Side reaction of significance in preparation of peptide- or peptidomimetic-based hydroxamate enzyme inhibitors.
Peptidic and peptidomimetic hydroxamates are increasingly being developed as potential pharmaceutical agents in targeting metalloenzymes. For a number of practical considerations, the hydroxamate moiety is often introduced in the synthesis onto valuable advanced synthetic precursors. The approach entails activation of the carboxylate of the synthetic precursor by any number of methods for the preparation of the hydroxamate. We report herein that this widely used approach in preparation of an entire class of enzyme inhibitors is problematic as documented by the formation of an undesirable cyclization product (characterized in this report), which could at times be the exclusive outcome of the carboxylate activation process.
Hesek
Dusan
D
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
Noll
Bruce C
BC
Mobashery
Shahriar
S
D018360:Crystallography, X-Ray; D003500:Cyclization; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D008968:Molecular Conformation; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D061965:Matrix Metalloproteinase Inhibitors; D010455:Peptides; D011480:Protease Inhibitors