Project Overview

Synthesis of Metabolically Stable Tn Antigen Mimics with Conformational Integrity

Faculty Sponsor

Ernie Nolen (enolen@colgate.edu)

Department(s)

Chemistry

Abstract

DESIGN AND SYNTHESIS OF CONFORMATIONALLY REALISTIC, METABOLICALLY STABLE Tn ANTIGEN ANALOG FOR IMMUNOLOGICAL STUDIES
Tn antigen, α-GalNAc-O-Ser/Thr, is the core component of the mucin family of cell surface glycoproteins.  The GalNAc unit, while normally buried within a glycan array, is exposed during cancer and has been detected in many solid tumors. The expression of Tn antigen alters properties such as adhesion, migration, and metastasis, and so has potential as a biomarker for diagnostic and prognostic purposes, as an antigen for cancer vaccine development, and for use in the development of anti-Tn mAbs to target drug delivery. There are caveats to the use of Tn antigen directly as it is a self-antigen. 
  Modulation of Tn antigen presentation for binding studies, increased bioavailability, and the opportunity to overcome immunotolerance has led to the design and synthesis of various structural analogs, most of which do little mimic the peptide-glycoside interactions.  With NMR studies of glycopeptides containing O-linked Tn demonstrating the importance of water and the establishment of a hydrogen bond network, we became interested in a new potential mimic (Figure 1—see link below) that positions hydroxyl off a linking C-chain with the understanding that the hydroxyl will favor conformations similar to those observed with the water-mediated hydrogen bonding.
  To date we have demonstrated the potential to install the asymmetric center a C1’ via a Z-alkene, and now we need to apply this end-game strategy on a glycosyl amino acid,  Toward that end, the Z-alkene 7 has been prepared (Scheme 1—see link below), but improvements are needed. Conversion to 9 following the protocol developed in our laboratory compound will be carried out. Finally, protection of the hydroxyl as the acetate, allows for a Jones oxidation to deprotect the N,O-acetal and subsequently give the carboxylic acid 10 in one final step.
    
  Derivative 10 will provide material for collaborative studies on the conformational analysis by NMR and for incorporation into a key O-mucin peptide sequence for immunological investigation.
https://documentcloud.adobe.com/link/review?uri=urn:aaid:scds:US:f84f8367-28c2-49da-87fb-9be4027dc8e2

Student Qualifications

Completion of CHEM 264

Number of Student Researchers

2 students

Project Length

10 weeks


Applications open on 01/03/2022 and close on 02/04/2022


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If you have questions, please contact Karyn Belanger (kgbelanger@colgate.edu).