Inhibition of Human Immunodeficiency Virus Type 1 Replication by Phosphonoformate- and Phosphonoacetate-2',3'-Dideoxy-3'-thiacytidine Conjugates

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 carboxyl...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1994-07, Vol.37 (14), p.2216-2223
Main Authors: Charvet, Anne-Sophie, Camplo, Michel, Faury, Philippe, Graciet, Jean-Christophe, Mourier, Nicolas, Chermann, Jean-Claude, Kraus, Jean-Louis
Format: Article
Language:English
Subjects:
AIDS/HIV
Antiviral Agents - chemical synthesis
Carbohydrates. Nucleosides and nucleotides
Chemistry
Exact sciences and technology
Foscarnet - chemical synthesis
Foscarnet - pharmacology
HIV-1 - drug effects
HIV-1 - physiology
human immunodeficiency virus
Lamivudine
Nucleosides, nucleotides and oligonucleotides
Organic chemistry
Phosphonoacetic Acid - chemical synthesis
Phosphonoacetic Acid - pharmacology
Preparations and properties
Prodrugs - chemical synthesis
Structure-Activity Relationship
Virus Replication - drug effects
Zalcitabine - analogs & derivatives
Zalcitabine - chemical synthesis
Zalcitabine - pharmacology
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00040a014