title: Two-step synthesis of novel, bioactive derivatives of the ubiquitous cofactor nicotinamide adenine dinucleotide (NAD).
abstract: We report the design and concise synthesis, in two steps from commercially available material, of novel, bioactive derivatives of the enzyme cofactor nicotinamide adenine dinucleotide (NAD). The new synthetic dinucleotides act as sirtuin (SIRT) inhibitors and show isoform selectivity for SIRT2 over SIRT1. An NMR-based conformational analysis suggests that the conformational preferences of individual analogues may contribute to their isoform selectivity.
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich, NR4 7TJ, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pesnot
authors.forename: Julia
authors.initials: J
authors.lastname: Kempter
authors.forename: Jörg
authors.initials: J
authors.lastname: Schemies
authors.forename: Giulia
authors.initials: G
authors.lastname: Pergolizzi
authors.forename: Urszula
authors.initials: U
authors.lastname: Uciechowska
authors.forename: Tobias
authors.initials: T
authors.lastname: Rumpf
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sippl
authors.forename: Manfred
authors.initials: M
authors.lastname: Jung
authors.forename: Gerd K
authors.initials: GK
authors.lastname: Wagner
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008956:Models, Chemical; D009243:NAD / Q000737:chemistry*; D010084:Oxidation-Reduction; D011485:Protein Binding; D011487:Protein Conformation; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors / Q000737:chemistry*
chemical_list: D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D009243:NAD; C447939:SIRT1 protein, human; C474199:SIRT2 protein, human; D056564:Sirtuin 1; D056565:Sirtuin 2