ABSTRACT
New N-For-Met-Leu-Phe-OMe (fMLF-OMe) analogues incorporating three different gamma-delta-didehydro-alpha-aminoacid residues (namely: Alg = (S)-Allylglycine; Dag = Diallylglycine; Cpg = 1-Aminocyclopent-3-ene-1-carboxylic acid) replacing the native (S)-Leucine have been synthesized and their activity towards human neutrophils has been evaluated in comparison with that shown by the reference tripeptide fMLF-OMe. Chemotaxis, lysozyme release and superoxide anion production have been measured. (1)H NMR titration experiments and NOESY spectrum of the Cpg containing model 10 have been discussed in order to ascertain the preferred solution conformations. A fully extended (C(5)) conformation at position 2 and a folded conformation with two consecutive gamma-turns (C(7) structure) have been proposed for the Dag and Cpg containing tripeptides, respectively.
Subject(s)
Allyl Compounds/chemistry , Allylglycine/chemistry , Carboxylic Acids/chemistry , Chemotactic Factors/pharmacology , Cyclopentanes/chemistry , Glycine/analogs & derivatives , N-Formylmethionine Leucyl-Phenylalanine/analogs & derivatives , N-Formylmethionine Leucyl-Phenylalanine/pharmacology , Neutrophils/drug effects , Chemotactic Factors/chemical synthesis , Chemotactic Factors/chemistry , Glycine/chemistry , Humans , Magnetic Resonance Spectroscopy/methods , Molecular Conformation , Muramidase/chemistry , Muramidase/metabolism , N-Formylmethionine Leucyl-Phenylalanine/chemical synthesis , Protein Folding , Superoxides/chemistry , Superoxides/metabolismABSTRACT
The two fMLF-OMe analogues For-Met-beta(3)hAc(6)c-Phe-OMe (6) and For-Met-beta(2)hAc(6)c-Phe-OMe (12) and their corresponding N-Boc derivatives 5 and 11 have been synthesized and their biological activity towards human neutrophils evaluated. The N-formyl peptides 6 and 12 exhibit good activity as chemoattractans and 12 is highly active in superoxide anion production. The preferred solution conformation of the two N-formyl derivatives has been discussed.
