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M9480509.TXT
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1994-08-20
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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).