A novel potent nicotinamide phosphoribosyltransferase inhibitor synthesized via click chemistry.
Basic Information
ID: ALA1154743
Journal: J Med Chem
Title: A novel potent nicotinamide phosphoribosyltransferase inhibitor synthesized via click chemistry.
Authors: Colombano G, Travelli C, Galli U, Caldarelli A, Chini MG, Canonico PL, Sorba G, Bifulco G, Tron GC, Genazzani AA.
Abstract: The inhibition of NAD synthesis or salvage pathways has been proposed as a novel target for antitumoral drugs. Two molecules with this mechanism of action are at present undergoing clinical trials. In searching for similar novel molecules, we exploited copper-catalyzed [3 + 2] cycloaddition between azides and alkynes (click chemistry) to synthesize 185 novel analogues. The most promising compound displays an IC(50) for cytotoxicity in vitro of 3.8 +/- 0.3 nM and an IC(50) for NAD depletion of 3.0 +/- 0.4 nM. Herein, we strengthen previous data suggesting that this class of compounds induces autophagic cell death. In addition to characterizing this compound and providing a rationale via molecular docking, we reinforce the excellent potential of click chemistry for rapidly generating structure-activity relationships and for drug screening.
CiteXplore: 19961183
DOI: 10.1021/jm9010669
Patent ID: ┄