Synthesis and evaluation of peptidic irreversible inhibitors of tissue transglutaminase.
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.
Pardin
Christophe
C
Département de Chimie, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montréal, Que., Canada H3C 3J7.
Gillet
Steve M F G
SM
Keillor
Jeffrey W
JW
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*
D000577:Amides; D004791:Enzyme Inhibitors; D008301:Maleimides; D010446:Peptide Fragments; C043592:maleimide; D011503:Transglutaminases