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.

Synthesis and anti-inflammatory and analgesic activities of 3-methyl-N-phenyl-1H-pyrazol-5-ylcarboxamides.

The anti-inflammatory and analgesic activities of a series of 3-methyl-N-phenyl-1H-pyrazol-5-ylcarboxamides were investigated and compared with flufenamic acid. The compounds were synthesized by condensation of diketopiperazines 2 with the appropriate aniline. The pharmacological tests showed that some compounds have good anti-inflammatory activity in rat paw edema induced by carrageenin and low toxicity.

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

Two analogs of chemotactic peptide N-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 of N-formyl-L-methionyl-L-leucyl-L-phenylalanine. The analog containing a tert-butyloxycarbonyl group at the N-terminus, as well as the C-terminal 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.

Structure activity studies on chemically modified homologues of the antibiotic phytotoxic leucinostatin A.

The synthesis and a conformational study of a number of homologues of the well known antibiotic, phytotoxic leucinostatin A are reported. The circular dichroism of all the compounds are discussed. Some conclusions on the SAR of these compounds are drawn. The influence of the alpha-helical conformation and/or the increased lipophile character on their interesting biological activities is emphasized.

Synthesis, biological activity and conformational studies of geometrically restricted tripeptide analogues of the chemoattractant HCO-Met-Leu-Phe-OMe.

The formyl tripeptides containing 2-azetidinecarboxylic acid 2, 2-piperidinecarboxylic acid 3 and norvaline 4 in position 2 were synthesized and their biological activity was evaluated. The conformation of peptides was studied by CD and FT-IR techniques. While 2 and 3 do not show either chemotactic activity or superoxide production, 4 retains both activities.

Opioid peptides. Conformational studies of dermorphin and its constitutive fragments by circular dichroism. IX.

Dermorphins are potent opiate-like heptapeptides which have been isolated from the skin of South American frogs. The Circular Dichroism spectra carried out on dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2), on the analogous [L-Ala2] dermorphin and on N-terminal fragments suggest that, in solution, the native molecule possesses a peculiar folded conformation responsible for its pharmacological activity. The presence of alanine in D configuration and of aminoacid residues possessing a high "beta-turn" potential, seems to be the main reason for such active conformation.

[Antibacterial activity of the derivatives of dehydro-and deoxy-colic acids (author's transl)]. / Attivita' antimicrobica di derivati degli acidi deidro- e desossi-colico

The synthesis of derivatives of dehydro-and deoxy-colic acids with L-lysine and Lysil-lysine with antibacterial activity, is here described. Results show no antibacterial activity of dehydrocolic acid derivatives, while deoxycol-lys-OH-HCl, and particularly deoxycol-lys-NH2-2HCl, seem to be very effective on Gram-positive bacteria at 5 mug/ml, and on Gram-negatives at 25 mug/ml.

[Antibacterial activity of the derivatives of cholic acid (author's transl)]. / Attivita' antibatterica di alcuni derivati dell'acido colico

The synthesis of derivatives of cholic acid with L-lysine and Lysil-lysine with antibacterial activity, is here described. Derivatives with one molecule of lysine show antibacterial activity at 100 mug/ml concentration, while lysil-lysine derivatives, particularly Col-Lys-Lys-NH2-2HCl, are effective also at 25 mug/ml.

[Derivatives of 4-nitroso-aminopyrazole as antifungal agents]. / Derivati del 4-nitroso-5-amminopirazolo come antifungini.

The synthesis of 4-nitroso-5-amminopyrazoles and of 4-nitroso-5-pyrazolylurethans and -ureas is described. The chemicals were tested for antifungal activity against Erysiphe graminis, Erysiphe cichoracearum, Puccinia recondita, Septoria apii and Rhizoctonia solani. A number of the described compounds showed some antifungal activity.

[Bile acid derivatives with antimicrobial activity]. / Derivati di acidi biliari ad attività antimicrobica.

A series of condensation products of cholic and dehydrocholic acids with (L)-aminoacids was prepared and tested in vitro for antimicrobial activity. The derivatives of cholic acid with basic aminoacids showed significant activity, especially marked when (L)-arginine was the condensed aminoacid.

The importance of the peptide bond at position 2 in HCO-Met-Leu-Phe-OMe analogues as shown by studies on human neutrophils.

