MODIFIED CHEMOTACTIC PEPTIDES - SYNTHESIS, CONFORMATION, AND ACTIVITYOF HCO-THP-AC(6)C-PHE-OME

HCO-Thp-Ac(6)c-Phe-OMe (3) has been synthesized as a new analogue of t he prototypical chemotactic agent HCO-Met-Leu-Phe-OMe (fMLP-OMe). Comp ound 3 contains 4-aminotetrahydrothiopyran-4-carboxylic acid (Thp) and 1-aminocyclohexane-1-carboxylic acid (Ac(6)c) as achiral, conformatio nally restricted mimics of Met and Leu, respectively. In the crystal, the formyltripeptide adopts an helical conformation at the Thp and Ac( 6)c residues, of the type alpha(R) and alpha(L), respectively, whereas the C-terminal phenylalanine is quasi-extended. A system of two conse cutive gamma-turns, centered at the first two residues, better explain s the nmr data as compared with an alternative beta-turn structure. Th e conformation of the new analogue 3 is compared with those of two rel ated peptides containing Thp as N-terminal residue. The biological act ivity of 3 has been determined on human neutrophils and compared to th at of the previously studied model [Ac(6)c(2)] fMLP-OMe. While the abo ve analogue is highly active in the superoxide anion production, the n ew tripeptide 3 is practically unable to elicit any of the tested biol ogical activities. (C) 1996 John Wiley & Sons, Inc.