G. Pochetti

γ-Turn conformation induced by α,α-disubstituted amino acids with a cyclic six-membered side chain

Abstract 4-Aminotetrahydrothiopyran-4-carboxylic acid (Thp) is an unusual achiral cyclic α,α-disubstituted amino acid mimicking the natural Met residue. The conformational energy map computed for Ac-Thp-NHMe shows that the γ-turn is the lowest minimum. 1 H-NMR and IR studies performed on For-Thp-Leu-OMe ( 2a ), a short peptide unable to give a 4…>1 H-bond, indicate that the γ-turn is adopted in CDCl 3 solution, whereas is not retained in (CD 3 ) 2 SO. An analogous conformational behaviour in solution has been observed for the strictly related For-Ac 6 c-Leu-OMe ( 2b ), containing 1-aminocyclohexane carboxylic acid (Ac 6 c).

2 Å X-ray structure of adamalysin II complexed with a peptide phosphonate inhibitor adopting a retro-binding mode

The search of reprolysin inhibitors offers the possibility of intervention against both matrixins and ADAMs. Here we report the crystal structure of the complex between adamalysin II, a member of the reprolysin family, and a phosphonate inhibitor modeled on an endogenous venom tripeptide. The inhibitor occupies the primed region of the cleavage site adopting a retro‐binding mode. The phosphonate group ligates the zinc ion in an asymmetric bidentate mode and the adjacent Trp indole system partly fills the primary specificity subsite S1′. An adamalysin‐based model of tumor necrosis factor‐α‐converting enzyme (TACE) reveals a smaller S1′ pocket for this enzyme.

Synthesis, conformation, and biological activity of two fMLP‐OMe analogues containing the new 2‐[2′‐(methylthio) ethyl] methionine residue

The new Cα‐tetrasubstituted α‐amino acid residue 2‐[2′‐(methylthio) ethyl]methionine (Dmt) has been introduced into the reference chemotactic tripeptide HCO‐Met‐Leu‐Phe‐OMe (fMLP‐OMe) in place of the leucine or methionine, respectively. The biological activity of the new analogues [Dmt2] fMLP‐OMe (2) and [Dmt1] fMLP‐OMe (3) has been determined; whereas 2 is active toward human neutrophils, stimulating directed migration, superoxide anion generation, and lysozyme release, 3 results practically inactive in all tested assays. A conformational analysis on 2 and 3 has been performed in solution by using ir absorption and 1H‐nmr. The conformation of 2 was also examined in the crystal by x‐ray diffraction methods. Both 2 and 3 adopt fully extended conformation in correspondence with the Dmt residue. Biological and conformational results are discussed and compared with related previously studied models.

Modified chemotactic peptides: Synthesis, conformation, and activity of HCO‐Thp‐Ac6c‐Phe‐OMe

HCO-Thp-Ac6c-Phe-OMe (3) has been synthesized as a new analogue of the prototypical chemotactic agent HCO-Met-Leu-Phe-OMe (fMLP-OMe). Compound 3 contains 4-aminotetra-hydrothiopyran-4-carboxylic acid (Thp) and 1-aminocyclohexane-1-carboxylic acid (Ac6c) as achiral, conformationally restricted mimics of Met and Leu, respectively. In the crystal, the formyltripeptide adopts an helical conformation at the Thp and Ac6c residues, of the type alpha R and alpha L, respectively, whereas the C-terminal phenylalanine is quasi-extended. A system of two consecutive gamma-turns, centered at the first two residues, better explains the nmr data as compared with an alternative beta-turn structure. The conformation of the new analogue 3 is compared with those of two related peptides containing Thp as N-terminal residue. The biological activity of 3 has been determined on human neutrophils and compared to that of the previously studied model [Ac6c2] fMLP-OMe. While the above analogue is highly active in the superoxide anion production, the new tripeptide 3 is practically unable to elicit any of the tested biological activities.

Peptides containing the sulfonamide junction: Synthesis, structure, and conformation of Z-Tau-Pro-Phe-NHiPr

The taurine (Tau) containing tripeptide derivative Z-Tau-Pro-Phe-NHiPr (1) has been synthesized as suitable sulfonamido-pseudopeptide model to investigate formation and conformational properties of folded secondary structures stabilized by intramolecular H bonds directly involving the sulfonamide junction. In the crystal the pseudopeptide 1 adopts a type I β-turn with the Pro and Phe residues located at the (i + 1) and (i + 2) corner positions, respectively. The turn is stabilized by a 4 1 H bond engaging one of the SO2 oxygen atoms and the isopropylamide NH. In CDCl3 solution the β-turn folding is accompanied by a γ-turn centered at the Pro and involving a 3 1 H bond between the SO2 and the Phe NH. A comparison of the structural and conformational properties found in 1 with those of the already known sulfonamido-pseudopeptides, with particular reference to the models containing the Tau-Pro junction, is also reported.

Topographically constrained aromatic α-aza-amino acids. Synthesis, molecular structure, and conformation of two azaTic derivatives

Abstract 3,4-Dihydro-2(1 H )-phthalazinecarboxylic acid (azaTic) is a new conformationally restricted analogue of phenylalanine which, due to its α-aza-nature, should allow, in addition to the topographical control typical of the Tic residue, a definite local perturbation of the backbone conformation. Two azaTic models, namely azaTic-NH 2 ( 2 ) and MeCO-azaTic-NHMe ( 5 ), have been synthesized and their conformation has been determined and compared to that of the related Tic and azaPro models.

Studies related to cephalosporins. 61. Bromination of 3-exomethylene in cepham derivatives

Abstract The methyl 3-methylene-7-phthalimidocepham-4-carnoxylate 3, the corresponding (R)-oxide 2 and the 1,1-dioxide 1 add bromine affording stereoisomeric mixtures of dibromoderivatives. These results are at variance with previous reports regarding 3-exomethylene sulfides and sulfoxides. The stereochemistry of the dibromoderivatives was unambiguously determined via X ray crystallography of 5a, following 1H-NMR correlations. The single dibromo derivatives as well as the isomeric mixtures, can be dehydrobrominated to afford 3-bromomethyl cephem derivatives (7,8,9) in very good yields.