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 ⁴C₁ 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 ⁴C₁ 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 ⁴C₁ 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^2,2-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