β-1,2,3-Triazolyl-Nucleosides as Nicotinamide Riboside Mimics

Abstract

The synthesis of a series of pyridine- and piperidine-substituted 1,2,3-triazolides linked to a riboside moiety is described. The presence of a triazolide substituent on the pyridine moiety permitted the facile reduction of the latter under mild hydrogenation conditions. These analogues were modelled as to define their similarity to nicotinamide riboside and quantify their ability to bind NAD-dependent protein deacetylases.

Keywords:

• Nucleoside
• nucleotide
• sirtuin
• inhibition

M. E. Migaud and M. Huang share joint authorship this article.

The authors thank Professor R. Marmorstein and Ms. B. Sanders (from the Wistar Institute, Philadelphia, USA) for carrying out the preliminary inhibition studies and extensive discussions, and the EPSRC/MRC GR0100461 and the EC-FP6-EST program, which financially supported this work.

Notes

^aWith a nicotinamide molecule in the D site

^bCapital A, C or D in bold represents that the named compound is docked in the adenosine monophosphate binding fold or the C or D pockets, respectively.

^cCell in red indicates that the docked pose flapped in the pocket.