Abstract
2′,3′-dideoxyadenosine (ddA) has activity against the human immunodeficiency virus-1 (HIV), but is rapidly catabolized by human T cells, even when adenosine deaminase is inhibited by deoxycoformycin. To overcome this problem, we developed a simple method to synthesize the 2-fluoro-, 2-chloro-, and 2-bromo-derivatives of ddA. The isolated 2-halo-ddA derivatives were not deaminated significantly by cultured T lymphoblasts, which converted the dideoxynucleosides to the respective 5′-monophosphate, 5′- diphosphate, and 5′- triphosphate metabolites. At concentrations lower than those producing cytotoxicity in uninfected cells (3-10 μM), the 2-halo-ddA derivatives inhibited the cytopathic effects of HIV toward T lymphoblasts, and retarded viral replication. Experiments with a deoxycytidine kinase deficient mutant CEM T cell line showed that this enzyme was necessary for the phosphorylation and anti-HIV activity of the 2-halo-ddA derivatives. Thus, the 2-halo-ddA congeners, in contrast to ddA itself, are not degraded by T lymphocytes, and represent promising compounds for in vivo chemotherapy of HIV infection.
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Carson, D., Haertle, T., Carrera, C. et al. 19 2-HALO-2′,3′-DIDEOXYADENOSINES: METABOLICALLY STABLE DIDEOXYNUCLEOSIDES WITH ACTIVITY AGAINST THE HUMAN IMMUNODEFICIENCY VIRUS (HIV). Pediatr Res 24, 114 (1988). https://doi.org/10.1203/00006450-198807000-00043
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DOI: https://doi.org/10.1203/00006450-198807000-00043