ABSTRACT
[reaction: see text]. General stereocontrolled synthesis of all four (2,3)-stereoisomers of 2-substituted statines is described. The 2,3-syn and 2,3-anti isomers were synthesized via beta-ketoester reduction and aldol reactions, respectively. Peptides containing 2-substituted statines inhibit porcine pepsin with nanomolar IC50 values.
Subject(s)
Amino Acids/chemical synthesis , Aspartic Acid Endopeptidases/antagonists & inhibitors , Protease Inhibitors/chemical synthesis , Amino Acids/chemistry , Animals , Protease Inhibitors/chemistry , Stereoisomerism , SwineABSTRACT
The NMR structure of a small, side-chain-cyclized tripeptide mimic of the turn in the helix-turn-helix (HTH) motif was determined. The four beta-protons were stereospecifically assigned by stereoselective deuterium replacement of only the proR beta-protons. All 24 of 30 NOESY cross-peaks not involving chemically defined or freely rotating protons, and six of seven coupling constants from the P.COSY were used as distance and angle constraints in molecular modeling. MacroModel found 33/1000 structures in the NMR constrained search and 263/1000 structures in the unconstrained search, indicating meaningful constraint by the NMR data. However, the 10 lowest-energy structures from the unconstrained and constrained searches are very similar, so modeling alone was able to find the experimentally determined structure.
