Gianni Vertuani

Response of human neutrophils to formyl-peptide modified at the terminal amino and carboxyl groups

Two analogs of chemotactic peptideN-formyl-l-methionyl-l-leucyl-l-phenylalanine were examined for their capacity to activate several functions of human neutrophils. The C-terminus methyl ester derivative of the chemotactic peptide was found to possess strong biological activity and was able to induce levels of chemotaxis, enzyme secretion, and Superoxide generation comparable to those observed with the same concentrations ofN-formyl-l-methionyl-l-leucyl-l-phenylalanine. The analog containing atert-butyloxycarbonyl group at the N-terminus, as well as the C-terrninal methyl ester, was completely devoid of activity towards neutrophils. From these results, it appears that the free carboxyl group is not necessary for biological function. In contrast, the substituent at the N-terminus may play a critical role in the induction of the cellular response.

The role of peptide bond in chemotactic for-Met-Leu-Phe-Ome focused by depsipeptide analogs

Abstract The formyl tridepsipeptides HCO-Met-Ψ[COO]Leu-Phe-OMe 3 HCO-Met-Ψ[COO]Aib-Phe-OMe 4 and HCO-Met-Leu-Ψ[COO]Phe-NHBzl 5 were synthesized in order to investigate the biological consequences arising from introduction of an ester bond at various positions in the chemotactic tripeptides. While analogs 3 and 4 were found lacking in biological activity, stressing an essential role for peptide bond at position 2, compound 5 showed to retain activity.

Met-Ile-Phe-Leu derivatives: full and partial agonists of human neutrophil formylpeptide receptors.

The biological action of a series of Met-Ile-Phe-Leu analogues was analyzed on human neutrophils, to evaluate their ability to interact with formylpeptide receptors and to induce the related neutrophil responses. Three in vitro assays were carried out: receptor binding, chemotaxis and superoxide anion release. Our results demonstrate that formyl-Met-Ile-Phe-Leu derivatives act as more potent full agonists than formyl-Met-Leu-Phe, the tripeptide normally used as a model chemoattractant for the study of cell functions. On the other hand, the presence of N-ureidoisopropyl substituent in tetrapeptides imparts weak partial agonist properties. It has furthermore been demonstrated that the C-terminal methyl esterification or amination weakly influences the properties of tetrapeptide homologues. Finally, t-Boc-Met-Ile-Phe-Leu derivatives do not appear able to interact with formylpeptide receptors.

Conformation studies on bombesin receptor antagonists: 500 MHz NMR and CD characterization of synthetic (D-Phe12, Leu14)-bombesin

The conformation flexibility of the tetradecapeptide hormone bombesin and its synthetic antagonist (DPhe12, Leu14)-bombesin has been studied using nuclear magnetic resonance and circular dichroism techniques. The spectral features observed indicate that the ordered structure present in the C-terminal pentapeptide moiety of native BBS is lost in the (DPhe12, Leu14) analog.

Platinum assisted cyclization of S-methyl 3-acyl-2-methyldithiocarbazates under mild conditions. Crystal structure of [Pt2(µ-SMe)(terpy)2][ClO4]3†

The reaction of the newly synthesized aqua complex [Pt(terpy)(OH2)][BF4]2 with S-methyl 3-acyl-2-methyldithiocarbazates under a variety of experimental conditions has been studied. Using a 2∶1 metal to ligand ratio in methanol, a platinum assisted cyclization was observed. The reaction products were Δ2-1,3,4-oxadiazoline-5-thione derivatives and the binuclear tricationic complex [Pt2(µ-SMe)(terpy)2]3+ whose molecular structure has been determined by X-ray crystallography. This platinum assisted transformation is proposed as a new synthetic route to Δ2-1,3,4-oxadiazoline-5-thiones under mild conditions. In the presence of an excess of a non-co-ordinating acid (HClO4, CH3SO3H or CF3SO3H) the cyclization is completely quenched and complexes with co-ordinated S-methyl 3-acyl-2-methyldithiocarbazates have been isolated. A general mechanism which accounts for the observed transformations is proposed on the basis of 1H NMR and UV/Vis evidence.

Conformational studies of chemotactic HCO-Met-Leu-Phe-OMe analogues

SummaryIn order to investigate the proper peptide backbone conformation able to elicit a biological activity, HCO-Met-Pro-Phe-OMe, HCO-Met-Ψ[COO]Leu-Phe-OMe, and HCO-Met-OLeu-Phe-OMe, analogues of the prototypical chemotactic peptide HCO-Met-Leu-Phe-OMe, were studied by CD and IR techniques. The results obtained comparing biological and conformational data evidence the critical presence of (i) the NH group at position 2, (ii) a rather flexible backbone, (iii) the chemical structure of the central residue which can affect the stability of a possible active conformer.

Synthesis, characterization, properties and structures of rhenium-(II), -(III), and -(V) complexes containing amino acids conjugated with a 2-aminothiazole ligand

The one-step reaction of KReO4 with benzoylhydrazine in the presence of concentrated HCl and PPh3 afforded [ReV(NNC(Ph)O)(PPh3)2Cl2] 1 which was converted with carbon monoxide into the dinitrogen Re(I) complex [ReN2(CO)2(PPh3)2Cl] 2 in good yield. A new class of ligands, of general formula HLn (n = 1–5), was obtained by conjugation of N-protected amino acids and benzoic acid with 2-aminothiazole. Complex 2 reacted with HLn to give neutral Re(II) chelate complexes [Re(Ln)(CO)(PPh3)2Cl] 5–9 (n = 1–5), by substitution of N2 and CO groups. The molecular structure of complex 9 was determined by X-ray diffraction. When reactions between [Re(NNC(Ph)O)(PPh3)2Cl2] 1 and HLn (n = 2, 5) were carried out in different stoichiometric ratios, neutral mono- and di-substituted Re(III) organodiazenido complexes [Re(NNCOPh)(L2,5)(PPh3)2Cl] 10, 11 and [Re(NNCOPh)(L5)2(PPh3)] 12 were obtained. In these complexes the organodiazenido Re–N–N moiety adopts a linear conformation, as has been authenticated by X-ray diffraction analysis for 11 and 12. Treatment of Re(I) dinitrogen precursors [ReN2(P)4Cl] (P = PMe2Ph, 3 and PMePh2, 4) with ligands resulted in interesting dinuclear oxo-(μ-oxo)-Re(V) species [Re2(O)3(Ln)2(P)2] (P = PMe2Ph, n = 1, 13; n = 2, 14; n = 4, 15. P = PMePh2, n = 2, 16). Suitable crystals for an X-ray analysis have been obtained for complex 14. The structure represents one of the few cases where, for steric reasons, the Re–O–Re bridging unit is not linear but rather bent. All the compounds have been characterized by elemental analyses, IR and NMR spectroscopy. The Re(II) complexes 5–7 and 9 were further characterized by electrochemical measurements.