3 -Azido-3 -deoxythymidine antiviral activity

Schwendener RA, et al. New lipophilic acyl/alkyl dinucleoside phosphates as derivatives of 3 -azido-3 -deoxythymidine Inhibition of HIV-1 replication in vitro and antiviral activity against Rauscher leukemia virus infected mice with delayed treatment regimens. Antivir Res 1994 24 79. 

However, equivalent potency of enzyme inhibition has been reported for the triphosphates of 3 -deoxythymidine and 3 -amino-3 -deoxythymidine despite the weak antiviral activity of the parent nucleosides (163) and (90) in vitro, both of which are poor substrates for phosphorylation [213, 214]. These observations suggest that the antiviral aetivity of 2, 3 -dideoxynucleo-sides may depend less on the relative inhibitory activities of the triphosphates against isolated RT, but rather reflects the affinity of the parent nucleosides for the cellular kinase enzymes effecting triphosphorylation. Nevertheless, other studies of RT inhibition by nucleoside triphosphates have demonstrated a defined SAR for modifications at the 3 -position [215], and it is likely that the azido substituent of AZT contributes both to the requisite substrate activity for the cellular phosphorylating enzymes, and the specificity of RT inhibition following conversion to the triphosphate. 

Royer, R. E., Mills, R. G., Young, S. A., and Vander Jagt, D. L. (1995b). Comparison of the antiviral activities of 3 -azido-3 -deoxythymidine (AZT) and gossylic iminolactone (GIL) against clinical isolates of HIV-1. Pharmacol. Res. 31,49-52. 

Zidovudine (200 mg every 4 hours) is indicated in the management of patients with HIV infection who show evidence of impaired immunity. Trimethoprim-sulfamethoxazole, pyrimethamine, and acyclovir may be necessary for the management or prevention of opportunistic infections. Zidovudine (3 -azido-3 -deoxythymidine, commonly referred to as AZT) is a thymidine analog with antiviral activity against HIV-1, HIV-2, human T-lymphotropic (or leukemia) virus (HTLV)-I, and other retroviruses. Low concentrations (<0.001 to 0.04 pg/ml) inhibit acute HIV-1 infection in human T-cell lines and peripheral blood lymphocytes. Zidovudine is less active in human monocyte-macrophages or quiescent cells but inhibits HIV replication in human brain macrophages. Zidovudine is also inhibitory for HBV and EBV... 

Mukheiji, E. Au, J.L.-S. Mathes, L.E. Differential antiviral activities and intracellular metabolism of 3 -azido-3 -deoxythymidine and 2, 3 -dideoxyinosine in human cells. Antimicrob.Agents Chemother., 1994, 38, 1573-1579... 

Several 2,5 -anhydro analogues of 3 -azido-2, 3 -dideoxyuridine (1, AZDU), 3 -azido-3 -deoxythymidine (2, AZT), 3 -azido-5-bromo-2, 3 -dideoxyuridine (5), 3 -azido-2, 3 -dideoxy-5-iodouridine (6), and the 3 -azido derivative of 2 -deoxy-5-methylisocytidine, compounds 38-42, have been synthesized and evaluated against human immunodeficiency virus (HIV-1) and Rauscher-murine leukemia virus (R-MuLV). in general, the parent compounds 1,2,5, and 6 were approximately 1.8 to 6 times more active against HIV-1 than their corresponding 2,5 -anhydro derivatives (compounds 38-41, Table 3). Compounds 38-41 have significant antiviral activity with respective EC50 values of 4.95,0.56, 28, and 27.1 pM. 3 -Azido-2, 3 -dideoxy-5-methylisocytidine (42) also demonstrated anti-HIV-1... 

In order to study the molecular basis of the antiviral activity, as well as the inhibitory activity to mitochondrial DNA synthesis concerning these anhydro nucleoside derivatives, [2-l C]2,5 -anhydro-3 -azido-3 -deoxythymidine ([2-l C]anhydro-AZT) and [2-l C]2,5 -anhydro-3 -azido-2, 3 -dideoxy-5-iodouridine ([2-l C]anhydo-5-I-AZDU) have also been... 

Synthesis and antiviral activity of several 2,5 -anhydro analogues of 3 -azido-3 -deoxythymidine, 3 -azido-2 ,3 -dideoxyuridine, 3 -azido-2 ,3 -dideoxy-5-halouridines, and 3 -deoxythymidine against human immunodeficiency virus and Rauscher-murine leukemia virus, J. Med. Chem. 32 1891 (1989). 

Buckheit RW Jr., White EL, Germany-Decker J, Allen LB, Ross LJ, Shannon WM, et al. Cell-based and biochemical analysis of the anti-HIV activity of combinations of 3 -azido-3 -deoxythymidine and analogues of TIBO. Antiviral Chem Chemother 1994 5 35 12. 

D. Synthesis and anti-HIV activity of some novel phosphorodiamidate derivatives of 3 -azido-3 -deoxythymidine (AZT). Antiviral Chem. Chemother., 1991, 2 35-39. 

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