Synthesis and biological evaluation of isosteric analogues of FK866, an inhibitor of NAD salvage.
One of the great challenges of medicinal chemistry is to create novel, effective, chemotherapeutic agents that show specificity for cancer cells combined with low systemic toxicity. A novel idea is to target the enzymes of the NAD biosynthesis and recycling pathways given that cancer cells display a higher NAD turnover rate than healthy cells. To this end, the compound FK866 (APO866; (E)-N-[4-(1-benzoylpiperidin-4-yl) butyl]-3-(pyridin-3-yl) acrylamide), which blocks nicotinamide phosphoribosyltransferase (NMPRTase) has entered clinical trials as a potential chemotherapeutic agent. Here we report the synthesis of analogues of FK866 synthesized by click chemistry.
Galli
Ubaldina
U
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche and Drug and Food Biotechnology Center Università degli Studi del Piemonte Orientale A. Avogadro, Via Bovio 6, 28100 Novara, Italy.
Ercolano
Emanuela
E
Carraro
Lorenzo
L
Blasi Roman
Cintia R
CR
Sorba
Giovanni
G
Canonico
Pier Luigi
PL
Genazzani
Armando A
AA
Tron
Gian Cesare
GC
Billington
Richard A
RA
D000178:Acrylamides / Q000138:chemical synthesis*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002384:Catalysis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003300:Copper / Q000737:chemistry; D006801:Humans; D009243:NAD / Q000378:metabolism*; D010880:Piperidines / Q000138:chemical synthesis*; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology
D000178:Acrylamides; D000970:Antineoplastic Agents; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; D014230:Triazoles; D009243:NAD; D003300:Copper