Document 0433
 DOCN  M9490433
 TI    Synthesis of naphthalenesulfonic acid small molecules as selective
       inhibitors of the DNA polymerase and ribonuclease H activities of HIV-1
       reverse transcriptase.
 DT    9411
 AU    Mohan P; Loya S; Avidan O; Verma S; Dhindsa GS; Wong MF; Huang PP;
       Yashiro M; Baba M; Hizi A; Department of Medicinal Chemistry and
       Pharmacognosy, College of; Pharmacy, University of Illinois at Chicago
       60680.
 SO    J Med Chem. 1994 Aug 5;37(16):2513-9. Unique Identifier : AIDSLINE
       MED/94334908
 AB    Over 25 selected naphthalenesulfonic acid derivatives were evaluated for
       their inhibitory effect on two different functional domains of the HIV-1
       reverse transcriptase (RT), namely the ribonuclease H and DNA polymerase
       activities. Most of the analogues were found to be either specific
       toward the DNA polymerase activity or showed nonselective inhibition of
       both catalytic functions. The most active compounds are either
       symmetrical derivatives or nonsymmetrical derivatives containing a
       lipophilic appendage consisting of a palmitoyl or cholesteryl moiety.
       The six most active compounds in the preliminary screen, derivatives 6,
       16, 17, 23, 26, and 27, were subjected to experiments to determine their
       50% inhibitory concentration (IC50) values in the assays that measure
       RNA-dependent DNA polymerase (RDDP), DNA-dependent DNA polymerase
       (DDDP), and ribonuclease H (RNase H) functions of HIV-1 RT. The most
       potent derivative was a nonsymmetric cholesterol-linked
       4-amino-5-hydroxy-2,7-naphthalenedisulfonic acid analogue, compound 23,
       which demonstrated an IC50 value of 0.06 microM for inhibiting RDDP
       activity. Inhibition of DDDP and RNase H activity for this compound was
       demonstrated at concentrations that were over 100-fold of that for
       inhibiting RDDP activity. However, the potency of this active compound
       does not correlate in the whole virus assay, probably due to a lack of
       cellular entry. The cholesterol derivative, 23, also possesses HIV-1
       protease inhibitory activity and belongs to a unique class of
       multifunctional HIV-1 inhibitors.
 DE    Cholesterol/*ANALOGS & DERIVATIVES/CHEMICAL SYNTHESIS/  PHARMACOLOGY
       DNA Polymerases/*ANTAGONISTS & INHIB  HIV Protease Inhibitors/CHEMICAL
       SYNTHESIS/PHARMACOLOGY  HIV-1/DRUG EFFECTS  Molecular Structure
       Naphthalenesulfonates/*CHEMISTRY  Reverse Transcriptase/*ANTAGONISTS &
       INHIB  Ribonuclease H, Calf Thymus/*ANTAGONISTS & INHIB  RNA
       Replicase/ANTAGONISTS & INHIB  Structure-Activity Relationship  JOURNAL
       ARTICLE

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