Structure-Based Design of Potent Tumor-Associated Antigens: Modulation of Peptide Presentation by Single-Atom O/S or O/Se Substitutions at the Glycosidic Linkage.

GalNAc-glycopeptides derived from mucin MUC1 are an important class of tumor-associated antigens. α- O-glycosylation forces the peptide to adopt an extended conformation in solution, which is far from the structure observed in complexes with a model anti-MUC1 antibody. Herein, we propose a new strategy for designing potent antigen mimics based on modulating peptide/carbohydrate interactions by means of O → S/Se replacement at the glycosidic linkage. These minimal chemical modifications bring about two key structural changes to the glycopeptide. They increase the carbohydrate-peptide distance and change the orientation and dynamics of the glycosidic linkage. As a result, the peptide acquires a preorganized and optimal structure suited for antibody binding. Accordingly, these new glycopeptides display improved binding toward a representative anti-MUC1 antibody relative to the native antigens. To prove the potential of these glycopeptides as tumor-associated MUC1 antigen mimics, the derivative bearing the S-glycosidic linkage was conjugated to gold nanoparticles and tested as an immunogenic formulation in mice without any adjuvant, which resulted in a significant humoral immune response. Importantly, the mice antisera recognize cancer cells in biopsies of breast cancer patients with high selectivity. This finding demonstrates that the antibodies elicited against the mimetic antigen indeed recognize the naturally occurring antigen in its physiological context. Clinically, the exploitation of tumor-associated antigen mimics may contribute to the development of cancer vaccines and to the improvement of cancer diagnosis based on anti-MUC1 antibodies. The methodology presented here is of general interest for applications because it may be extended to modulate the affinity of biologically relevant glycopeptides toward their receptors

Nucleophilicity Prediction via Multivariate Linear Regression Analysis

The concept of nucleophilicity is at the basis of most transformations in chemistry. Understanding and predicting the relative reactivity of different nucleophiles is therefore of paramount importance. Mayr's nucleophilicity scale likely represents the most complete collection of reactivity data, which currently includes over 1200 nucleophiles. Several attempts have been made to theoretically predict Mayr's nucleophilicity parameters N based on calculation of molecular properties, but a general model accounting for different classes of nucleophiles could not be obtained so far. We herein show that multivariate linear regression analysis is a suitable tool for obtaining a simple model predicting N for virtually any class of nucleophiles in different solvents for a set of 341 data points. The key descriptors of the model were found to account for the proton affinity, solvation energies, and sterics

Cu(I)-Bis(phosphine) Dioxides as Catalysts for the Enantioselective \u3b1-Arylation of Carbonyl Compounds

The transition-metal-catalyzed \u3b1-arylation of carbonyl compounds was first reported by Buchwald and Hartwig in 1997. This transformation has been used and studied extensively over the last two decades. Enantioselective variants were also developed that allow for controlling the product stereochemistry. However, these suffer several limitations in the context of formation of tertiary stereocenters. Presented here is our group's contribution to this research area. The chiral Cu-bis(phosphine) dioxides catalytic system that we reported allowed accessing the enantioselective \u3b1-arylation of ketones that were not suitable for this transformation before in good yields and er up to 97.5:2.5. Preliminary insight and speculation concerning the reaction mechanism involving the unusual pairing of bis(phosphine) dioxides with transition-metal catalysts is also given. 1 Introduction 2 State of the Art 3 Enantioselective \u3b1-Arylation of Acyclic Ketones 4 Summary and Conclusions

Transition-Metal-Catalyzed Enantioselective α-Arylation of Carbonyl Compounds to Give Tertiary Stereocenters

Enantioenriched α-aryl carbonyl compounds are ubiquitous in natural products and biologically active compounds. Their synthesis has been explored over the last few decades and several methods now exist that allow for the enantioselective formation of a C(sp3)-C(sp2) bond in the α-position to a carbonyl group. However, although the formation of quaternary stereocenters has been fairly well established, the enantioselective formation of tertiary stereocenters proved more challenging due to facile product post-reaction racemization. In this short review, we summarize the methods reported to date for the asymmetric E-arylation of enolates and analogues that rely on transition-metal catalysis. 1 Introduction 2 Nucleophile Pre-activation 3 Activation via Aminocatalysis 4 Formation of Constrained Stereocenters 5 Concluding Remarks

Enantioselective \u3b1-Arylation of Ketones via a Novel Cu(I)-Bis(phosphine) Dioxide Catalytic System

A novel catalytic system based on copper(I) and chiral bis(phosphine) dioxides is described. This allows the arylation of silyl enol ethers to access enolizable \u3b1-arylated ketones in good yields and enantiomeric excess up to 95%. Noncyclic ketones are amenable substrates with this method, which complements other approaches based on palladium catalysis. Optimization of the ligand structure is accomplished via rational design driven by correlation analysis. Preliminary mechanistic hypotheses are also evaluated in order to identify the role of chiral bis(phosphine) dioxides

Structure-Based Design of Potent Tumor-Associated Antigens: Modulation of Peptide Presentation by Single-Atom O/S or O/Se Substitutions at the Glycosidic Linkage.

GalNAc-glycopeptides derived from mucin MUC1 are an important class of tumor-associated antigens. α- O-glycosylation forces the peptide to adopt an extended conformation in solution, which is far from the structure observed in complexes with a model anti-MUC1 antibody. Herein, we propose a new strategy for designing potent antigen mimics based on modulating peptide/carbohydrate interactions by means of O → S/Se replacement at the glycosidic linkage. These minimal chemical modifications bring about two key structural changes to the glycopeptide. They increase the carbohydrate-peptide distance and change the orientation and dynamics of the glycosidic linkage. As a result, the peptide acquires a preorganized and optimal structure suited for antibody binding. Accordingly, these new glycopeptides display improved binding toward a representative anti-MUC1 antibody relative to the native antigens. To prove the potential of these glycopeptides as tumor-associated MUC1 antigen mimics, the derivative bearing the S-glycosidic linkage was conjugated to gold nanoparticles and tested as an immunogenic formulation in mice without any adjuvant, which resulted in a significant humoral immune response. Importantly, the mice antisera recognize cancer cells in biopsies of breast cancer patients with high selectivity. This finding demonstrates that the antibodies elicited against the mimetic antigen indeed recognize the naturally occurring antigen in its physiological context. Clinically, the exploitation of tumor-associated antigen mimics may contribute to the development of cancer vaccines and to the improvement of cancer diagnosis based on anti-MUC1 antibodies. The methodology presented here is of general interest for applications because it may be extended to modulate the affinity of biologically relevant glycopeptides toward their receptors