Enrico Gavuzzo

Exploring the interest of 1,2-dithiolane ring system in peptide chemistry. Synthesis of a chemotactic tripeptide and X-ray crystal structure of a 4-amino-1,2-dithiolane-4-carboxylic acid derivative

Due to their relevant biological functions and specific chemical reactivity 1,2-dithiolanes (five-membered cyclic disulfides) represent an emerging class of heterocyclic compounds. However, despite the extensive research centered on lipoic acid and its analogues, only very few data are at the present available on peptides containing this ring system. We report here synthesis, conformation and bioactivity of a fMLF-OMe analogue, namely For-Met-Adt-Phe-OMe (7), in which the residue of the 4-amino-1,2-dithiolane-4-carboxylic acid (Adt) (4) replaces the central L-leucine. The crystal conformation of the synthetic intermediate Boc-Adt-OMe (5) is also described and compared to that of lipoic acid (R-1,2-dithiolane-3-pentanoic acid) (3) and asparagusic acid (1,2-dithiolane-4-carboxylic acid) (2).

Retrosulfonamido peptide analogues. Synthesis and crystal conformation of Boc-Pro-Leu-Ψ(NH-SO2)-Gly-NH2

Abstract Boc-Pro-Leu-Ψ(NH-SO 2 )-Gly-NH 2 ( 3 ) has been synthesized as the first example of a pseudopeptide incorporating the NH-SO 2 junction. The crystal structure of 3 indicates that the Ψ(NH-SO 2 ) induces a cisoidal (gauche − ) conformation which induces a backbone folding and prevents the H-bonded β-turn found in the parent peptide.

Alkali cation ‘conformational templation’ in 1,5-bridged calix[8]arenes: a single crystal X-ray proof

Abstract X-Ray crystallography proves that alkali cations can act as conformational templates for 1,5-bridged calix[8]arenes 1 H 6 – 3 H 6 , folding their skeleton in a ‘tub-shaped’ conformation composed of four 3/4-cone clefts. This templation occurs even for neutral 1 H 6 to give a ( 1 H 6 Cs) + ·Cl − complex, where Cs + was found perfectly fitting inside the eight calix[8]arene oxygens cavity. Conventional ‘electrostatic’ coordination with O atoms occurs whereas cation-π interactions can be excluded.

Laurencianol, a new halogenated diterpenoid from the marne alga

Abstract The structure of an anitmicrobial dibromomochloroditerpene alcohol, laurencianol, has been determined by spectral and X-ray crystallographic techniques. The compound has been isolated from the Mediterranean red alga barLaurencia obtusa .

Synthesis and x-ray crystal structure of a tripeptidic cyclol

Abstract Properties, spectral data and X-ray crystallographic analysis of a tetracyclic tripeptidic aza-cyclol, obtained by cyclization of CF3COOH·Pro-Phe-Pro-CNp in aqueous medium, are reported.

INHIBITION OF ADAMALYSIN II AND MMPS BY PHOSPHONATE ANALOGUES OF SNAKE VENOM PEPTIDES

Phosphonate analogues of the peptidomimetic N-(Furan-2-yl)carbonyl-Leu-Trp-OH were prepared with the goal of evaluating the effect of phosphonate for carboxylate replacement on binding with snake venom metalloproteinases and MMPs. N-(Furan-2-yl)carbonyl-Leu-L-Trp(P)-(OH)2 showed a 75-fold increase of the inhibiting activity against adamalysin II, a snake venom metalloproteinase structurally related to MMPs and TACE. Both the phosphonate and carboxylate peptidomimetics fit into the active site adopting a retrobinding mode and provide the structural base for a new class of metalloproteinases inhibitors.

Three-component supramolecular self-assembly based on a 5,5%-bicalix(4)arene exoditopic receptor

5,5′-Bicalix[4]arene 1 , a ditopic host possessing two divergent cavities, crystallizes from CH 2 Cl 2 and p -xylene to give an iterative assembly of a three-component zigzag array. This array is formed by CH-π inclusion of a linear CH 2 Cl 2 · p -xylene connector within the facing cavities of two molecules of 1 . Each zigzag array is perpendicularly interconnected to the lateral one through hydrophilic interactions of calixarene-OH groups.

For-Met-ΔzLeu-Phe-OMe: A new active analog of chemotactic N-formyltripeptides with β-turn crystal conformation

Abstract The title Δ z Leu containing N-formyltripeptide 2 , has been synthesized and found active in the superoxide production whereas inactive in the stimulation of human neutrophil migration. The X-ray crystallographic analysis reveals that 2 adopts a β-turn conformation stabilized by an intramolecular H-bond.

Approaches to pseudopeptidic ergopeptines. Synthesis and molecular structure of an α-aza-phenylalanine-containing oxa-cyclol

A synthesis of the tetrahedral adduct (oxa-cyclol)6 structurally related to the peptide portion of ergotamine and possessing an α-aza-phenylalanine residue in place of the central phenylalanine is described. The reaction sequence comprises acylation of cyclo-(-azaPhe-Pro-) with (S)-2-benzyloxypropionyl chloride, followed by chemoselective hydrogenolytic removal of the O-benzyl protecting group. The intermediate N-(α-hydroxyacyl)-cyclo-(-azaPhe-Pro-) undergoes spontaneous ring enlargement leading stereospecifically to the tetrahedral adduct 6 tautomeric with the 9-membered cyclodepsitripeptide cyclo-(-Lac-azaPhe-Pro-)7. The stereochemistry of 6 has been confirmed by an X-ray crystallographic analysis which provides, in addition, detailed information on the structural and conformational features of the newly formed pseudopeptide system.

Computational study of the catalytic domain of human neutrophil collagenase. specific role of the S3 and S'3 subsites in the interaction with a phosphonate inhibitor.

Human neutrophil collagenase (HNC, MMP-8) is one of the target enzymes for drug treatment of pathologic extracellular matrix degradation. Peptidomimetic inhibitors bind in the S′-side of the enzyme active site occupying the S′1primary specificity pocket by their large hydrophobic side-chains. The crystal structure of the complex between the catalytic domain of MMP-8 and Pro-Leu-l-TrpP(OH)2(PLTP) showed that this phosphonate inhibitor binds in the S side of the active site. This finding was unexpected since it represents the first example of accommodation of the bulky Trp indolyl chain in the S1rather than in the S′1subsite. Dynamical and structural factors favouring this uncommon mode of binding were therefore investigated.MD simulations performed on the uncomplexed enzyme show that its structure in aqueous solution is only slightly different from the crystal structure found in the complex with PLTP. ED analysis of the MD simulations, performed on PLTP alternatively interacting with the S- or S′-side of the active site, shows that the enzyme fluctuation increases in both cases. The main contribution to the overall enzyme fluctuation is given by the loop 164–173. The fluctuation of this loop is spread over more degrees of freedom when PLTP interacts with the S-side. This dynamical factor can enhance the preference of PLTP for the S subsites of MMP-8. MD simulations also show that ligation of PLTP in the S subsites is further favoured by better zinc chelation, a cation-π interaction at the S3subsite and unstrained binding conformations. The role of the S3, S′3and S′1subsites in determining the inhibitor binding is discussed.