MC-2562

Using benzylamines as the C4 source of 1,4‐dihydropyridines (1,4‐DHPs), a Cu‐catalyzed oxidative [1+2+1+2] cascade cyclization for the synthesis of 1,4‐DHPs was firstly developed. A broad range of easily available N,N‐dimethyl enaminones and benzylamines are employed smoothly to provide a diverse range of 1,4‐DHPs with high efficiency. This method is performed by a one‐pot cascade C(sp3)−H bond functionalization/C(sp3)−N cleavage/cyclization strategy to form simultaneously two C(sp3)−C(sp2) bonds, two C(sp2)−N bonds, and a 1,4‐DHP ring.

Sirtuins are NAD⁺-dependent protein deacylases involved in metabolic regulation and aging-related diseases. Specific activators for seven human Sirtuin isoforms would be important chemical tools and potential therapeutic drugs. Activators have been described for Sirt1 and act via a unique N-terminal domain of this isoform. For most other Sirtuin isoforms, including mitochondrial Sirt3-5, no potent and specific activators have yet been identified. We here describe the identification and characterization of 1,4-dihydropyridine-based compounds that either act as pan Sirtuin activators or specifically stimulate Sirt3 or Sirt5. The activators bind to the Sirtuin catalytic cores independent of NAD⁺ and acylated peptides and stimulate turnover of peptide and protein substrates. The compounds also activate Sirt3 or Sirt5 in cellular systems regulating, e.g., apoptosis and electron transport chain. Our results provide a scaffold for potent Sirtuin activation and derivatives specific for Sirt3 and Sirt5 as an excellent basis for further drug development.