title: A novel potent nicotinamide phosphoribosyltransferase inhibitor synthesized via click chemistry.
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.
authors: Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Università degli Studi del Piemonte Orientale A. Avogadro, Via Bovio 6, 28100 Novara, Italy.
authors: Giampiero
authors: G
authors: Colombano
authors: Cristina
authors: C
authors: Travelli
authors: Ubaldina
authors: U
authors: Galli
authors: Antonio
authors: A
authors: Caldarelli
authors: Maria Giovanna
authors: MG
authors: Chini
authors: Pier Luigi
authors: PL
authors: Canonico
authors: Giovanni
authors: G
authors: Sorba
authors: Giuseppe
authors: G
authors: Bifulco
authors: Gian Cesare
authors: GC
authors: Tron
authors: Armando A
authors: AA
authors: Genazzani
mesh_terms: D000480:Alkynes / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001343:Autophagy; D001386:Azides / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D000480:Alkynes; D000970:Antineoplastic Agents; D001386:Azides; D004791:Enzyme Inhibitors; D054409:Nicotinamide Phosphoribosyltransferase