The formylpeptides formyl-methionyl-N-methylleucyl-phenylalanine methyl ester [for-Met-(NMe)Leu-Phe-OMe] 1, formyl-methionyl-2-aminotetralin-2-carboxyl-phenylalanine methyl ester [for-Met-Atc-Phe-OMe] 2, formyl-methionyl-1,2,3,4-tetrahydroisoquinoline-3-carboxyl-phenylalanine methyl ester [for-Met-Tic-Phe-OMe] 3 and formyl-methionyl-2-aminoxy-4-methylvaleryl-phenylalanine methyl ester [for-Met-OLeu-Phe-OMe] 4 were synthesized in order to investigate the role of the amide bond at position 2 on biological activities on human neutrophils. Only analogue 2, which keeps the NH group at position 2, was found to retain activity though sterically encumbered.

Modifications of the amide bond at position 3 in fMLP analogs select neutrophil functions.

The formylpeptides formyl-L-methionyl-L-leucyl-L-N-methylphenylalanine methyl ester 1, formyl-L-methionyl-L-leucyl-L-2-oxy-3-phenylpropionic acid methyl ester 2 and formyl-L-methionyl-L-leucyl-L-2-aminoxy-3-phenylpropionic acid methyl ester 3 were synthesized to investigate the role of the amide bond at position 3 in biological activity in human neutrophiles. Our results indicate that this amide bond is required for optimal chemotactic activity, but not for superoxide anion production.

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

In 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 and anti-fungal activity of 5-aminopyrazole derivatives]. / Sintesi ed attività antifungina di derivati del 5-aminopirazolo.

4-Thiocyanato-5-amino or acylaminopyrazoles were prepared and their antifungal activity was tested against Candida albicans and Trichophyton mentagrophytes: the 4-thiocyanato-5-aminopyrazoles were the most effective in both tests.

[Amides of amino acids and peptides as antifungal agents]. / Ammidi di amminoacidi e peptidi come antifungini.

The synthesis of pyrazolyl-amides of aminoacids and peptides is described. The chemicals were tested for antifungal activity against wheat powdery mildew (Erysiphe graminis DC.), cucumber powdery mildew (Erysiphe cichoracearum DC.), wheat brown rust (Puccinia recondita Rob. ex Desm. f. sp. tritici Erikss et Henn.), celery leaf spot (Septoria Apii Briosi ed Cav. Chest.) and collar rot (Rhizoctonia solani Kuhn). Some of these compounds showed antifungal activity.

Conformational studies of synthetic tripeptide chemoattractants.

The conformational behavior of the chemotactic peptide analogs formylmethionylleucylphenylalanine methyl ester (CHO-Met-Leu-Phe-OMe) and formylmethionylleucylcyclohexylalanine methyl ester (CHO-Met-Leu-Cha-OMe) has been studied in solvents of different polarity by circular dichroism and infrared absorption. Both analogs and very probably the chemotactic peptide formylmethionylleucylphenylalanine (CHO-Met-Leu-Phe-OH) preferably adopt in solution a folded "active" conformation which allows a strong interaction with the receptor on the human polymorphonuclear leukocyte surface.

Formyl peptide chemoattractants. Synthesis and chemotactic activity.

The tetrapeptides CHO-Met-Leu-Phe-CO-NH-(CH2)n-COOMe (n = 1-5) have been synthesized. These peptides containing an omega-amino acid residue in position 4 exhibit a very high chemotactic activity. Like the chemotactic peptide CHO-Met-Leu-Phe-OMe, these tetrapeptides in solution undoubtedly adopt an "active" conformation which allows a strong interaction with the receptor on the human polymorphonuclear leukocyte surface.

[An analog of formyl-met-leu-phe effects the movement of human leukocytes]. / Analogo del formil-met-leu-phe influenza il movimento dei leucociti umani.

Two tripeptides, related to the chemotactic formyl-peptide, are tested for its ability to affect random and directional locomotion and to induce chemotaxis of polymorphonuclear leukocytes. The results indicate that the methyl ester of formyl-methyonyl-leucyl-phenylalanine possesses a biological activity towards human phagocytes, including a chemotactic potency, comparable to that of unmodified peptide. Therefore, the free carboxyl group does not seem essential to generate active leukoattractant. On the contrary, the replacement of the formyl group by the butyloxycarbonyl results in a drastic loss of biological activity. Our data may indicate that the two formyl-peptides interact with the same binding site on the cell membrane.

Conformational aspects of human formylpeptide receptor antagonists.

The conformation of several Phe-D-Leu-Phe-D-Leu-Phe analogues was analyzed using infrared absorption and circular dichroism. Their effect on human neutrophils was verified by receptor binding and chemotaxis assays. The results demonstrate that the compounds examined prefer an ordered conformation (beta-turn) in amphipatic environment, and that they are able to antagonize the neutrophil functions evoked by CHO-Met-Leu-Phe.