There is considerable interest in molecules which mimic carbohydrates involved in mechanisms associated with health disorders. Carbohydratees analogs in which the exocyclic or endocyclic acetal oxygen is replaced by a methylene, C-glycoside or carbasugar respectively have attracted interest. These molecules are expected to have similar conformational and steric properties, and therefore similar ligating characteristics as the natural O-saccharide. Importantly, they are not glycosides and therefore will be stable to glycosyl processing enzymes and to chemical hydrolysis. They are potentially useful as therapeutic agents or tools for biochemical research. This project deals with new methodology for the synthesis of three groups of glycomimetics: C-glycosides and carbasugars of Galbeta glycosides, and C-glycosides of glycophospatidyl (GPI) subunits.
The specific aims are: (I) C-glycosides which are potential Iselectin ligands and could provide the basis for the design of novel, hydrolytically, stable anti-inflammatory agents. (II) C-Glycosides and carbasugars of Gal-beta-disaccharides, which are substrates for preparation of stable complexes with glycosyl processing enzymes and may have inhibitory properties. (III) C-glycoside analogs of GPI components, which are relevant to the investigation of GPI related processes, such as survival mechanisms in parasitic protozoa and signal transduction related to insulin action. The synthetic strategy centers on novel chemistry of thio- isopropylidinated acetals (TIA's). The method is well suited for making disaccharide mimetics, although it may be just as easily applied to monosaccharide structures. The concept for making disaccharide analogs involves the initial linking of a cyclic sugar derivative to a TIA synthon. Subsequently, the second ring is formed by an oxocarbenium ion-alkene cyclization to give a dihydropyran or cyclohexene derivative, depending on the choice of the TIA fragment used. Stereoselective functionalization of the alkene leads to the targeted glycomimetics. This strategy provides solutions to the problems of coupling efficiency and stereoselectivity which limit the direct connection of two intact cyclic sugar derivatives.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM057865-01A1
Application #
2842256
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1999-03-01
Project End
2003-02-28
Budget Start
1999-03-01
Budget End
2000-02-29
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Hunter College
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
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
Hans, Sunej K; Camara, Fatoumata; Altiti, Ahmad et al. (2010) Synthesis of C-glycoside analogues of beta-galactosamine-(1-->4)-3-O-methyl-D-chiro-inositol and assay as activator of protein phosphatases PDHP and PP2Calpha. Bioorg Med Chem 18:1103-10
Tony, Kurissery A; Dabideen, Darrin; Li, Jialiang et al. (2009) Olefin metathesis-iodoetherification-dehydroiodination strategy for spiroketal subunits of polyether antibiotics. J Org Chem 74:7774-80
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Li, Jialiang; Todaro, Louis J; Mootoo, David R (2008) Synthesis of the AB subunit of angelmicin B through a tandem alkoxy radical fragmentation-etherification sequence. Org Lett 10:1337-40
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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