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.

Novel 1,4-Dihydropyridines as Specific Binders and Activators of SIRT3 Impair Cell Viability and Clonogenicity and Downregulate Hypoxia-Induced Targets in Cancer Cells / 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. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 66:14(2023), pp. 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

Clemens Zwergel;Michele Aventaggiato;Sabrina Garbo;Elisabetta Di Bello;Beatrice Noce;Carola Castiello;Chiara Lambona;Federica Barreca;Dante Rotili;Rossella Fioravanti;Marco Tripodi;Cecilia Battistelli
;
Marco Tafani
;
Sergio Valente
;
Antonello Mai
2023

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.
2023
epigenetics, SIRT3, hypoxia, cancer
01 Pubblicazione su rivista::01a Articolo in rivista
Novel 1,4-Dihydropyridines as Specific Binders and Activators of SIRT3 Impair Cell Viability and Clonogenicity and Downregulate Hypoxia-Induced Targets in Cancer Cells / 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. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 66:14(2023), pp. 9622-9641. [10.1021/acs.jmedchem.3c00337]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1684985
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