Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
SYNTHESIS OF NEW DIDEOXYNUCLEOSIDES OF ANTIVIRAL INTEREST
Diss Abstr Int [B]; 51(12):5869 1991. Unique Identifier : AIDSLINE ICDB/92677052 Buenger GS; Univ. of Iowa
Abstract:
Since the discovery of the anti-HIV activity of dideoxynucleosides, much attention has focused on the synthesis of more potent and selective analogs. New congeners of 2',3'-dideoxyadenosine, with greater hydrolytic and enzymatic stability, would be of interest in helping to define structure-activity relationships in this area. New methodologies were applied for the synthesis of dideoxyadenosine analogs. A palladium-catalyzed cross-coupling reaction, as well as thermal radical, photochemical, and metal-mediated reactions were utilized for modifying the heterocyclic base. The ribonucleosides were deoxygenated via the 2',3'-thionocarbonate which provided 2'-deoxy, 3'-deoxy, and 2',3'-unsaturated nucleosides. The monodeoxy nucleosides were deoxygenated via the imidazolide to the dideoxynucleoside. Thus, 2- and 8-substituted ddA analogs were synthesized and examined for anti-HIV activity. The hydrolytic stability of the glycosidic bond of these new ddA congeners under acidic conditions was studied by differential UV spectroscopy. Substituents at the 8-position produced very dramatic differences in hydrolysis rates as compared to the 2-position. 8-Hydroxy ddA was totally resistant to hydrolysis while 8-amino ddA was cleaved 20 times faster than ddA. These results suggest that protonation of N-7 may be an important factor in the hydrolytic cleavage of the glycosidic bond. The ddA analogs were also investigated for substrate activity with adenosine deaminase (ADA). The 2-substituted ddA congeners were not substrates for ADA but did act as competitive inhibitors of the enzyme. Small groups at the 8-position gave ddA analogs with reduced substrate activity while larger groups abolished substrate activity. (Full text available from University Microfilms International, Ann Arbor, MI, as Order No. AAD91-12402).
Keywords: Adenosine Deaminase/ANTAGONISTS & INHIB Antiviral Agents/*CHEMICAL SYNTHESIS/PHARMACOLOGY Dideoxyadenosine/ANALOGS & DERIVATIVES/*CHEMICAL SYNTHESIS/ PHARMACOLOGY Structure-Activity Relationship THESIS
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Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
