Donna Mary Huryn

Synthesis of iso-ddA, member of a novel class of anti-HIV agents

Abstract Iso-ddA ( 3 ) represents a new class of potential anti-AIDS drugs. Synthetic approaches to this compound involving nucleophilic additions to a novel carbohydrate framework are discussed.

Synthesis of E-selectin inhibitors: Use of an aryl-cyclohexyl ether as a disaccharide scaffold

Abstract A series of potential E-selectin antagonists were designed and synthesized based on the bound conformation of sLex, as well as the functional group requirements for anti-adhesion activity. A non-carbohydrate scaffolding using an aryl-cyclohexyl ether which can orient the critical acid and fucose residues in appropriate positions has been investigated. The inhibitory activity of members of this series suggests the feasibility of non-carbohydrate E-selectin antagonists.

1.01 Carbanions of Alkali and Alkaline-Earth Cations: (II) Selectivity of Carbonyl Addition Reactions

The nucleophilic addition of Grignard and organolithium reagents to carbonyl compounds is one of the most widely used reactions in organic chemistry. Selectivity in these reactions to generate diastereomeric or enantiomeric products is influenced by the structure of the substrate and the reactant, as well as by the reaction mechanism. Advances in this area include a better understanding of the steric and electronic factors that govern addition of nucleophiles to chiral substrates; the development of chiral auxiliaries that consistently and efficiently generate one diastereomer over another and their conversion to enantiomerically pure products; the improvements in chiral reagents that predictably add to a carbonyl to afford one enantiomer; and the development of chiral ligands that can be used to control the stereoselectivity of reactions between achiral substrates and achiral ligands.

Synthesis of the 6′-Fluoro Derivatives of Carbocyclic 2′,3′-Dideoxy-3′-oxa-adenosine

Abstract Different strategies for the synthesis of the 6′-α and β-fluoro derivatives of carbocyclic 2′,3′-dideoxy-3′-oxa-adenosine are described.

Synthesis of 3′-C-Substituted-2′,3′-Dideoxynucleosldes as Potential Antcaids Agents

Abstract In this paper we report an efficient synthetic route to some novel 3′-C-substituted-2,3′-dideoxy-nucleosides. The critical 3′- C-C bond was constructed by an application of free radical methodology. This type of reaction was found to be stereoselective forming exclusively the 3′-“down” isomer. The stereo-chemical assignment at C-3′ was confirmed by both nmr nOe experiments and single crystal X-ray analysis.

Anabolism and Mechanism of Action of Ro24-5098, an Isomer of 2′,3′-Dideoxyadenosine (ddA) with Anti-HIV Activity

The potential of dideoxynucleosides as inhibitors of HIV replication has been demonstrated in vitro by Mitsuya and Broder. This stimulated a great deal of interest in possible use of these compounds for therapy of HIV infections and led to clinical trials with 2,3-dideoxycytidine (ddC)2 and 2,3-dideoxyinosine (ddI).3 One factor that may limit the clinical utility of dideoxypurine nucleosides is the instability of the glycosidic bond at low pH, resulting in destruction of a pharmacologically active compound. This creates difficulties when oral administration is desired. A second factor affecting the usefulness of ddA and ddI is biochemical catabolism. Studies in cell culturec7 revealed that ddA is readily converted to ddI by adenosine deaminase (ADA). A portion of ddI is then degraded by purine nucleoside phosphorylase (PNP),* whereas the remainder is anabolized, possibly by S-nucle~tidase.~ The end result of cellular anabolism of both ddA and ddI is ddATP, which interacts with HIV reverse transcriptase. Although ddA can be anabolized directly by deoxyadenosine kinase (dAK) and deoxycytidine kinase (dCK) to ddAMP, these reactions occur to a small extent compared to the indirect route of anabolism by way of ddI. Therefore, both ddI and ddA (following deamination) are subject to catabolism by PNP.

Synthesis and anti-HIV activity of a novel series of isomeric dideoxynucleosides

Recently a class of potent inhibitors of the HIV reverse transcriptase, the 2,3-dideoxynucleosides (e.g.. ddA/ddI, ddC), has been described. The therapeutic use of these compounds, particularly ddA and other dideoxypurine nucleosides, however, is limited by their rapid degradation through hydrolysis of the sugar-base To overcome this deficiency we designed a modified dideoxynucleoside in which a more stable nucleoside linkage exists, e.g., iso-ddA, 1 (FIG. 1). The exchange of oxygen and carbon atoms, while maintaining an isomeric relationship with the model compounds, imparts stability at the sugar-base union. Starting material for the synthesis of 1 was the erythro-pentofuranose derivative, 2 (FIG. 2). This compound, when treated with a 1 % HOAc/methanol solution, initially yielded a mixture of the methyl glycoside, the ring-opened dimethyl acetal, and the desired cyclized product. With continued stimng, complete conversion to 3 was achieved in greater than 95% overall yield from 2. Tosylation of 3 under standard conditions, followed by hydrolysis and reduction, provided the iso-sugar, 4. The preparation of iso-ddA (1) was carried out by direct nucleophilic displacement of adenine on the iso-sugar unit, 4.4 Other members of this class of compounds (e.g., iso-ddC (5) and iso-ddT (6)) could be similarly synthesized. Additional isomeric purine dideoxynucleosides were prepared by the use of standard purine transformations. TABLE 1 details their synthesis.