Document 0104
 DOCN  M9650104
 TI    Synthesis and structure-activity relationships of
       phenylenebis(methylene)-linked bis-tetraazamacrocycles that inhibit
       human immunodeficiency virus replication. 2. Effect of heteroaromatic
       linkers on the activity of bicyclams.
 DT    9605
 AU    Bridger GJ; Skerlj RT; Padmanabhan S; Martellucci SA; Henson GW; Abrams
       MJ; Joao HC; Witvrouw M; De Vreese K; Pauwels R; De Clercq E; Johnson
       Matthey Pharmaceutical Research, West Chester,; Pennsylvania 19380, USA.
 SO    J Med Chem. 1996 Jan 5;39(1):109-19. Unique Identifier : AIDSLINE
       MED/96136793
 AB    A series of bicyclam analogs connected through a heteroaromatic linker
       have been synthesized and evaluated for their inhibitory effects on
       HIV-1 (IIIB) and HIV-2 (ROD) replication in MT-4 cells. The activity of
       pyridine- and pyrazine-linked bicyclams was found to be highly dependent
       upon the substitution of the heteroaromatic linker connecting the cyclam
       rings. For example, 2,6- and 3,5-pyridine-linked bicyclams were potent
       inhibitors of HIV-1 and HIV-2 replication, whereas the 2,5- and
       2,4-substituted pyridine-linked compounds exhibited substantially
       reduced activity and, in addition, were found to be highly toxic to MT-4
       cells. We have subsequently discovered that these effects are not
       unique; amino-substituted linkers also have the potential to deactivate
       phenylenebis(methylene)-linked bicyclams. A model is proposed to explain
       the deactivating effects of the pyridine group in certain substitution
       patterns based on the ability of the pyridine nitrogen to participate in
       pendant conformations (complexation) with the adjacent azamacrocyclic
       ring, which may involve hydrogen bonding or coordination to a transition
       metal. The introduction of a sterically hindering group such as phenyl
       at the 6-position of the 2,4-substituted pyridine-linked bicyclam
       appears to prevent pendant conformations, providing an analog with
       comparable anti-HIV-1 and anti-HIV-2 activities to the parent
       m-phenylenebis(methylene)-linked bicyclam. The results of this study
       have been used to develop a quantitative structure-activity relationship
       model with improved predictive capability in order to aid the design of
       antiviral bis-azamacrocyclic analogs.
 DE    Antiviral Agents/CHEMISTRY/*CHEMICAL SYNTHESIS/PHARMACOLOGY  Aza
       Compounds/CHEMISTRY/CHEMICAL SYNTHESIS/PHARMACOLOGY  Cell Line  Cell
       Survival/DRUG EFFECTS  Heterocyclic Compounds/CHEMISTRY/*CHEMICAL
       SYNTHESIS/PHARMACOLOGY  Human  Hydrogen Bonding  Hydrogen-Ion
       Concentration  HIV-1/*DRUG EFFECTS  HIV-2/*DRUG EFFECTS  Molecular
       Conformation  Molecular Structure  Spectrophotometry, Ultraviolet
       Structure-Activity Relationship  Support, Non-U.S. Gov't  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).