       Document 0153
 DOCN  M9640153
 TI    Anti-human immunodeficiency virus (HIV) activities of halogenated
       gomisin J derivatives, new nonnucleoside inhibitors of HIV type 1
       reverse transcriptase.
 DT    9604
 AU    Fujihashi T; Hara H; Sakata T; Mori K; Higuchi H; Tanaka A; Kaji H; Kaji
       A; Department of Pharmacology, Jefferson Medical College,; Philadelphia,
       Pennsylvania 19107, USA.
 SO    Antimicrob Agents Chemother. 1995 Sep;39(9):2000-7. Unique Identifier :
       AIDSLINE MED/96050732
 AB    Halogenated gomisin J (a derivative of lignan compound), represented by
       the bromine derivative 1506 [(6R, 7S,
       S-biar)-4,9-dibromo-3,10-dihydroxy-1,2,11,12-tetramethoxy-6,
       7-dimethyl-5,6,7,8- tetrahydrodibenzo[a,c]cyclo-octene], was found to be
       a potent inhibitor of the cytopathic effects of human immunodeficiency
       virus type 1 (HIV-1) on MT-4 human T cells (50% effective dose, 0.1 to
       0.5 microM). Gomisin J derivatives were active in preventing p24
       production from acutely HIV-1-infected H9 cells. The selective indices
       (toxic dose/effective dose) of these compounds were as high as > 300 in
       some systems. 1506 was active against
       3'-azido-3'-deoxythymidine-resistant HIV-1 and acted synergistically
       with AZT and 2',3'-ddC. 1506 inhibited HIV-1 reverse transcriptase (RT)
       in vitro but not HIV-1 protease. From the time-of-addition experiment,
       1506 was found to inhibit the early phase of the HIV life cycle. A
       1506-resistant HIV mutant was selected and shown to possess a mutation
       within the RT-coding region (at position 188 [Tyr to Leu]). The mutant
       RT expressed in Escherichia coli was resistant to 1506 in the in vitro
       RT assay. Some of the HIV strains resistant to other nonnucleoside HIV-1
       RT inhibitors were also resistant to 1506. Comparison of various gomisin
       J derivatives with gomisin J showed that iodine, bromine, and chlorine
       in the fourth and ninth positions increased RT inhibitory activity as
       well as cytoprotective activity.
 DE    Antiviral Agents/*PHARMACOLOGY  Blotting, Southern  Cell Line  Drug
       Resistance  Drug Synergism  Human  HIV Core Protein p24/BIOSYNTHESIS
       HIV-1/*DRUG EFFECTS/ENZYMOLOGY/METABOLISM  Kinetics
       Lignans/*PHARMACOLOGY  Plaque Assay  Polycyclic
       Hydrocarbons/*PHARMACOLOGY  Reverse Transcriptase
       Inhibitors/*PHARMACOLOGY  RNA-Directed DNA Polymerase/*METABOLISM
       Structure-Activity Relationship  Zidovudine/PHARMACOLOGY  JOURNAL
       ARTICLE

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

