Highly oxygenated tetrahydropyrans and cyclohexanes are of interest as biochemical probes for disease related mechanisms, and, or drug leads for new therapeutic agents. These include unnatural analogs of carbohydrates that can act as glycomimetics, and natural products with potent activity. The broad long-term goal of this proposal is the development of synthetic methodology for such structures. We have shown that activation of 1-thio-1,2-0- isopropylideneacetals (TIA's) under mild conditions, lead to complex oxocarbenium ions, and this allows for novel approaches to highly oxygenated ring systems. In this project TIA chemistry will be applied to synthesis in three specific areas. We have prepared a novel C-disaccharide mimetic of sialyl Lewis X and determined its formational behavior and binding to P-selectin. Based on this information, the solution conformations of sLex, and the widely accepted model for selectin binding, we have proposed a bound conformation for this C-disaccharide. The first group of synthetic targets are a set of conformationally restrained analogs of this C-glycoside. These structures have been designed to investigate the optimal requirements for selectin binding. This information is relevant to the discovery of more potent, small molecule, selectin antagonists. The second target is a C-linked analog of myoinositol. This structure is a versatile precursor to a number of interesting mechanistic probes for interrogating the biosynthesis and function of phosphatidylinositol mannans (PIM's) in mycobacteria. This molecule therefore constitutes a valuable tool in drug development related to tuberculosis and other mycobacterial infections. the third target is an unnatural analog of the highly oxygenated natural product fumagillin. Derivatives of fumagillin have attracted attention as anti-angiogenic agents. Novel structures are in demand for drug optimization. This new analog has been designed to answer questions on drug specificity. The methods developed in this project promise to be of wider significance to other areas of carbohydrate recognition and synthesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM057865-06
Application #
6755137
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
1999-03-01
Project End
2007-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
6
Fiscal Year
2004
Total Cost
$296,974
Indirect Cost
Name
Hunter College
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
620127915
City
New York
State
NY
Country
United States
Zip Code
10065
Li, Jialiang; Todaro, Louis; Mootoo, David R (2011) Synthesis of an A'B' Precursor to Angelmicin B: Product Diversification in the Suarez Lactol Fragmentation. European J Org Chem 2011:6281-6287
Bachan, Stewart; Fantini, Jacques; Joshi, Anjali et al. (2011) Synthesis, gp120 binding and anti-HIV activity of fatty acid esters of 1,1-linked disaccharides. Bioorg Med Chem 19:4803-11
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Garg, Himanshu; Francella, Nicholas; Tony, Kurissery A et al. (2008) Glycoside analogs of beta-galactosylceramide, a novel class of small molecule antiviral agents that inhibit HIV-1 entry. Antiviral Res 80:54-61
Wang, Feng; Kawamura, Akira; Mootoo, David R (2008) Synthesis and antitumor activity of C-9 epimers of the tetrahydrofuran containing acetogenin 4-deoxyannoreticuin. Bioorg Med Chem 16:8413-8
Tony, K A; Li, Xiaohua; Dabideen, Darrin et al. (2008) An iodoetherification-dehydroiodination strategy for the synthesis of complex spiroketals from dihydroxyalkene precursors. Org Biomol Chem 6:1165-9

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