M. Paglialunga Paradisi

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.

Hybrid α/β-peptides: For-Met-Leu-Phe-OMe analogues containing geminally disubstituted β2,2- and β3,3-amino acids at the central position

Summary.The two fMLF-OMe analogues For-Met-β3hAc6c-Phe-OMe (6) and For-Met-β2hAc6c-Phe-OMe (12) and their corresponding N-Boc derivatives 5 and 11 have been synthesized and their biological activity towards human neutrophils evaluated. The N-formyl peptides 6 and 12 exhibit good activity as chemoattractans and 12 is highly active in superoxide anion production. The preferred solution conformation of the two N-formyl derivatives has been discussed.

Peptides containing the sulfonamide junction. 2. Structure and conformation of Z–Tau–Pro–D-Phe–NHiPr†

The taurine (Tau) containing N-protected pseudotripeptide isopropylamide Z-Tau-Pro-D-Phe-NHiPr (1) has been specifically designed and synthesized as suitable model to test the ability of the sulfonamido group to participate as H-bond acceptor to a type II beta-turn and to get information on the preferred rotameric conformation around the S-N bond and the hybridization state of the nitrogen atom. The present structural investigation reveals that, although the sulfonamide junction is invariably folded in a gauche mode, the beta-turn structure, stabilized by the 4 --> 1 hydrogen bond, is not found in the crystal and the sulfonamido oxygen atoms are not involved in any intra- or intermolecular hydrogen-bond interaction. More than one conformer populates the CDCl(3) solution with only a minor contribution by the expected beta-turn. The Pro nitrogen is significantly pyramidalized and the nitrogen lone pair points in opposite direction to that of the Pro C(alpha)H bond thus adopting R chirality, in an arrangement practically identical to that found in the previously studied homochiral analogue Z-Tau-Pro-Phe-NHiPr.

Selective reduction of 3-keto group in steroidal ketoaldehydes

Abstract Convenient preparation of some steroidal 3-hydroxyaldehydes from corresponding 3-ketoaldehydes was achieved by protection of the aldehyde group with t-butylamine followed by in situ reduction of the keto group with Li (t-BuO)3AlH. Final cleavage of hydroxyaldimine was accomplished by eluting the reduction mixture on basic alumina.

Reduction of steroidal dicarbonyl compounds with poly(n-isopropyliminoalane)

Abstract Reduction of 6,17- and 6,20-dioxo-3α,5-cyclo-5α-steroids with poly(N-isopropyliminoalane) (HAlN-i-Pr) 6 yields 6α-hydroxyketones as the major products. The unexpected reduction outcome observed in the case of some steroidal ketoaldehydes is discussed. Treatment of methyl lithocholate 16 and methyl 3β-hydroxy-5α-etianate 18 with the same hydride is also reported.

Synthesis, conformation and biological activity of centrally modified pseudopeptidic analogues of For-Met-Leu-Phe-OMe

Summary.For-Met-βAlaψ[CSNH]-Phe-OMe (3), For-Met-βAlaψ[CH2NH]-Phe-OMe (5), For-Met-NH-pC6H4-SO2-Phe-OMe (8a), For-Met-NH-mC6H4-SO2-Phe-OMe (8b) and the corresponding N-Boc precursors (2, 4, 7a, b) have been synthesized and their activity towards human neutrophils has been evaluated in comparison with that shown by the reference tripeptide For-Met-Leu-Phe-OMe (fMLF-OMe). Chemotaxis, lysozyme release and superoxide anion production have been measured. 1H NMR titration experiments and IR spectra have been discussed in order to ascertain the preferred solution conformation adopted by the tripeptide 3 with particular reference to the presence of a folded conformation centred at the centrally positioned thionated β-residue.

In situ selective protection of aldehydes via aldimines : Simple conversions of ketoaldehydes to methylene aldehydes and to methylhydroxy aldehydes

Abstract Selective methylenation with Ph3PCH2 and methylation with MeMgI or MeLi of keto group of ketoaldehydes was accomplished by protection of aldehyde with t-butylamine. The intermediate aldimines were cleaved during chromatographic purifications on silica to afford the corresponding methylene aldehydes and methylhydroxy aldehydes as the only isolable reaction products.