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- Title
Enzymatic and Biological Characterization of Novel Sirtuin Modulators against Cancer.
- Authors
Carafa, Vincenzo; Poziello, Angelita; Della Torre, Laura; Giovannelli, Pia; Di Donato, Marzia; Safadeh, Elham; Yu, Zhijun; Baldi, Alfonso; Castoria, Gabriella; Tomaselli, Daniela; Mai, Antonello; Rotili, Dante; Nebbioso, Angela; Altucci, Lucia
- Abstract
Sirtuins, a family of nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacetylases, are promising targets for anticancer treatment. Recently, we characterized a novel pan-sirtuin (SIRT) inhibitor, MC2494, displaying antiproliferative effects and able to induce death pathways in several human cancer cell lines and decrease tumor growth in vivo. Based on the chemical scaffold of MC2494, and by applying a structure–activity relationship approach, we developed a small library of derivative compounds and extensively analyzed their enzymatic action at cellular level as well as their ability to induce cell death. We also investigated the effect of MC2494 on regulation of cell cycle progression in different cancer cell lines. Our investigations indicated that chemical substitutions applied to MC2494 scaffold did not confer higher efficacy in terms of biological activity and SIRT1 inhibition, but carbethoxy-containing derivatives showed higher SIRT2 specificity. The carbethoxy derivative of MC2494 and its 2-methyl analog displayed the strongest enzymatic activity. Applied chemical modifications improved the enzymatic selectivity of these SIRT inhibitors. Additionally, the observed activity of MC2494 via cell cycle and apoptotic regulation and inhibition of cell migration supports the potential role of SIRTs as targets in tumorigenesis and makes SIRT-targeting molecules good candidates for novel pharmacological approaches in personalized medicine.
- Subjects
CELL cycle regulation; CELL migration inhibition; CELLULAR control mechanisms; SIRTUINS; CELL death; STRUCTURE-activity relationships
- Publication
International Journal of Molecular Sciences, 2019, Vol 20, Issue 22, p5654
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms20225654