Synthesis and antiviral evaluation of 2',3'-dideoxy-L-pyrimidine nucleosides with an improved in vitro therapeutic index against hepatitis B and human immunodeficiency virus (Meeting abstract).

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Synthesis and antiviral evaluation of 2',3'-dideoxy-L-pyrimidine nucleosides with an improved in vitro therapeutic index against hepatitis B and human immunodeficiency virus (Meeting abstract).

Proc Annu Meet Am Assoc Cancer Res; 35:A1848 1994. Unique Identifier : AIDSLINE ICDB/94603534
Lin TS; Luo MZ; Liu MC; Pai SB; Dutschman GE; Cheng YC; Dept. of Pharmacology, Yale Univ. School of Medicine, New Haven,; CT 06510

Abstract: The limiting toxicity of the clinically approved antiviral drug 2',3'-dideoxycytidine (beta-D-ddC) is peripheral neuropathy, which may be caused by the inhibition of mitochondrial DNA synthesis. Various new 2',3'-dideoxy-L-pyrimidine nucleosides (L-ddN) were synthesized by coupling 1-0-acetyl-5-O-(tert-butyldimethylsilyl)-2,3-dideoxy-L-ribofurano- se with sialylated pyrimidine derivatives in the presence of ethyl aluminum dichloride, which when deblocked yielded mixtures of the alpha and beta-anomers. Among the L-ddN synthesized 2',3'-dideoxy-beta-L-5-fluorocytidine was 3-fold more active against human immunodeficiency virus (HIV) in MT-2 cells with the HTLV-IIIB at 0.1 MOI and 280 fold more active against hepatitis B (HBV) in the 2.2.15 human hepatoma cell system than beta-D-ddC, whereas 2',3'-dideoxy-beta-L-cytidine was 280 fold more effective against HBV but 4-fold less active against HIV. The advantage of these analogs with the 'unnatural' L-configuration compared to beta-D-ddC is represented by the 2-fold decrease in cellular toxicity and the greater than 1000 fold decrease in mitochondrial toxicity. This improved therapeutic index should allow for the long term antiviral treatment necessary for HIV and HBV without inhibition of mitochondrial synthesis.

Keywords: Antiviral Agents/*CHEMICAL SYNTHESIS/*TOXICITY Carcinoma, Hepatocellular Cell Line Comparative Study Dideoxynucleosides/*CHEMICAL SYNTHESIS/*TOXICITY Hepatitis B Virus/*DRUG EFFECTS Human HIV/*DRUG EFFECTS Mitochondria/DRUG EFFECTS/METABOLISM Pyrimidines Structure-Activity Relationship Tumor Cells, Cultured ABSTRACT
941230
M94C4324

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