Document 0424
 DOCN  M9620424
 TI    Hydroxylated aromatic inhibitors of HIV-1 integrase.
 DT    9602
 AU    Burke TR Jr; Fesen MR; Mazumder A; Wang J; Carothers AM; Grunberger D;
       Driscoll J; Kohn K; Pommier Y; Laboratories of Medicinal Chemistry and
       Molecular Pharmacology,; National Cancer Institute, National Institutes
       of Health,; Bethesda, Maryland 20892, USA.
 SO    J Med Chem. 1995 Oct 13;38(21):4171-8. Unique Identifier : AIDSLINE
       MED/96028186
 AB    Efficient replication of HIV-1 requires integration of a DNA copy of the
       viral genome into a chromosome of the host cell. Integration is
       catalyzed by the viral integrase, and we have previously reported that
       phenolic moieties in compounds such as flavones, caffeic acid phenethyl
       ester (CAPE, 2), and curcumin confer inhibitory activity against HIV-1
       integrase. We now extend these findings by performing a comprehensive
       structure-activity relationship using CAPE analogues. Approximately 30
       compounds have been prepared as HIV integrase inhibitors based on the
       structural lead provided by CAPE, which has previously been shown to
       exhibit an IC50 value of 7 microM in our integration assay. These
       analogues were designed to examine specific features of the parent CAPE
       structure which may be important for activity. Among the features
       examined for their effects on inhibitory potency were ring substitution,
       side chain length and composition, and phenyl ring conformational
       orientation. In an assay which measured the combined effect of two
       sequential steps, dinucleotide cleavage and strand transfer, several
       analogues have IC50 values for 3'-processing and strand transfer lower
       than those of CAPE. Inhibition of strand transfer was assayed using both
       blunt-ended and precleaved DNA substrates. Disintegration using an
       integrase mutant lacking the N-terminal zinc finger and C-terminal
       DNA-binding domains was also inhibited by these analogues, suggesting
       that the binding site for these compounds resides in the central
       catalytic core. Several CAPE analogues were also tested for selective
       activity against transformed cells. Taken together, these results
       suggest that the development of novel antiviral agents for the treatment
       of acquired immune deficiency syndrome can be based upon inhibition of
       HIV-1 integrase.
 DE    Animal  Antiviral Agents/*CHEMICAL SYNTHESIS  Apoptosis/DRUG EFFECTS
       Base Sequence  Binding Sites  Caffeic Acids/*CHEMISTRY/PHARMACOLOGY
       Cell Line, Transformed  DNA/CHEMISTRY/METABOLISM  DNA
       Nucleotidyltransferases/*ANTAGONISTS & INHIB  Enzyme
       Inhibitors/*CHEMICAL SYNTHESIS  Human  Hydroxylation  HIV/DRUG EFFECTS
       Molecular Conformation  Molecular Sequence Data  Molecular Structure
       Nuclear Magnetic Resonance  Phenylethyl Alcohol/*ANALOGS &
       DERIVATIVES/CHEMISTRY/PHARMACOLOGY  Rats  Structure-Activity
       Relationship  Support, Non-U.S. Gov't  Tumor Cells, Cultured  Zinc
       Fingers  JOURNAL ARTICLE

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