Document 0787
 DOCN  M94B0787
 TI    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).
 DT    9412
 AU    Lin TS; Luo MZ; Liu MC; Pai SB; Dutschman GE; Cheng YC; Dept. of
       Pharmacology, Yale Univ. School of Medicine, New Haven,; CT 06510
 SO    Proc Annu Meet Am Assoc Cancer Res; 35:A1848 1994. Unique Identifier :
       AIDSLINE ICDB/94603534
 AB    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.
 DE    Antiviral Agents/*CHEMICAL SYNTHESIS/*TOXICITY  Carcinoma,
       Hepatocellular  Cell Line  Comparative Study
       Dideoxynucleosides/*CHEMICAL SYNTHESIS/*TOXICITY  HIV/*DRUG EFFECTS
       Hepatitis B Virus/*DRUG EFFECTS  Human  Mitochondria/DRUG
       EFFECTS/METABOLISM  Pyrimidines  Structure-Activity Relationship  Tumor
       Cells, Cultured  MEETING ABSTRACT

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).