Document 0509
 DOCN  M9480509
 TI    Inhibition of human immunodeficiency virus type 1 replication by
       phosphonoformate- and phosphonoacetate-2',3'-dideoxy-3'-thiacytidine
       conjugates.
 DT    9410
 AU    Charvet AS; Camplo M; Faury P; Graciet JC; Mourier N; Chermann JC; Kraus
       JL; Laboratoire de Chimie Biomoleculaire, Faculte des Sciences de;
       Luminy, Marseille, France.
 SO    J Med Chem. 1994 Jul 8;37(14):2216-23. Unique Identifier : AIDSLINE
       MED/94309075
 AB    The synthesis of potential combined prodrugs where phosphonoformic acid
       (PFA) or phosphonoacetic acid (PAA) was attached to the 5'-O or N4
       position of 2',3'-dideoxy-3'-thiacytidine (BCH-189) is described. The
       anti-HIV-1 activity of 11 analogues which included carboxylic ester or
       phosphoric ester linkages of PFA or PAA to BCH-189 was determined in
       MT-4 cells. Of these compounds, the IC50 of analogues 3, 4, 6, and 7
       ranged from 0.2 to 100 microM, while IC50 for BCH-189 in this system was
       0.1 microM. In vitro hydrolysis of the various esters or amides in human
       plasma indicated that these agents were relatively stable in the
       presence of plasma esterases with t1/2 values of up to 120 min.
       Moreover, lipophilicity of these compounds (partition coefficient) was
       determined in order to establish correlation between lipophilicity and
       diffusion of BCH-189 analogues into the cells. The active compounds may
       exert their effects by extracellular or intracellular hydrolysis to the
       corresponding antiviral agent BCH-189, but intrinsic anti-HIV-1 activity
       of some of PAA and PFA adducts, themselves, may also be involved.
 DE    Antiviral Agents/*CHEMICAL SYNTHESIS  Foscarnet/*CHEMICAL
       SYNTHESIS/PHARMACOLOGY  HIV-1/*DRUG EFFECTS/PHYSIOLOGY  Phosphonoacetic
       Acid/*CHEMICAL SYNTHESIS/PHARMACOLOGY  Prodrugs/*CHEMICAL SYNTHESIS
       Structure-Activity Relationship  Support, Non-U.S. Gov't  Virus
       Replication/*DRUG EFFECTS  Zalcitabine/*ANALOGS & DERIVATIVES/CHEMICAL
       SYNTHESIS/  PHARMACOLOGY  JOURNAL ARTICLE

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