11 research outputs found
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 sp<sup>2</sup>-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<sup>I</sup>,3<sup>I</sup>-<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<sup>I</sup>,3<sup>I</sup>-<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 kemiyarakat 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)<sub>2</sub> 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