20 research outputs found
A Double Diastereoselective Michael-Type Addition as an Entry to Conformationally Restricted Tn Antigen Mimics
A totally stereocontrolled <i>C</i>-Michael addition
of serine-equivalent <i>C</i>-nucleophiles to tri-<i>O</i>-benzyl-2-nitro-d-galactal was used as the key
step to synthesize several pyrano[3,2-<i>b</i>]pyrrole structures.
These scaffolds could be regarded as conformationally restricted Tn
antigen mimics, as we have demonstrated by biological assays. The
pyranose rings retain their <sup>4</sup>C<sub>1</sub> chair conformation,
as shown by molecular modeling and NMR spectroscopy. The expected
bioactivity was established by a competition-tailored enzyme-linked
lectin assay using both soybean and Vicia villosa agglutinins as model lectins. The facile described synthetic route
and the strategic combination of computational and experimental techniques
to reveal conformational features and bioactivity demonstrate the
prepared glycomimics to be promising candidates for further exploitation
of this scaffold to give glycans for lectin blocking and vaccination
A Double Diastereoselective Michael-Type Addition as an Entry to Conformationally Restricted Tn Antigen Mimics
A totally stereocontrolled <i>C</i>-Michael addition
of serine-equivalent <i>C</i>-nucleophiles to tri-<i>O</i>-benzyl-2-nitro-d-galactal was used as the key
step to synthesize several pyrano[3,2-<i>b</i>]pyrrole structures.
These scaffolds could be regarded as conformationally restricted Tn
antigen mimics, as we have demonstrated by biological assays. The
pyranose rings retain their <sup>4</sup>C<sub>1</sub> chair conformation,
as shown by molecular modeling and NMR spectroscopy. The expected
bioactivity was established by a competition-tailored enzyme-linked
lectin assay using both soybean and Vicia villosa agglutinins as model lectins. The facile described synthetic route
and the strategic combination of computational and experimental techniques
to reveal conformational features and bioactivity demonstrate the
prepared glycomimics to be promising candidates for further exploitation
of this scaffold to give glycans for lectin blocking and vaccination
A Double Diastereoselective Michael-Type Addition as an Entry to Conformationally Restricted Tn Antigen Mimics
A totally stereocontrolled <i>C</i>-Michael addition
of serine-equivalent <i>C</i>-nucleophiles to tri-<i>O</i>-benzyl-2-nitro-d-galactal was used as the key
step to synthesize several pyrano[3,2-<i>b</i>]pyrrole structures.
These scaffolds could be regarded as conformationally restricted Tn
antigen mimics, as we have demonstrated by biological assays. The
pyranose rings retain their <sup>4</sup>C<sub>1</sub> chair conformation,
as shown by molecular modeling and NMR spectroscopy. The expected
bioactivity was established by a competition-tailored enzyme-linked
lectin assay using both soybean and Vicia villosa agglutinins as model lectins. The facile described synthetic route
and the strategic combination of computational and experimental techniques
to reveal conformational features and bioactivity demonstrate the
prepared glycomimics to be promising candidates for further exploitation
of this scaffold to give glycans for lectin blocking and vaccination
<i>S</i>‑Michael Additions to Chiral Dehydroalanines as an Entry to Glycosylated Cysteines and a Sulfa-Tn Antigen Mimic
Stereoselective sulfa-Michael addition
of appropriately protected
thiocarbohydrates to chiral dehydroalanines has been developed as
a key step in the synthesis of biologically important cysteine derivatives,
such as <i>S</i>-(β-d-glucopyranosyl)-d-cysteine, which has not been synthesized to date, and <i>S</i>-(2-acetamido-2-deoxy-α-d-galactopyranosyl)-l-cysteine, which could be considered as a mimic of Tn antigen.
The corresponding diamide derivative was also synthesized and analyzed
from a conformational viewpoint, and its bound state with a lectin
was studied
<i>S</i>‑Michael Additions to Chiral Dehydroalanines as an Entry to Glycosylated Cysteines and a Sulfa-Tn Antigen Mimic
Stereoselective sulfa-Michael addition
of appropriately protected
thiocarbohydrates to chiral dehydroalanines has been developed as
a key step in the synthesis of biologically important cysteine derivatives,
such as <i>S</i>-(β-d-glucopyranosyl)-d-cysteine, which has not been synthesized to date, and <i>S</i>-(2-acetamido-2-deoxy-α-d-galactopyranosyl)-l-cysteine, which could be considered as a mimic of Tn antigen.
