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Previously, we identified a potent antimicrobial analogue of temporin L (TL), [Pro3 ]TL, in which glutamine at position 3 was substituted with proline. In this study, a series of analogues in which position 3 is substituted with non-natural proline derivatives, was investigated for correlations between the conformational properties of the compounds and their antibacterial, cytotoxic, and hemolytic activities. Non-natural proline analogues with substituents at position 4 of the pyrrolidine ring were considered. Structure-activity relationship (SAR) studies of these analogues were performed by means of antimicrobial and cytotoxicity assays along with circular dichroism (CD) and NMR spectroscopic analyses for selected compounds. The most promising peptides were additionally evaluated for their activity against some representative veterinary microbial strains to compare with those from human strains. We identified novel analogues with interesting properties that make them attractive lead compounds.

The synthesis of isoxazolino-carbocyclic nor-nucleosides incorporating an anthracene moiety was properly tuned through nitrosocarbonyl intermediates chemistry, and a variety of analogues were attained starting from stereodefined heterocyclic aminols through the linear construction of purine heterocyclic rings. The synthesis hinges on the exo selective 1,3-dipolar cycloaddition of the stable anthracenenitrile oxide to the N-benzoyl-2,3-oxazanorborn-5-ene and simple elaborations of the cycloadducts. A selection of nucleoside derivatives were initially tested for their inhibitory activity against a variety of viruses, including Hepatitis B and C, Human Papilloma virus as well as Influenza viruses of type A and B. Modest anti-viral activities were observed in Hepatitis assays while the activities in the cases of Influenza viruses were almost negligible. Good anti-viral activity was found for compound 11bC with no cellular toxicity at the dose tested in the case of Human Papilloma virus.

Thumbnail image of graphical abstract A subtle change: Structural changes upon amide bond methylation improve the selectivity of the anti-angiogenic drug Cilengitide, which after N-methylation at distinct positions discriminates between the closely related pro-angiogenic integrins avß3 and avß5 (see scheme).

The cyclic octapeptide cyclo[‐Pro1‐Pro‐Phe‐Phe‐Ac6c‐Ile‐ala‐Val8‐] [C8‐Ac6c], containing the Pro1‐Pro‐Phe‐Phe sequence, followed by a bulky helicogenic Cα,α‐dialkylated glycine residue Ac6c (1‐aminocyclohexane‐1‐carboxylic acid), and a D‐Ala residue at position 7 has been synthesized. This cyclic peptide is a deletion analogue of the naturally occurring cyclic nonapeptide cyclolinopeptide A (CLA). It has been designed with the aim of studying the role that the Ac6c and D‐Ala residues play on the conformational behaviour of the whole molecule and their influence on the conformation of the Pro1‐Pro‐Phe‐Phe sequence when compared with cyclolinopeptide A. C8Ac6c has been investigated in chloroform and acetonitrile solutions by 2D NMR techniques. Only one set of sharp signals is observed in both solvents. This evidence strongly supports the hypothesis that only one conformational state exists in the chosen solvents. The interpretation of the experimental data points to the existence for C8‐Ac6c of a very rigid structure stabilized by intramolecular hydrogen bonds. The measured NOE effects allow the calculation of internuclear distances, which have been used as restraints in molecular dynamic calculations. The proposed conformation of the molecule shows that the Pro‐Pro‐Phe segment retains the conformation observed in natural CLA both in solution and in the solid state and that the Ac6c residue indeed reinforces the ring rigidity not permitting the formation of any appropriate cavity in which inorganic cations could be complexed. Copyright © 1995 European Peptide Society and John Wiley & Sons Ltd.

Thymosin-beta 4 (T beta 4) is a G-actin sequestering peptide involved in regeneration and remodeling of injured tissues. In this work, we have designed and synthesized three peptide sequences containing the N-terminus (TYB4-n), the central part (TYB4-i) or the C-terminus (TYB4-c) of T beta 4. All fragments are overlapping on the main central binding actin site. After a structural characterization, we have evaluated in vitro and in vivo their pro-angiogenic effects. The results of this study have shown that: (i) each fragment reproduces the native conformation; (ii) T beta 4-derived peptides exert both in vitro and in vivo pro-angiogenic effects; (iii) their in vitro effect seem to be related to the activation of several signaling pathways and is positively modulated by the N-terminus of T beta 4. (C) 2011 Elsevier Inc. All rights reserved.

