Understanding how oligosaccharide structure controls these cellular recognition events has major implications for the treatment of many infectious diseases. Furthermore, understanding oligosaccharides structures and bio-synthesis are critical elements for discovering new chemotherapies. Due to the growing problem of bacterial resistance, there is a great need for new antibacterial/antifungal compounds. The project proposed herein is a tandem synthetic/biological investigation of the papulacandins, a class of potent mono-, di-, and trisaccharide antifungal antibiotics. Our study revolves around a unique de novo asymmetric synthetic approach to the papulacandin ring system, which should allow for easy access to these di and trisaccharides. In addition, this approach will allow simple access to unnatural analogs of this class of natural products and allow for easy screening for activity. Access to the papulacandin ring system and analogs will enable us to probe the mechanism of action to this antifungal agent and ultimately allow for the discovery of new more potent and stable antifungal agents. Additionally, these biological studies should also lead to new antibacterial, anticancer and antiviral compounds.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM063150-04
Application #
6718377
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
2002-09-01
Project End
2006-02-28
Budget Start
2004-02-29
Budget End
2005-02-28
Support Year
4
Fiscal Year
2004
Total Cost
$248,200
Indirect Cost
Name
West Virginia University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
191510239
City
Morgantown
State
WV
Country
United States
Zip Code
26506
Harsh, Philip; O'Doherty, George A (2009) De Novo Asymmetric Syntheses of (+)-Goniothalamin, (+)-Goniothalamin oxide and 7,8-Bis-epi-Goniothalamin using Asymmetric Allylations. Tetrahedron 65:5051-5055
Guo, Haibing; O'Doherty, George A (2008) De Novo Asymmetric Syntheses of d-, l- and 8-epi-Swainsonine. Tetrahedron 64:304-313
Zhou, Maoquan; O'Doherty, George (2008) The de novo synthesis of oligosaccharides: application to the medicinal chemistry SAR-study of digitoxin. Curr Top Med Chem 8:114-25
Zhou, Maoquan; O'Doherty, George A (2007) De novo approach to 2-deoxy-beta-glycosides: asymmetric syntheses of digoxose and digitoxin. J Org Chem 72:2485-93
Mortensen, Matthew S; Osbourn, Joshua M; O'Doherty, George A (2007) De novo formal synthesis of (-)-virginiamycin M2 via the asymmetric hydration of dienoates. Org Lett 9:3105-8
Guppi, Sanjeeva R; O'Doherty, George A (2007) Synthesis of aza-analogues of the glycosylated tyrosine portion of mannopeptimycin-E. J Org Chem 72:4966-9
Guo, Haibing; O'Doherty, George A (2007) De novo asymmetric synthesis of the anthrax tetrasaccharide by a palladium-catalyzed glycosylation reaction. Angew Chem Int Ed Engl 46:5206-8
Guo, Haibing; O'Doherty, George A (2006) De novo asymmetric synthesis of D- and L-swainsonine. Org Lett 8:1609-12
Ahmed, Md Moinuddin; Cui, Hu; O'Doherty, George A (2006) De novo asymmetric syntheses of muricatacin and its analogues via dihydroxylation of dienoates. J Org Chem 71:6686-9
Ahmed, Md Moinuddin; O'Doherty, George A (2006) De novo asymmetric syntheses of C-4-substituted sugars via an iterative dihydroxylation strategy. Carbohydr Res 341:1505-21

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