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M94B0787.TXT
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1994-11-11
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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).