Luigi Panza

Differential alteration of lipid antigen presentation to NKT cells due to imbalances in lipid metabolism.

Deficiencies in enzymes of the lysosomal glycosphingolipid degradation pathway or in lysosomal lipid transfer proteins cause an imbalance in lipid metabolism and induce accumulation of certain lipids. A possible impact of such an imbalance on the presentation of lipid antigens to lipid‐reactive T cells has only been hypothesized but not extensively studied so far. Here we demonstrate that presentation of lipid antigens to, and development of, lipid‐reactive CD1d‐restricted NKT cells, are impaired in mice deficient in the lysosomal enzyme β‐galactosidase (βGal) or the lysosomal lipid transfer protein Niemann‐Pick C (NPC) 2. Importantly, the residual populations of NKT cells selected in βGal–/– and NPC2–/– mice showed differential TCR and CD4 repertoire characteristics, suggesting that differential selecting CD1d:lipid antigen complexes are formed. Furthermore, we provide direct evidence that accumulation of lipids impairs lipid antigen presentation in both cases. However, the mechanisms by which imbalanced lipid metabolism affected lipid antigen presentation were different. Based on these results, the impact of lipid accumulation should be generally considered in the interpretation of immunological deficiencies found in mice suffering from lipid metabolic disorders.

SYNTHESIS OF AZASUGARS BY GRIGNARD REACTION ON GLYCOSYLAMINES

Abstract Pyrrolidines 5a-b, and piperidines 10a,b and 15, were synthesised by Grignard reaction on a glycosylamine, easily obtained from the parent sugar and a primary amine, followed by cyclization with triflic anhydride.

Improvement of water solubility and dissolution rate of ursodeoxycholic acid and chenodeoxycholic acid by complexation with natural and modified β-cyclodextrins

The inclusion complexes of ursodeoxycholic and chenodeoxycholic acid with β-cyclodextrin, heptakis-(2,6-di-O-methyl)-β-cyclodextrin and soluble polymerized β-cyclodextrin were investigated in solution (1H-NMR spectrometry) and solid state (FT-IR spectroscopy and differential scanning calorimetry). Stability constants were determined at pH 7.4 and different temperatures and consequently thermodynamic parameters were obtained. All cyclodextrins are able to increase water solubility of the bile acids, particularly polymerized β-cyclodextrin. All complexes show high dissolution rate at 37°C and pH 1.1 and in particular freeze-dried complexes.

Synthesis of carboranyl derivatives of alkynyl glycosides as potential BNCT agents

Abstract A series of amphiphilic carbohydrate-carborane hybrids consisting of a lipophilic core (carborane cage) and a glycoside moiety for conferring high-affinity recognition by the cellular lectins have been prepared in a chemically accessible fashion.

Carborane derivatives loaded into liposomes as efficient delivery systems for boron neutron capture therapy.

Boron neutron capture therapy (BNCT) is an anticancer therapy based on the incorporation of (10)B in tumors, followed by neutron irradiation. Recently, the synthesis and delivery of new boronated compounds have been recognized as some of the main challenges in BNCT application. Here, we report on the use of liposomes as carriers for BNCT active compounds. Two carborane derivatives, i.e., o-closocarboranyl beta-lactoside (LCOB) and 1-methyl-o-closocarboranyl-2-hexylthioporphyrazine (H(2)PzCOB), were loaded into liposomes bearing different surface charges. The efficacy of these formulations was tested on model cell cultures, that is, DHD/K12/TRb rat colon carcinoma and B16-F10 murine melanoma. These induce liver and lung metastases, respectively, and are used to study the uptake of standard BNCT drugs, including borophenylalanine (BPA). Boron concentration in treated cells was measured by alpha spectrometry at the TRIGA mark II reactor (University of Pavia). Results showed high performance of the proposed formulations. In particular, the use of cationic liposomes increased the cellular concentration of (10)B by at least 30 times more than that achieved by BPA.

Epoxidation of exoxyclic glycals: A new access to glycosides of ketosugars

Abstract A novel approach to the synthesis of glycosides and disaccharides of ketofuranoses and ketopyranoses by epoxidation of exocyclic glycals and reaction of the intermediate epoxides with different alcohols is described.

Fine tuning by human CD1e of lipid-specific immune responses

CD1e is a member of the CD1 family that participates in lipid antigen presentation without interacting with the T-cell receptor. It binds lipids in lysosomes and facilitates processing of complex glycolipids, thus promoting editing of lipid antigens. We find that CD1e may positively or negatively affect lipid presentation by CD1b, CD1c, and CD1d. This effect is caused by the capacity of CD1e to facilitate rapid formation of CD1–lipid complexes, as shown for CD1d, and also to accelerate their turnover. Similar results were obtained with antigen-presenting cells from CD1e transgenic mice in which lipid complexes are assembled more efficiently and show faster turnover than in WT antigen-presenting cells. These effects maximize and temporally narrow CD1-restricted responses, as shown by reactivity to Sphingomonas paucimobilis-derived lipid antigens. CD1e is therefore an important modulator of both group 1 and group 2 CD1-restricted responses influencing the lipid antigen availability as well as the generation and persistence of CD1–lipid complexes.

A new procedure for the synthesis of azasugars

Abstract Reaction of the commercially available 2,3,5-tri-O-benzyl-D-arabinose with a primary amine (RNH2) affords the arabinofuranosylamine 2, which on treatment with a Grignard reagent stereoselectively gives the aminoalcohol 3. 3 is an useful precursor of azasugars: it is converted into the pyrrolidine 4 by treatment with Tf2O-Py, whereas by oxidation with PCC it affords the lactam 5 which can be reduced to the corresponding amine 6.

Capsular polysaccharide of Streptococcus pneumoniae type 19F: synthesis of the repeating unit

A new and more versatile synthesis of beta-D-ManpNAc-(1-->4)-alpha-D-Glcp-(1-->2)-alpha-L-Rhap, the trisaccharide repeating unit of the Streptococcus pneumoniae type 19F capsular polysaccharide, is described. The present approach allows a simple access to different fragments containing the trisaccharide and the conjugation of the product(s) to a protein through the selective manipulation of the anomeric position at the reducing end and of the HO-4 function at the nonreducing end. The synthetic scheme shows an efficient application of the sulfoxide method for the stereoselective and high yielding formation of the glycosidic linkages.

Selective Acylation of 4,6-O-Benzylidene Glycopyranosides by Enzymatic Catalysis

Abstract Selective acylation of different hydroxyls is of great importance, and widespread applications are found in carbohydrate chemistry.1 Ass protecting groups, esters offer the advantage of being easily prepared and easily removed, and accordingly, partially acylated monosaccharides have been used for the preparation of other O-substituted derivatives as well as for the synthesis of oligosaccharides. For this latter purpose 4,6-O-benzylidene-D-glycopyranosides like la, once selectively modified at one of their two free hydroxy groups, are particularly suitable compounds.