- Synthesis and antiviral activity of N-4'-dihydropyridinyl and dihydroquinolinylcarbonyl-2-hydroxymethyl-5-[cytosin-1'-yl]-1, 3-oxathiolane derivatives against human immunodeficiency virus and duck hepatitis B virus
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Dihydropyridine and dihydroquinoline derivatives of 2-hydroxymethyl-5-[cytosin-1'-yl]-1,3-oxathiolane ((±)-3TC) have been prepared. The N-4-nicotinate or the N-4-quinoline-carboxylate amides were obtained by reacting nicotinic or quinolinecarboxylic acids with (±)-3TC in the presence of DCC and HOBT. These derivatives were converted into their corresponding N-methylpyridinium and N-methyl quinolinium salts by treatment with MeI in acetone. Reduction of the latter with Na2S2O4 gave dihydropyridine and dihydroquinoline compounds. The N-4-trifluorotoluidinonicotinate derivative was obtained from the coupling of niflumic acid and (±)-3TC using BOP and DIEA. The anti-HIV-1 activities of seven derivatives were determined in MT-4 infected cell cultures. Of these compounds, the IC50 values ranged from 0.1-100 μM, while the IC50 for (±)-3TC was 0.1 μM. The anti-HBV activities were determined in infected duck hepatocytes. Anti-HBV activities of the (±)-3TC derivatives were half that of the parent drug (±)-3TC. The lipophilicity (partition coefficients) of these compounds were determined. The dihydroquinoline prodrugs had greater lipophilicity than the dihydropyridine analogues.
- Camplo,Charvet-Faury,Borel,Turin,Hantz,Trabaud,Niddam,Mourier,Graciet,Chermann,Kraus
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p. 539 - 546
(2007/10/03)
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- Synthesis and anti-human immunodeficiency virus type 1 activities of new peptido-nucleoside analogues
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In order to investigate whether antiproteasic peptides coupled to anti-reverse transcriptase nucleosides can act as inhibitors at the different stages of the HIV life cycle, various peptido-nucleosides were synthesized using methodologies involving (benzotriazol-1-yloxy)-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) as a coupling reagent between the N4-cytosinyl moiety and the peptide carboxy terminus. The anti-HIV-1 activity in MT4 cells of this new class of compounds and their anti-HIV protease activities were determined. Fourteen peptido-nucleosides have been synthesized and six act against both the HIV-protease and viral replication in vitro. Although the activity of the most potent compounds against HIV was found to be one order of magnitude lower than that of the parent nucleoside drug 2',3'-dideoxy-3'-thiacytidine, this new class of compound could be of biological interest. Indeed, since the in vitro half-lives (t( 1/2 )) of the hydrolysis of the most potent compounds in human plasma were found to be longer than 2.5 h, these analogues could reach the infected cells in their structural integrity. This observation does not exclude that these compounds may exert their antiviral effects as combined prodrugs through extracellular or intracellular hydrolysis.
- Camplo,Niddam,Barthelemy,Faury,Mourier,Simon,Charvet,Trabaud,Graciet,Chermann,Kraus
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p. 789 - 800
(2007/10/03)
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- Inhibition of human immunodeficiency virus type 1 replication by phosphonoformate- and phosphonoacetate-2',3'-dideoxy-3'-thiacytidine conjugates
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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 μM, while IC50 for BCH-189 in this system was 0.1 μM. 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 t( 1/2 ) 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.
- Charvet,Camplo,Faury,Graciet,Mourier,Chermann -,Kraus
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p. 2216 - 2223
(2007/10/02)
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