Document 0103
 DOCN  M9650103
 TI    (-)-Arctigenin as a lead structure for inhibitors of human
       immunodeficiency virus type-1 integrase.
 DT    9605
 AU    Eich E; Pertz H; Kaloga M; Schulz J; Fesen MR; Mazumder A; Pommier Y;
       Institut fur Pharmazeutische Biologie, Freie Universitat; Berlin,
       Germany.
 SO    J Med Chem. 1996 Jan 5;39(1):86-95. Unique Identifier : AIDSLINE
       MED/96136791
 AB    The natural dibenzylbutyrolactone type lignanolide (-)-arctigenin (2),
       an inhibitor of human immunodeficiency virus type-1 (HIV-1) replication
       in infected human cell systems, was found to suppress the integration of
       proviral DNA into the cellular DNA genome. In the present study 2 was
       tested with purified HIV-1 integrase and found to be inactive in the
       cleavage (3'-processing) and integration (strand transfer) assays.
       However, the semisynthetic 3-O-demethylated congener 9 characterized by
       a catechol substructure exhibited remarkable activities in both assays.
       Structure-activity relationship studies with 30 natural (1-6),
       semisynthetic (7-21), and synthetic (37-43, 45, 46) lignans revealed
       that (1) the lactone moiety is crucial since compounds with a
       butane-1,4-diol or tetrahydrofuran substructure and also lignanamide
       analogues lacked activity and (2) the number and arrangement of phenolic
       hydroxyl groups is important for the activity of lignanolides. The
       congener with two catechol substructures (7) was found to be the most
       active compound in this study. 7 was also a potent inhibitor of the
       disintegration reaction which models the reversal of the strand transfer
       reaction. The inhibitory activity of 7 with the core enzyme fragment
       consisting of amino acids 50-212 suggests that the binding site of 7
       resides in the catalytic domain.
 DE    Antiviral Agents/*CHEMICAL SYNTHESIS/PHARMACOLOGY  Base Sequence
       Binding Sites  DNA Nucleotidyltransferases/*ANTAGONISTS &
       INHIB/METABOLISM  Enzyme Inhibitors/*CHEMICAL SYNTHESIS/PHARMACOLOGY
       Furans/*PHARMACOLOGY  Human  HIV-1/DRUG EFFECTS/*ENZYMOLOGY
       Lactones/CHEMISTRY  Lignans/CHEMISTRY/*CHEMICAL SYNTHESIS/*PHARMACOLOGY
       Molecular Sequence Data  Molecular Structure  Structure-Activity
       Relationship  4-Butyrolactone/*ANALOGS & DERIVATIVES/CHEMISTRY/CHEMICAL
       SYNTHESIS/PHARMACOLOGY  JOURNAL ARTICLE

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