       Document 0326
 DOCN  M9610326
 TI    Synthesis and biological evaluation of N6-cycloalkyl derivatives of
       1-deazaadenine nucleosides: a new class of anti-human immunodeficiency
       virus agents.
 DT    9601
 AU    Cristalli G; Vittori S; Eleuteri A; Volpini R; Camaioni E; Lupidi G;
       Mahmood N; Bevilacqua F; Palu G; Dipartimento di Scienze Chimiche,
       Universita di Camerino, Italy.
 SO    J Med Chem. 1995 Sep 29;38(20):4019-25. Unique Identifier : AIDSLINE
       MED/96005101
 AB    A series of 1-deazaadenine nucleosides with the N6 nitrogen
       unsubstituted or bearing methyl or cycloalkyl substituents, with or
       without a chloro group in the 2-position, and with the glycosylic moiety
       being ribose (1-16), 2'-deoxyribose (17-32), or 2', 3'-dideoxyribose
       (33-48) were designed and synthesized starting from
       5,7-dichloro-3H-imidazo[4,5-b] pyridine (50). These compounds were
       evaluated for their in vitro activity against human immunodeficiency
       virus type-1 (HIV-1) and herpes simplex virus type-1 (HSV-1). In
       addition they were tested for their ability to inhibit adenosine
       deaminase (ADA) from calf intestine. While the parent compounds
       1-deazaadenosine (9), 2'-deoxy-1-deazaadenosine (25), and
       2',3'-dideoxy-1- deazaadenosine (41) and the corresponding 2-chloro
       derivatives were inactive, nucleosides bearing cycloalkyl substituents
       on N6 exhibited moderate to good anti-HIV-1 activity, compared to
       2',3'-dideoxyadenosine, with the degree and pattern of improvement
       depending on the structure of the sugar moiety. In general, 2'-deoxy-
       and 2',3'-dideoxy derivatives were more potent compounds than the
       corresponding ribose nucleosides. Compounds bearing a 6-cycloheptyl or
       cyclooctylamine were the most active in every series. The presence of a
       chloro group in the 2-position improved both activity and therapeutic
       index in every series, the most active compound being
       2'-deoxy-2-chloro-N6-cycloheptyl-1-deazaadenosine (23; ED50 = 0.2
       microM). On the other hand, most of these derivatives were inactive as
       anti-HSV-1 agents, showing a high degree of virus selectivity. The
       1-deazaadenine derivatives were not substrates of adenosine deaminase,
       and some of them proved to be good inhibitors of the enzyme. However,
       the ADA inhibitory activity does not account for the antiviral potency
       since increased lipophilicity and steric hindrance of substituents
       resulted in derivatives much less active than the parent compounds.
 DE    Adenosine/*CHEMICAL SYNTHESIS/PHARMACOLOGY  Adenosine
       Deaminase/ANTAGONISTS & INHIB  Animal  Antiviral Agents/*CHEMICAL
       SYNTHESIS/PHARMACOLOGY  Cercopithecus aethiops  Herpesvirus 1,
       Human/DRUG EFFECTS  Human  HIV-1/*DRUG EFFECTS  Structure-Activity
       Relationship  Support, Non-U.S. Gov't  Vero Cells  JOURNAL ARTICLE

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