Improved synthesis of 1,3-disaccharides, obtained diastereomerically pure by [4+2] hetero cycloadditions between glycals and -thiono- -keto- -lactones, has been reported. The choice of appropriate protecting groups for -keto- -lactones, stable under cycloaddition conditions employed, sensibly shortened the synthesis of heterodienic precursors. The first example of a -oxy-imino- -lactone synthesized from -keto- -lactones was also reported. Molecular modeling and conformational evaluations about the cycloaddition features allowed tentatively rationalizing the experimental results. © 2009 Taylor & Francis Group.

A solid state analysis of the cyclic octapeptide c(-Pro1-Pro-Phe-Phe- Ac6c-Ile-D-Ala-Val8-) (C8-CLA), containing the Pro-Pro-Phe-Phe sequence, followed by the bulky helicogenic C(α,α)-dialkylated 1-aminocyclohexane-1- carboxylic acid (Ac6c) residue and a D-Ala residue in position 7, has been carried out by x-ray diffraction. The crystals, grown from a DMSO solution, are monoclinic, space group P21 with a 13.458(3) Å, b = 19.404(5) Å, c = 21.508(4) Å, and β = 90.83(6)*, with two independent cyclic molecules in the asymmetric unit, two DMSO molecules, and three water molecules. The structure has been solved using the half and bake procedure by Sheldrick, and refined to final R1 and wR2 indices of 0.0613 and 0.1534 for 9867 reflections with 1 > 2σ(I). This cyclic peptide, a deletion analogue of the naturally occurring cyclic nonapeptide cyclolinopeptide A [c(Pro-Pro-Phe-Phe-Leu-Ile- Ile-Leu-Val), CLA] has been designed to study the influence of the ring size reduction on the conformational behavior of CLA and more in general to obtain structural information on asymmetric cyclic octapeptides. The compound exhibits, in the solid state, a 'banana-twisted' conformation with a cis peptide bond located between the two proline residues. Five intramolecular H bonds stabilize the structure: one type VIa β-turn, two consecutive type III/I β-turns, one γ-turn, and one C16 bend. The structure has also been compared with either the solution structure previously reported by us and obtained by nmr and computational analysis, and with solid state structural data reported in the literature on cyclic octapeptides. (C) 2000 John Wiley and Sons, Inc.

The synthesis and conformational properties of a series of dipeptide taste ligands, differing from the commercial sweetener aspartame by the presence of a methylene group between the Cα and the C′ carbon atoms (as in homo-β-residues) in either the L-Asp or the L-Phe residues, are described. Homo-β-residues such as homo-β-aspartic acid, homo-β-phenylglycine and homo-β-phenylalanine, obtained by homologation of the corresponding proteinogenic α-amino acids, have been used in the solution peptide synthesis of the following aspartame analogues in protected and unprotected forms: NH2-homo-β-(L or D)-Asp-L-Phe-OMe, NH2-L-Asp-homo-β-L-Phg-OMe and NH2-L-Asp-homo-β-L-Phe-OMe. Lengthening of the peptide skeleton at the L-Asp site results in a drastic loss of sweetness with the production of tasteless compounds; on the other hand, lengthening of the skeleton at the C-terminal L-Phe site partially mantains the sweet taste in both NH2-L-Asp-hamo-β-L-Phe-OMe and NH2-L-Asp-homo-β-L-Phg-OMe. The solution conformation of the synthesized dipeptide taste ligands was investigated by NMR and circular dichroism techniques. The analysis of NMR data combined with restrained molecular dynamics calculations shows that all peptides are fairly flexible and they do not assume a preferred conformation in DMSO and methanol. The peptides containing homo-β-L-Phe and homo-β-L-Phg do adopt a discrete number of conformation among which mainly extended and 'L-shaped' conformation are represented The circular dichroism spectra are consistent with the NMR results, indicating a significant flexibility for these compounds. Copyright © 1999 John Wiley & Sons, Ltd.