Cyclic Analogs of Chemotactic Formylpeptides, I.: Synthesis and Biological Activity of For‐Cys‐Leu‐Phe‐Cys‐OMe

Abstract

By using the side chain to side chain mode of cyclization the 14-membered disulfide cyclopeptide For-Cis-Leu-Phe-Cys-OMe ( 5 ) has been synthesized as conformationally constrained analog of the prototypical chemotactic tripeptide For-Met-Leu-Phe-OMe. Compound 5 is inactive towards human neutrophils. The lack of biological activity of cyclotetrapeptide 5 is discussed taking into account the backbone folding and the side chain topography.Continuous efforts are being devoted to clarify the conformation-activity relationships in the field of chemotactic N-formylmethionyl peptides. Much results derive from a systematic alteration of the backbone conformational preferences performed on For-Met-Leu-Phe-OH (fMLP), the prototypical ligand of formylpeptide receptors. The adopted strategy consists in the replacement of native a-amino acids with suitable a,a-disubstituted'-i), a,P-unsat~rated~.~) and related conformationally constrained resi-dues6), in order to induce specific backbone conformations into the parent linear tripeptide.An analysis of the literature reveals that the complementary approach, based on the introduction of conformational restriction through medium and long-range backbone cyclizationnamely cyclization between residue i and i + n (with n > 1)7) -has not been examined. Thus, as a prosecution of our efforts to elucidate the conformational requirements of formylpeptide receptors, we are now examining a series of cyclic peptide analogs of fMLP-OMe and here report data concerning the first model, namely the cyclotetrapeptide 5. 5 This compound has been obtained by using the side chain to side chain mode of cyclization, an approach which allows the maintenance of the formylated N-terminal amino group, which is critical for the bioactivity, as well as the C-Cyclische Analoga chemotaktischer Formylpeptide, 1. Mitt.: Synthese und biologische Aktivitat von For-Cys-Leu-Phe-Cys-OMe Durch Cyclisierung von Seitenkette zu Seitenkette wurde das 14-gliedrige Disulfid-Cyclopeptid For-Cys-Leu-Phe-Cys-OMe ( 5 ) als Analogon des chemotaktischen Tripeptides For-Met-Leu-Phe-OMe mit eingeschrankter konformativer Beweglichkeit hergestellt. 5 ist gegeniiber menschlichen Neutrophilen inaktiv. Der Mange1 an biologischer Aktivitat des Cyclotetrapeptides 5 wird unter den Gesichtspunkten der Faltung des Peptides und der Seitenketten-Topographie diskutiert.terminal carboxymethyl group. Compound 5 shares with the parent tripeptide the presence of the lipophilic side chains of leucine and phenylalanine at the second and third position respectively and contains a fourth amino acid residue at the C-terminal position. This latter feature appears of interest since both early8) and recent') observations clearly indicate the positive effect on the bioactivity of the incorporation of a fourth amino acid residue at the C-terminal position of the chemotactic tripeptide fMLP.Although 5 lacks the N-terminal methionine side chain ( Fig. 1,a) which is important for the receptor recognition, it maintains both the &sulfur and the &-carbon atom ( F...