       Document 0146
 DOCN  M9640146
 TI    Novel sulfonated and phosphonated analogs of distamycin which inhibit
       the replication of HIV.
 DT    9604
 AU    Clanton DJ; Buckheit RW Jr; Terpening SJ; Kiser R; Mongelli N; Borgia
       AL; Schultz R; Narayanan V; Bader JP; Rice WG; Anti-AIDS Virus Drug
       Screening Laboratory, Program Resources,; Inc./Dyncorp, NCI-Frederick
       Cancer Research and Development; Center, MD 21702-1201, USA.
 SO    Antiviral Res. 1995 Aug;27(4):335-54. Unique Identifier : AIDSLINE
       MED/96049782
 AB    A series of novel distamycin-related polyanionic compounds were compared
       for their anti-HIV activity. Several were highly potent inhibitors of
       HIV virus-induced cell killing and viral replication of a wide variety
       of laboratory isolates, as well as a monocytotropic virus and a clinical
       isolate in human peripheral blood lymphocytes. These compounds are
       structurally different from other sulfonic acid containing compounds
       reported to be potent inhibitors of the human immunodeficiency virus
       (HIV) in two respects: (1) they are structurally related to the
       non-toxic minor groove DNA binder distamycin; and (2) a number of them
       contain the aromatic phosphonic acid group. The compounds that were
       evaluated can be categorized into monomeric or dimeric ureido structural
       classes incorporating the bisamido-N-methylpyrrolenaphthalene-sulfonic
       acid group, with differences in the number and position of the sulfonic
       acids on the naphthalene rings. Broader structure-activity studies were
       made possible through the synthesis and evaluation of the compounds
       containing only a single N-methylpyrrole unit, those incorporating the
       N-methylpyrazole structure, and compounds having the isosteric
       phosphonic acid group substituted for the sulfonic acid group. One of
       the most potent of the inhibitors was
       2,2'[4,4'[[aminocarbonyl]amino]bis[N,4'-di[pyrrole-2-carboxamide-
       1,1'-dimethyl]]-4,6,8 naphthalenetrisulfonic acid] hexasodium salt, NSC
       651015. This compound, the phosphonic acid analog NSC 662162, and the
       monomeric compound NSC 651018 were studied to determine the mechanism of
       their inhibitory activity. Mechanistic studies revealed that inhibition
       was due to the disruption of virus attachment to CD(4+)-susceptible
       cells and a further restraint on fusion of virus and cell membranes. The
       relative tolerance of these compounds in mice suggests that sufficient
       antiviral concentrations could be reached in vivo and thus may prove
       valuable in the treatment of AIDS patients.
 DE    Amino Acid Sequence  Animal  Antiviral Agents/CHEMISTRY/*PHARMACOLOGY
       Cell Line  Distamycins/CHEMISTRY/*PHARMACOLOGY  Human  HIV-1/*DRUG
       EFFECTS/PHYSIOLOGY  HIV-2/*DRUG EFFECTS/PHYSIOLOGY  Mice  Molecular
       Sequence Data  Structure-Activity Relationship  Sulfur  Support,
       Non-U.S. Gov't  Support, U.S. Gov't, P.H.S.  Virus Replication/DRUG
       EFFECTS  JOURNAL ARTICLE

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

