e verfasserin |4 aut | |
| 700 | 1 | |a Rotili, Dante |e verfasserin |4 aut | |
| 700 | 1 | |a Fioravanti, Rossella |e verfasserin |4 aut | |
| 700 | 1 | |a Schmalz, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Weyand, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Niedermeier, Amelie |e verfasserin |4 aut | |
| 700 | 1 | |a Tripodi, Marco |e verfasserin |4 aut | |
| 700 | 1 | |a Colotti, Gianni |e verfasserin |4 aut | |
| 700 | 1 | |a Steegborn, Clemens |e verfasserin |4 aut | |
| 700 | 1 | |a Battistelli, Cecilia |e verfasserin |4 aut | |
| 700 | 1 | |a Tafani, Marco |e verfasserin |4 aut | |
| 700 | 1 | |a Valente, Sergio |e verfasserin |4 aut | |
| 700 | 1 | |a Mai, Antonello |e verfasserin |4 aut | |
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