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Francesco Nicotra

Publications and source records attributed to Francesco Nicotra.

11 recordsLinked to original sources
PubMed2006

Bicyclic carbohydrate-derived scaffolds for combinatorial libraries.

A bicyclic scaffold derived from the natural monosaccharide d-glucose, and possessing several diversity sites, was linked to various resins through the primary (C-6) hydroxyl and decorated on the solid phase: the hydroxyl group at C-4 was functionalized as ester, ether, and carbamate, the amino group in the second cycle (C-3' position) was functionalized as amide, sulfonamide, and ureido- and thioureido-derivatives. The compounds synthesized on the solid phase were tested for their antiproliferative activity on tumor cell lines.

Antineoplastic Agents↗
PubMed2005

Synthesis and biological evaluation of novel lipid A antagonists.

A mimetic of Lipid A with a beta-N(OMe) glycosidic linkage, four linear C-14 hydrophobic chains and without phosphate groups has been prepared together with its beta-O-linked analogue. Both these molecules were active in inhibiting the inflammatory action of Escherichia coli lipid A on MT2 macrophages in a dose-dependent manner, while they were completely devoid of inflammatory activity.

Carbohydrate Sequence↗
PubMed2005

Role of the N terminus in enzyme activity, stability and specificity in thermophilic esterases belonging to the HSL family.

A superposition between the structures of Alicyclobacillus acidocaldarius esterase 2 (EST2) and Burkholderia cepacia lipase, the latter complexed with a phosphonate inhibitor, allowed us to hypothesize for the EST2 N terminus a role in restricting the access to the active site and therefore in modulating substrate specificity. In order to test this hypothesis we generated by site-directed mutagenesis some truncated versions of EST2 and its double mutant M211S/R215L (S/L) at the N terminus. In parallel, an analysis of the Sulfolobus solfataricus P2 genome allowed us to identify a gene coding for a putative esterase of the HSL family having a natural deletion of the corresponding region. The product of this gene and the above-mentioned EST2 mutants were expressed in Escherichia coli, purified and characterised. These studies support the notion that the N terminus affects substrate specificity other than several other enzyme parameters. Although the deletions afforded a tenfold and 550-fold decrease in catalytic efficiency towards the best substrate pNP-hexanoate at 50 degrees C for EST2 and S/L, respectively, the analysis of the specific activities with different triacylglycerols with respect to pNP-hexanoate showed that their ratios were higher for deleted versus non-deleted enzymes, on all tested substrates. In particular, the above ratios for glyceryl tridecanoate were 30-fold and 14-fold higher in S/L and EST2 deleted forms, respectively, compared with their full-length versions. This behaviour was confirmed by the analysis of the S.solfataricus esterase, which showed similar specific activities on pNP-hexanoate and triacylglycerols; in addition, higher activities on the latter substrates were observed in comparison with EST2, S/L and their deleted forms. Finally, a dramatic effect on thermophilicity and thermostability in the EST2 deleted forms was observed. This is the first report highlighting the importance of the "cap" domain in the HSL family, since the N terminus partly contributes to the building up of this structure.

Amino Acid Sequence↗
PubMed2005

Design, synthesis and biological evaluation of sugar-derived Ras inhibitors.

The design and synthesis of novel Ras inhibitors with a bicyclic scaffold derived from the natural sugar D-arabinose are presented. Molecular modelling showed that these ligands can bind Ras by accommodating the aromatic moieties and the phenylhydroxylamino group in a cavity near the Switch II region of the protein. All the synthetic compounds were active in inhibiting nucleotide exchange on p21 human Ras in vitro, and two of them selectively inhibited Ras-dependent cell growth in vivo.

Animals↗
PubMed2004

Synthesis and conformational analysis of novel N(OCH3)-linked disaccharide analogues.

N(OMe)-linked disaccharide analogues, isosteric to the corresponding natural disaccharides, have been synthesized by chemoselective assembly of unprotected natural monosaccharides with methyl 6-deoxy-6-methoxyamino-alpha-D-glucopyranoside in an aqueous environment. The coupling reactions were found to be chemo- and stereoselective affording beta-(1-->6) disaccharide mimics when using Glc and GlcNAc; in the case of Gal, the beta-anomer was prevalent (beta:alpha=7:1). An iterative method for the synthesis of linear N(OMe) oligosaccharide analogues was demonstrated, based on the use of an unprotected monosaccharide building block in which an oxime functionality at C-6 is converted during the synthesis into the corresponding methoxyamino group. The conformational analysis of these compounds was carried out by using NMR spectroscopy, ab initio, molecular mechanics, and molecular dynamics methods. Optimized geometries and energies of fourteen conformers for each compound have been calculated at the B3LYP/6-31G* level. Predicted conformational equilibria were compared with the results based on NMR experiments and good agreement was found. It appears that N(OMe)-linked disaccharide analogues exhibit a slightly different conformational behavior to their parent natural disaccharides.

