An increasing awareness of the crucial roles that carbohydrates play in biological processes, including the progression of human disease, has focused attention and effort on the rapidly advancing field of glycoscience. Within this realm, 2-amino sugars occupy important positions, constituting, for example, key elements of cell- surface glycoproteins, including in oligosaccharide structures characteristic of certain cancer types, so that carbohydrate-based vaccines containing 2-amino sugar units could stimulate tumor-specific immune response. Other medicinal uses of 2-amino sugars and their analogues include antibiotics and anti-influenza drugs. New chemical methods for preparing 2-amino sugars will increase opportunities to study and apply these structures in biology and medicine. Synthetic challenges include introduction of the nitrogen-containing functional group and control of stereochemistry in linking 2-amino sugar units to nucleophilic glycosyl acceptors. Access to a diverse range of sugar stereoisomers is also desirable to enable a more complete mapping of structure-activity relationships. The goal of the proposed research is to provide efficient and versatile chemical synthesis tools to meet the challenges inherent in construction of 2-amino sugars. The approach will be modular, involving synthesis of 2-amino sugar glycosyl donors that will be linked stereoselectively to acceptor nucleophiles. Construction of these units will apply metallanitrene-mediated amidoglycosylation of glycal 3-carbamates, focusing on copper catalysis as an alternative to the rhodium- mediated reactions that have dominated recently. We will produce n-pentenyl glycoside and glycosyl phosphate building blocks, starting from each of the four D-glycal diastereomers and use these building blocks for O- and C-glycosylation reactions. The 2N,3O-oxazolidinone group of the donors, established in the nitrene- driven amidoglycosylation, will enable either 1,2-trans or 1,2-cis glycosylation. The resulting stereodiverse 2-amino sugar building blocks will be incorporated into a range of structures directly applicable to glycobiology studies. For example, O-linked serine and threonine aminoglycosides will be prepared, as will free reducing sugar derivatives and nitrophenyl glycosides for chemical and chemoenzymatic glycodiversification studies. Overall, the proposed work will enhance the chemical synthesis tools available for the advancement of glycoscience. The project will provide outstanding training opportunities for students at Barnard College, a liberal arts undergraduate institution for women. In this environment, participation in chemistry research provides students with experience and motivation for further study and careers in science-related areas, including graduate study in chemistry, high school science teaching, work in the pharmaceutical industry, and entry to health professions;Barnard has been a key source of women chemists in academia, industry, and government. Particular effort will be made to involve students from underrepresented groups in the proposed research.

Public Health Relevance

2-Amino sugars constitute a class of molecules having biological and medicinal roles as antibiotics, enzyme inhibitors, and components of anticancer vaccine candidates. This project will develop new modular methods for the chemical synthesis of 2-amino sugars, offering valuable tools for the investigation of these compounds in health-related applications.

Agency
National Institute of Health (NIH)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15GM107832-01A1
Application #
8771675
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Barnard College
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10027