       Document 0912
 DOCN  M9540912
 TI    Synthesis and structure-activity relationships of
       phenylenebis(methylene)-linked bis-tetraazamacrocycles that inhibit HIV
       replication. Effects of macrocyclic ring size and substituents on the
       aromatic linker.
 DT    9504
 AU    Bridger GJ; Skerlj RT; Thornton D; Padmanabhan S; Martellucci SA; Henson
       GW; Abrams MJ; Yamamoto N; De Vreese K; Pauwels R; et al; Johnson
       Matthey Pharmaceutical Research, West Chester,; Pennsylvania 19380.
 SO    J Med Chem. 1995 Jan 20;38(2):366-78. Unique Identifier : AIDSLINE
       MED/95131421
 AB    We have previously described the potent and selective inhibition of
       several strains of human immunodeficiency virus type 1 (HIV-1) and type
       2 (HIV-2) by JM2763, an n-propyl-linked dimer of the
       1,4,8,11-tetraazamacrocyclic (cyclam) ring system. Upon further
       investigation, we have also found that incorporating an aromatic rather
       than aliphatic linker leads to analogs with higher antiviral potency.
       The prototype, JM3100 (19a, isolated as the octahydrochloride salt),
       which contains a p-phenylenebis(methylene) moiety linking the cyclam
       rings, inhibited the replication of HIV-1 (IIIB) and HIV-2 (ROD) at
       EC50's of 4.2 and 5.9 nM, respectively, while remaining nontoxic to MT-4
       cells at concentrations exceeding 421 microM. In order to identify the
       structural features of bis-tetraazamacrocycles required for potent
       activity, we have prepared a novel series of
       phenylenebis(methylene)-linked analogs, in which the macrocyclic ring
       size was varied from 12 to 16 ring members. Depending upon the
       substitution of the phenylenebis(methylene) linker (para or meta),
       sub-micromolar anti-HIV activity was exhibited by analogs bearing
       macrocycles of 12-14 ring members but with varying cytotoxicity to MT-4
       cells. Furthermore, while we found that identical macrocyclic rings are
       not required for activity, substituting an acyclic polyamine equivalent
       for one of the cyclam rings in 19a resulted in a substantial reduction
       in anti-HIV potency, clearly establishing the importance of the
       constrained macrocyclic structure. A short series of transition metal
       complexes of 19a were also prepared and evaluated. Complexes of low
       kinetic stability such as the bis-zinc complex retained activity
       comparable to that of the parent compound. Finally, the activity of
       bicyclam analogs appears to be insensitive to the electron-withdrawing
       or -donating properties of substituents introduced onto the linker, but
       sterically hindering groups such as phenyl markedly reduced activity. As
       a result, several analogs with anti-HIV potency comparable to that of
       19a have been identified.
 DE    *Antiviral Agents/CHEMICAL SYNTHESIS  Cells, Cultured  Heterocyclic
       Compounds/*CHEMICAL SYNTHESIS  HIV-1/*DRUG EFFECTS/GROWTH & DEVELOPMENT
       HIV-2/*DRUG EFFECTS  In Vitro  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).

