Synthesis of Multibranched Australine Derivatives from Reducing Castanospermine Analogues through the Amadori Rearrangement of <i>gem</i>-Diamine Intermediates: Selective Inhibitors of β‑Glucosidase

A practical one-pot synthesis of bi- and triantennated australine analogues from a pivotal sp²-iminosugar-type reducing castanospermine precursor is reported. The transformation involves a <i>gem</i>-diamine intermediate that undergoes the indolizidine → pyrrolizidine Amadori-type rearrangement and proceeds under strict control of the generalized anomeric effect to afford a single diastereomer. The final compounds behave as selective competitive inhibitors of β-glucosidase and are promising candidates as pharmacological chaperones for Gaucher disease

Influence of the Macroring Size on the Self-Association Thermodynamics of Cyclodextrins with a Double-Linked Naphthalene at the Secondary Face

The conformational properties and aggregation behavior of two selectively modified cyclomaltooligosaccharides (cyclodextrins, CDs) containing a double-linked 1,8-dimethylnaphthalene cap-like moiety at the secondary face, namely, 2^I,3^I-<i>O</i>-(1,8-dimetylnaphthalene-α,α′-diyl)-per-<i>O</i>-Me-α- and -γ-cyclodextrins (N<i>m</i>αCD and N<i>m</i>γCD, respectively), in water and in organic solvents were investigated. Both CD derivatives self-associated in water to form dimer species, but the characteristics of the dimerization process and of the resulting dimer strongly depended on the size of the macrocycle. Dimerization constants, thermodynamic parameters upon association, and information about the preferred conformations of the monomer and dimer CD structures were obtained by using NMR, UV–vis, steady-state and time-resolved fluorescence, and circular dichroism experimental techniques, as well as molecular mechanics (MM) and molecular dynamics (MD) simulations. The complexation of 1,8-di­(methoxymethyl)­naphathalene (oNy) and the heteroassociation of both N<i>m</i>CDs with their permethylated CD partners (<i>m</i>CDs), lacking the aromatic cap, were examined. In addition, the influence of the size of the chromophore moiety on the thermodynamics of self-association was also assessed by comparison of the results obtained for the new naphthalene derivatives with those of the 2^I,3^I-<i>O</i>-(1,2-xylylene)-modified CD analogues (X<i>m</i>CDs)

Probing Carbohydrate-Lectin Recognition in Heterogeneous Environments with Monodisperse Cyclodextrin-Based Glycoclusters

A series of β-cyclodextrin (βCD)-scaffolded glycoclusters exposing heterogeneous yet perfectly controlled displays of α-mannosyl (α-Man) and β-lactosyl (β-Lact) antennas were synthesized to probe the mutual influence of varying densities of the saccharide motifs in the binding properties toward different plant lectins. Enzyme-linked lectin assay (ELLA) data indicated that the presence of β-Lact residues reinforced binding of α-Man to the mannose-specific lectin concanavalin A (Con A) even though homogeneous β-Lact clusters are not recognized at all by this lectin, supporting the existence of synergic recognition mechanisms (<i>heterocluster effect</i>). Conversely, the presence of α-Man motifs in the heteroglycoclusters also resulted in a binding-enhancing effect of β-Lact toward peanut agglutinin (PNA), a lectin strongly binding multivalent lactosides but having no detectable affinity for α-mannopyranosides, for certain architectural arrangements. Two-site, sandwich-type ELLA data corroborated the higher lectin clustering efficiency of heterogeneous glycoclusters compared with homogeneous displays of the putative sugar ligand with identical valency. A turbidity assay was also consistent with the previous observations. Most revealingly, the lectin cross-linking ability of heterogeneous glycoclusters was sensitive to the presence of high concentrations of the non-ligand sugar, strongly suggesting that “mismatching” saccharide motifs may modulate carbohydrate-lectin specific recognition in a lectin-dependent manner when present in highly dense displays together with the “matching” ligand, a situation frequently encountered in biological systems

Correction to “Generalized Anomeric Effect in <i>gem</i>-Diamines: Stereoselective Synthesis of α‑<i>N</i>‑Linked Disaccharide Mimics”

Correction to “Generalized Anomeric Effect in <i>gem</i>-Diamines: Stereoselective Synthesis of α‑<i>N</i>‑Linked Disaccharide Mimics

<i>o</i>‑Xylylene Protecting Group in Carbohydrate Chemistry: Application to the Regioselective Protection of a Single <i>vic</i>-Diol Segment in Cyclodextrins

A systematic study of the suitability of α,α′-dibromo-<i>o</i>-xylene as a reagent for cyclic <i>o</i>-xylylene protection of <i>vic</i>-diols in different monosaccharide substrates is reported. The installation of this protecting group, formally equivalent to a di-<i>O</i>-benzylation reaction, proceeds with good regioselectivity toward 1,2-<i>trans</i>-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, β, and γCD)

Xylylene Clips for the Topology-Guided Control of the Inclusion and Self-Assembling Properties of Cyclodextrins

