title: Synthesis and evaluation of peptidic irreversible inhibitors of tissue transglutaminase.
abstract: Herein we report the synthesis and the evaluation of eight novel compounds as irreversible inhibitors of transglutaminase (TGase). These compounds are based on a minimal peptidic scaffold shown previously [Chem. Biol.2005, 12, 469-475] to confer affinity for the TGase active site and bear electrophilic groups such as alpha,beta-unsaturated amide, chloroacetamide or maleimide; their general structure being Cbz-Phe-spacer-electrophile. The affinity conferred by the Cbz-Phe scaffold was determined by comparison to N-propylacrylamide and the length of the spacer was also varied to evaluate its importance. The inhibitory efficiencies (k(inact)/K(I)) of these compounds vary up to 10(5)M(-1)min(-1), among the highest reported for derivatives based on this simple Cbz-Phe peptidic scaffold.
authors.affiliation: Département de Chimie, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montréal, Que., Canada H3C 3J7.
authors.forename: Christophe
authors.initials: C
authors.lastname: Pardin
authors.forename: Steve M F G
authors.initials: SM
authors.lastname: Gillet
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Keillor
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D007700:Kinetics; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008301:Maleimides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D011503:Transglutaminases / Q000037:antagonists & inhibitors*
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D008301:Maleimides; D010446:Peptide Fragments; C043592:maleimide; D011503:Transglutaminases