The corresponding diamide derivative was also synthesized and analyzed
from a conformational viewpoint, and its bound state with a lectin
was studied
<i>S</i>‑Michael Additions to Chiral Dehydroalanines as an Entry to Glycosylated Cysteines and a Sulfa-Tn Antigen Mimic
Stereoselective sulfa-Michael addition
of appropriately protected
thiocarbohydrates to chiral dehydroalanines has been developed as
a key step in the synthesis of biologically important cysteine derivatives,
such as <i>S</i>-(β-d-glucopyranosyl)-d-cysteine, which has not been synthesized to date, and <i>S</i>-(2-acetamido-2-deoxy-α-d-galactopyranosyl)-l-cysteine, which could be considered as a mimic of Tn antigen.
The corresponding diamide derivative was also synthesized and analyzed
from a conformational viewpoint, and its bound state with a lectin
was studied
Unraveling the Conformational Landscape of Ligand Binding to Glucose/Galactose-Binding Protein by Paramagnetic NMR and MD Simulations
Protein dynamics
related to function can nowadays be structurally
well characterized (i.e., instances obtained by high resolution structures),
but they are still ill-defined energetically, and the energy landscapes
are only accessible computationally. This is the case for glucose–galactose
binding protein (GGBP), where the crystal structures of the apo and
holo states provide structural information for the domain rearrangement
upon ligand binding, while the time scale and the energetic determinants
for such concerted dynamics have been so far elusive. Here, we use
GGBP as a paradigm to define a functional conformational landscape,
both structurally and energetically, by using an innovative combination
of paramagnetic NMR experiments and MD simulations. Anisotropic NMR
parameters induced by self-alignment of paramagnetic metal ions was
used to characterize the ensemble of conformations adopted by the
protein in solution while the rate of interconversion between conformations
was elucidated by long molecular dynamics simulation on two states
of GGBP, the closed-liganded (<i>holo_cl</i>) and open-unloaded
(<i>apo_op</i>) states. Our results demonstrate that, in
its apo state, the protein coexists between open-like (68%) and closed-like
(32%) conformations, with an exchange rate around 25 ns. Despite such
conformational heterogeneity, the presence of the ligand is the ultimate
driving force to unbalance the equilibrium toward the <i>holo_cl</i> form, in a mechanism largely governed by a conformational selection
mechanism
Synthesis of Mixed α/β<sup>2,2</sup>-Peptides by Site-Selective Ring-Opening of Cyclic Quaternary Sulfamidates
A method for site- and stereoselective
peptide modification using
a cyclic sulfamidate scaffold containing peptides is described. A
peptide synthesis strategy allowing the rapid generation of mixed
α/β-peptides incorporating a sulfamidate residue, derived
from 2-methylisoserine, has been generalized. The unique electrophilic
nature of this scaffold for nucleophilic substitution at a quaternary
center with total inversion of its configuration, which was demonstrated
computationally, allows for site-selective conjugation with various
nucleophiles, such as anomeric thiocarbohydrates and pyridines. This
strategy provides rapid access to complex thioglyco-α/β-conjugates
and charged α/β-peptides
A Dynamic Combinatorial Approach for the Analysis of Weak Carbohydrate/Aromatic Complexes: Dissecting Facial Selectivity in CH/π Stacking Interactions
A dynamical
combinatorial approach for the study of weak carbohydrate/aromatic
interactions is presented. This methodology has been employed to dissect
the subtle structure–stability relationships that govern facial
selectivity in these supramolecular complexes
Tn Antigen Mimics by Ring-Opening of Chiral Cyclic Sulfamidates with Carbohydrate C1‑<i>S</i>- and C1‑<i>O</i>‑Nucleophiles
Starting from commercially available
(<i>S</i>)-isoserine
and effectively accessible (<i>S</i>)-α-methylserine,
enantiopure cyclic sulfamidates have been prepared as chiral building
blocks for the synthesis of various <i>S</i>- and <i>O</i>-glycosylated amino acid derivatives, including unnatural
variants of the Tn antigen, through highly chemo-, regio-, and stereoselective
nucleophilic ring-opening reactions with carbohydrate C1-<i>S</i>- and C1-<i>O</i>-nucleophiles