The topology of β-cyclodextrin can be molded, from toroidal to ovoid basket-shaped, by the installation of an <i>o</i>- or <i>m</i>-xylylene moiety connecting two consecutive d-glucopyranosyl units through the secondary O-2­(I) and O-3­(II) positions. This strategy can be exploited advantageously to precast the cavity for preferential inclusion of globular or planar guests as well as to privilege dimeric or monomeric species in water solution

Fluorinated Chaperone−β-Cyclodextrin Formulations for β‑Glucocerebrosidase Activity Enhancement in Neuronopathic Gaucher Disease

Amphiphilic glycomimetics encompassing a rigid, undistortable nortropane skeleton based on 1,6-anhydro-l-idonojirimycin and a polyfluorinated antenna, when formulated as the corresponding inclusion complexes with β-cyclodextrin (βCD), have been shown to behave as pharmacological chaperones (PCs) that efficiently rescue lysosomal β-glucocerebrosidase mutants associated with the neuronopathic variants of Gaucher disease (GD), including the highly refractory L444P/L444P and L444P/P415R single nucleotide polymorphs, in patient fibroblasts. The body of work here presented includes the design criteria for the PC prototype, the synthesis of a series of candidates, the characterization of the PC:βCD complexes, the determination of the selectivity profiles toward a panel of commercial and human lysosomal glycosidases, the evaluation of the chaperoning activity in type 1 (non-neuronopathic), type 2 (acute neuronopathic), and type 3 (adult neuronopathic) GD fibroblasts, the confirmation of the rescuing mechanism by immunolabeling, and the analysis of the PC:GCase binding mode by docking experiments

Wajib Belajar Sembilan Tahun Bagi Masyarakat Tidak Mampu

Pada tahuo 1994 nanti, pemerintah akan memberlakukanprogram wajib be~ajar 9 tahuo.. · yaitu pendidikan dasarminimal yang harus dialami oleh setiap warga negara. Programpemerataan kesempatan belajar ini dimaksudkan agarsetiap warga\u27 negara Indonesia menjadi anggota masyarakatyang tahu akan kewajiban dan haknya, memiliki keterampilanuntuk mengatasi kesulitan dan meningka\u27tkan kualitas hidupoya.Program ini sangat esensial terutama bagi masyarakattidak mampu yang sebagian besar tinggal di pedesaan karenaanak-anak usia sekolah yang tidak memperoleh kesempatanmenikmati perididikan formal SD dan SLTP sebagian besarberasal dari masyarakat ini. Mengingat kondisi sosial e"konomimasyarakat pedesaan yang kurang begitu menguntungkan,yaitu seperti kemi$kinan, rendahnya kesadaran tentang pendidikan,kondisi l.ingkungan dan lain-Iainnya, maka pelaksanaanwajib belajar 9 tahv.n hen,daknya direncanakan dengan mempertimbangkankon~si-kondisi tersebut sehingga programwajib belajar dapat terlaks~~:a dengan baik dan memberimanfaat yang sebesar-besarnya bagi peninglli;,tan kesejahteraanmasyarakat pedesaan. Di samping itu. sistem pendidikan(wajar 9 tahun) yang hendak diterapkan hendaknya sejalandBn berorientasi pada ltebutuhan masyarakat karena pendidikanbagi ma:$yarakat desa harus menyajikan model yang hidup.berfaedah, diperlukan dan cocok dengan situasi kebud:-.)\u27aanpedesaan setempat. baik lokal maupun regional

Stereoselective Synthesis of 2‑Acetamido-1,2-dideoxyallonojirimycin (DAJNAc), a New Potent Hexosaminidase Inhibitor

A practical synthesis of the previously unreported <i>N</i>-acetyl-d-allosamine glycomimetic DAJNAc is described. The reaction sequence involves Pd-catalyzed allylic substitution by phthalimide in an azaheterobicyclic scaffold as the key step. The new iminosugar resulted in being a stronger β-<i>N</i>-acetylglucosaminidase (human placenta) competitive inhibitor than the d-<i>gluco</i> (DNJNAc) and d-<i>galacto</i> (DGJNAc) stereoisomers

Conformationally-Locked <i>N</i>-Glycosides with Selective β-Glucosidase Inhibitory Activity: Identification of a New Non-Iminosugar-Type Pharmacological Chaperone for Gaucher Disease

A series of conformationally locked <i>N</i>-glycosides having a cis-1,2-fused pyranose–1,3-oxazoline-2-thione structure and bearing different substituents at the exocyclic sulfur has been prepared. The polyhydroxylated bicyclic system was built in only three steps by treatment of the corresponding readily available 1,2-anhydrosugar with KSCN using TiO­(TFA)₂ as catalyst, followed by S-alkylation and acetyl deprotection. In vitro screening against several glycosidase enzymes showed highly specific inhibition of mammalian β-glucosidase with a marked dependence of the potency upon the nature of the exocyclic substituent. The most potent representative, bearing an <i>S</i>-(ω-hydroxyhexadecyl) substituent, was further assayed as inhibitor of the human lysosomal β-glucocerebrosidase and as pharmacological chaperone in Gaucher disease fibroblasts. Activity enhancements in N370S/N370S mutants analogous to those achieved with the reference compound ambroxol were attained with a more favorable chaperone/inhibitor balance