o-Xylylene protecting group in carbohydrate chemistry: application to the regioselective protection of a single vic-diol segment in cyclodextrins.

A systematic study of the suitability of α,α'-dibromo-o-xylene as a reagent for cyclic o-xylylene protection of vic-diols in different monosaccharide substrates is reported. The installation of this protecting group, formally equivalent to a di-O-benzylation reaction, proceeds with good regioselectivity toward 1,2-trans-diequatorial diol systems in pyranose and furanose rings. Initially, the benzyl ether-type derivative of the more acidic hydroxyl is preferentially formed. Subsequent intramolecular etherification toward the equatorial-oriented vicinal OH is kinetically favored. The methodology has been implemented for the simultaneous protection of the secondary O-2 and O-3 positions of a single d-glucopyranosyl unit in cyclic oligosaccharides of the cyclodextrin (CD) family (cyclomaltohexa-, -hepta-, and -octaose; α, ß, and γCD).

Polycationic amphiphilic cyclodextrins for gene delivery: synthesis and effect of structural modifications on plasmid DNA complex stability, cytotoxicity, and gene expression.

A molecular-diversity-oriented approach for the preparation of well-defined polycationic amphiphilic cyclodextrins (paCDs) as gene-delivery systems is reported. The synthetic strategy takes advantage of the differential reactivity of primary versus secondary hydroxyl groups on the CD torus to regioselectively decorate each rim with cationic elements and lipophilic tails, respectively. Both the charge density and the hydrophobic-hydrophilic balance can be finely tuned in a highly symmetrical architecture that is reminiscent of both cationic lipids and cationic polymers, the two most prominent types of nonviral gene vectors. The monodisperse nature of paCDs and the modularity of the synthetic scheme are particularly well suited for structure-activity relationship studies. Gel electrophoresis revealed that paCDs self-assemble in the presence of plasmid DNA (pDNA) to provide homogeneous, stable nanoparticles (CDplexes) of 70-150 nm that fully protect pDNA from the environment. The transfection efficiency of the resulting CDplexes has been investigated in vitro on BNL-CL2 and COS-7 cell lines in the absence and presence of serum and found to be intimately dependent on architectural features. Facial amphiphilicity and the presence of a cluster of cationic and hydrogen-bonding centers for cooperative and reversible complexation of the polyanionic DNA chain is crucial to attain high transgene expression levels with very low toxicity profiles. Further enhancement of gene expression, eventually overcoming that of polyplexes from commercial polyethyleneimine (PEI) polymers (22 kDa), is achieved by building up space-oriented dendritic polycationic constructs.

Study of the conformational and self-aggregation properties of 2I,3I-O-(o-xylylene)-per-O-Me-alpha- and -beta-cyclodextrins by fluorescence and molecular modeling.

Steady-state and time-resolved fluorescence techniques were used to study the behavior of 2I,3I-O-(o-xylylene)-per-O-Me-alpha- and -beta-cyclodextrins in aqueous solution, based on the fluorescence of the bidentate xylylene moiety. Fluorescence decay profiles obtained upon excitation of the xylylene group were fitted to three-exponential decay functions. In addition to a fast component due to stray and/or scattered light, two other components ascribed to the monomer and dimer species, respectively, were identified. The dimer/monomer ratio increases with concentration and decreases with temperature, which is in agreement with an enthalpy-driven association process. The corresponding dimerization equilibrium constants (KD) were obtained from nonlinear regression analysis of the plots of tau against [CD] in the 5-45 degrees C range. A linear van't Hoff analysis for KD allows us to obtain the DeltaH and DeltaS associated to dimer formation. Molecular mechanics as well as molecular dynamics calculations in the presence of water were also employed to study the conformational behavior of such secondary-face-substituted cyclodextrins and rationalize the dimerization processes.

Rational design of cationic cyclooligosaccharides as efficient gene delivery systems.

Self-assembled cyclodextrin (CD)-DNA nanoparticles (CDplexes) exhibiting transfection efficiencies significantly higher than PEI-based polyplexes have been prepared from homogeneous seven-fold symmetric polyaminothiourea amphiphiles constructed on a beta-cyclodextrin scaffold.

One-pot regioselective synthesis of 2(I),3(I)-O-(o-xylylene)-capped cyclomaltooligosaccharides: tailoring the topology and supramolecular properties of cyclodextrins.

The alpha,alpha'-dibromo-o-xylylene cap has been installed at the secondary hydroxyls of a single glucopyranosyl residue in cyclodextrins in one pot and with total regioselectivity; the resulting cyclic ether acts as a removable hinge, allowing selective elaboration of the secondary face and modulating both the self-association and the inclusion capabilities of the hosts.

The o-xylylene protecting group as an element of conformational control of remote stereochemistry in the synthesis of spiroketals.

Protection of trans-1,2-diol segments as cyclic o-xylylene ethers strongly favours diequatorial over diaxial dispositions; the possibility of using this grouping for remote control of the stereochemistry in the synthesis of spiroketals is here demonstrated by the stereoselective synthesis of tricyclic spirodisaccharides (di-D-fructose dianhydrides).

Spacer-mediated synthesis of contra-thermodynamic spiroacetals: stereoselective synthesis of C2-symmetric difructose dianhydrides.

The xylylene moiety (ortho, meta, and para) was employed as a rigid tether in the spacer-mediated synthesis of difructose dianhydrides (DFAs), a unique class of bis-spiroacetal derivatives present in food products. The synthetic methodology exploits the suitability of triflic acid to promote spirocyclization in organic solvents under irreversible reaction conditions, using anomeric isopropylidene fructose derivatives as precursors. Advantage was taken of the strong dependence of the conformational properties of DFAs on the relative configuration of the spiroketal centers. Highly stereoselective syntheses of the contra-thermodynamic difructofuranose and difructopyranose diastereomers, namely the C2-symmetric derivatives having the beta-configuration at both anomeric centers, have been accomplished by judicious choice of the xylylene positional isomer and of the linking position to the fructose building blocks. Interestingly, the rigid spacer concept has also been implemented to favor intermolecular processes leading to higher macrocyclic architectures that incorporate the bis-spiro fructodisaccharide subunit.

Rigid spacer-mediated synthesis of bis-spiroketal ring systems: stereoselective synthesis of nonsymmetrical spiro disaccharides.

The application of the "rigid spacer-mediated linkage between nonreacting centers" concept to the preparation of nonsymmetrical bis-spiroketal structures is demonstrated by the stereoselective synthesis of the bis-spiro fructodisaccharide 1, a minor component of industrial caramels. An o-xylylene bridge has been used to limit the conformational space during the intramolecular glycosylation-spirocyclization reaction of a difructopyranose precursor, thus controlling both the ring size and the stereochemistry at the spiro centers. [Structure: see text]