Carbohydrate Conformation↗
PubMed2004

Design and characterization of a new class of inhibitors of ras activation.

The Ras proteins, which regulate intracellular signaling by a cyclic process involving interconversion between active GTP-bound and inactive GDP-bound states, play an essential role in controlling the activity of several crucial signaling pathways regulating normal cellular proliferation. Mutational activation of RAS genes can induce cancer in humans and other mammals. About 30% of human tumors contain an altered oncogenic Ras; therefore, inhibitors of Ras activation are potentially antineoplastic drugs. In this work we describe original molecules acting as Ras inhibitors. Recently a new class of inhibitors of the Ras nucleotide exchange process was described by Taveras et al. These molecules are able to form a noncovalent complex with Ras-GDP, inhibiting the GDP-GTP nucleotide exchange. We synthesized molecule SCH-53870 and we found that it inhibits p21-hRas nucleotide exchange in vitro, but it has very low solubility in water and undergoes rapid degradation at room temperature when dissolved in water-DMSO mixtures. This chemical instability could prejudice pharmacological activity in vivo. With the aim to improve solubility and chemical stability, we designed and synthesized other original bioactive molecules that have been characterized in vitro using purified human and yeast Ras proteins and in vivo using suitable Saccharomyces cerevisiae strains. In the long term we hope that the knowledge we derive from these compounds will help in the development of an alternative therapy targeting Ras for a specific inhibition of transformed cell proliferation.

Drug Design↗
PubMed2003

Chemoselective ligation in glycochemistry.

This feature article describes chemoselective techniques for the assembly of neoglycopeptides and oligosaccharide mimics. Chemoselective ligation, allowing the use of aqueous environments and non-protected substrates, provides rapid access to complex glycoconjugates. The role of these molecules in recognition, signal transduction pathways and other events of fundamental biomedical significance is an object of study in the emerging field of chemical glycomics.

Carbohydrate Sequence↗
PubMed2003

General methods for iminosugar synthesis.

Recent iminosugar syntheses starting both from commercially available sugars and non-glycidic precursors, are reported in this article. Exploiting carbohydrate starting materials, different synthetic approaches are described, mainly based on the introduction of an amino function in the sugar skeleton and the subsequent aminocyclization in order to generate the piperidine or pyrrolidine ring. The aminocyclization has been performed in different ways: reductive amination of azidoketones, intramolecular amino group attack on leaving groups and activated double bonds. In some cases one-pot amination and cyclization have been performed using ammonia or a primary amine and a di-functionalised sugar. Bicyclic compounds have also been obtained through these procedures. Starting from non-carbohydrate precursors, the nitrogen containing cycle, already present or easily obtained by Diels-Alder reactions, has been variously functionalised and stereo-differentiated by asymmetric induction or by resolution of the racemate. The syntheses of a variety of innovative structures, such as 1-N-iminosugars, iminosugars with two nitrogen atoms in the ring, iminosugars incorporating a guanidine function, imidazole-, triazole- and tetrazole-fused iminosugars, sugar-like aza-, oxa-, and thio-indolizidines, are reported. Finally the synthesis of glycoconjugate-related iminosugars, where the "pseudoanomeric" centre is linked to amino acid or peptide residues, and iminosugar phosphonates and nucleosides have been reviewed.

Bridged Bicyclo Compounds↗
PubMed2002

Synthesis and conformational analysis of fructose-derived scaffolds: molecular diversity from a single molecule.

Bi- and tricyclic compounds were synthesized starting from fructose. The different hydroxyl groups present in fructose were exploited in the formation of a number of conformationally constrained sugar-based scaffolds, including azido acids. Introduction of an azido group and carboxy terminus into different bicyclic iodo ethers, allowed the synthesis of different conformationally constrained azido acids. Conformational analysis of compounds 10, 11, 17, and 20 by NMR experiments assisted by molecular mechanics, allowed the determination of the distances between the relevant functional groups, that is the azido and carboxy functionalities.

Fructose↗
PubMed2002

Novel Tn antigen-containing neoglycopeptides: synthesis and evaluation as anti tumor vaccines.

The fully unprotected alpha-C-glycosyl analogue of N-acetylgalactosamine 9 was conjugated by a non-natural oxime bond to the segment peptides (328--340)OVA and (327--339)OVA, affording neoglycopeptides 1--2 and 3, having one or two sugar units, respectively. The three neoglycopeptides were tested in vitro in an antigen presentation assay as antitumor vaccines. Neoglycopeptides 1--3 could be presented to and recognized by the T cell receptor; neoglycopeptide 3, bearing two B-epitopes, was presented to the TCR with higher efficiency, compared to neoglycopeptide 2, having only one B-epitope.

Animals↗