Stereodivergent Access to Polyhydroxylated 10-Azabicyclo[4.3.1]decanes as New Calystegine Analogues
ABSTRACT A rapid and stereodivergent access to polyhydroxylated 10-azabicyclo[4.3.1]decanes as new calystegine analogues by way of a double benzotriazolyl/carbon nucleophile exchange followed by a ring-closing metathesis was achieved. Preliminary evaluation of the new compounds as glucocerebrosidase inhibitors was also performed.
SourceAvailable from: Teresa Mena-Barragán[Show abstract] [Hide abstract]
ABSTRACT: In view of recent reports of a strong multivalent effect in glycosidase inhibition, a library of β-CD-based multivalent iminosugars has been efficiently synthesized by way of Cu(I) -catalyzed azide-alkyne cycloaddition (CuAAC). In combination with the first application of isothermal titration calorimetry (ITC) experiments to the study of multivalent iminosugar-enzyme interactions, the inhibition properties of these click clusters were evaluated on a panel of glycosidases. The structural parameters that were varied include valency, peripheral ligand structure, and topology. The inhibition results obtained with the iminosugar clusters further highlight the importance of multivalency in the inhibition of α-mannosidase. Generally, the evaluated multivalent iminosugars displayed comparable thermodynamic signatures of binding towards α-mannosidase (Jack bean): that is, large negative enthalpies of complexation coupled with small entropies of either sign. In addition, the enthalpy-entropy compensation observed in all tested cases may be attributed to a common mechanism of dissociation for the enzyme-multivalent iminosugar interactions. The measured binding stoichiometries indicated that each iminosugar cluster interacts with no more than one protein molecule.ChemBioChem 10/2013; 14(15). DOI:10.1002/cbic.201300283 · 3.06 Impact Factor
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ABSTRACT: As part of our research program dedicated to the design and synthesis of new iminosugars as pharmacological chaperones for the treatment of lysosomal storage disorders, we developed a rapid and efficient methodology for the access to functionalized and non-functionalized 1-C-alkylated derivatives in the d-xylo and l-arabino series. These compounds, as gluco and galacto mimics, were designed to be potent inhibitors of, respectively, β-glucocerebrosidase, involved in Gaucher disease, and β-galactocerebrosidase, responsible for Krabbe disease. The key step of the synthesis is the diastereoselective addition of allyltrimethylsilane to the d-xylo or l-arabino N-benzyloxycarbonyl protected glycopyranosylamine. This protective group allows the direct functionalization of the obtained iminosugars using metathesis or oxidation reactions. For determination of the absolute configuration of dihydroxylation reaction products the in situ dimolybdenum methodology of electronic circular dichroism spectroscopy was successfully used.Tetrahedron 04/2013; 69(15):3348–3354. DOI:10.1016/j.tet.2012.12.082 · 2.82 Impact Factor
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ABSTRACT: A new tandem intramolecular azetidine ring-opening/closing cascade reaction affording spirocyclopropyl γ-lactams in high regio- and stereoselectivity is reported. The key step of the process is an SN2-type ring-opening of TMSOTf-activated azetidine rings by silyl ketene acetals generated by treatment with TMSOTf and triethylamine. This study is a very rare example of nucleophilic ring opening of azetidines that does not require formation of quaternary azetidinium salts by N-alkylation or the use of N-electron-withdrawing groups.European Journal of Organic Chemistry 11/2011; 2011(33). DOI:10.1002/ejoc.201101278 · 3.15 Impact Factor