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 α,β-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 (kinact/KI) of these compounds vary up to 105 M−1 min−1, among the highest reported for derivatives based on this simple Cbz-Phe peptidic scaffold.

Eight novel irreversible inhibitors of tissue transglutaminase were prepared and evaluated, bearing alkyl chains of varied length and different pharmacophores.Figure optionsDownload as PowerPoint slide