Functionalized tetrahydro-1H-pyrido[4,3-b]indoles: A novel chemotype with Sirtuin 2 inhibitory activity

• Sirtuins are protein deacylases that regulate metabolism and stress responses.
• Tetrahydropyridoindoles were identified as preferential Sirt2 inhibitors.
• A well defined SAR was deduced from in vitro inhibitory activities.
• A potent member 18 induced hyperacetylation of p53 and α-tubulin in cancer cells.
• Molecular docking pointed to occupancy of the NAD+ and substrate sites of Sirt2.

Sirtuins are protein deacylases with regulatory roles in metabolism and stress response. Functionalized tetrahydro-1H-pyrido[4,3-b]indoles were identified as preferential sirtuin 2 inhibitors, with in vitro inhibitory potencies in the low micromolar concentrations (IC50 3–4 μM) for the more promising candidates. The functional relevance of sirtuin inhibition was corroborated in western blots that showed hyperacetylation of p53 and α-tubulin in treated HepG2 and MDA-MB-231 cells. Molecular docking showed that the tetrahydropyridoindole scaffold was positioned in the NAD + pocket and the acetylated substrate channel of the sirtuin 2 protein by van der Waals/hydrophobic, H bonding and stacking interactions. Functionalized tetrahydropyridoindoles represent a novel class of sirtuin 2 inhibitors that could be further explored for its therapeutic potential.

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