145985-97-3Relevant academic research and scientific papers
Synthesis and biological evaluation of 1,3-oxathiolane 5-azapyrimidine, 6-azapyrimidine, and fluorosubstituted 3-deazapyrimidine nucleosides
Liu, Mao-Chin,Luo, Mei-Zhen,Mozdziesz, Diane E.,Lin, Tai-Shun,Dutschman, Ginger E.,Gullen, Elizabeth A.,Cheng, Yung-Chi,Sartorelli, Alan C.
, p. 603 - 618 (2007/10/03)
(2R,5S)-5-Amino-2-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,2,4- triazine-3(2H)-one (8) and (2R,5R)-5-amino-2-[2-(hydroxymethyl)-1,3- oxathiolan-5-yl]-1,2,4-triazine-3(2H)-one (9) have been synthesized via a multi-step procedure from 6-azauridine. (2R,5S)-4-Amino-1-[2-(hydroxymethyl)- 1, 3-oxathiolan-5-yl]-1,3,5-triazine-2(1H)-one (11) and (2R,5R)-4-amino-1-[2- (hydroxymethyl)-1,3-oxathiolan-5-yl]-1,3,5-triazine-2(1H)-one (12), and the fluorosubstituted 3-deazanucleosides (19-24) have been synthesized by the transglycosylation of (2R,5S)-1-{2-[[(tert-butyldiphenylsilyl) oxy]methyl]- 1,3-oxathiolan-5-yl}cytosine (2) with silylated 5-azacytosine and the corresponding silylated fluorosubstituted 3-deazacytosines, respectively, in the presence of trimethylsilyl trifluoromethanesulfonate as the catalyst in anhydrous dichloroethane, followed by deprotection of the blocking groups. These compounds were tested in vitro for cytotoxicity against L1210, B16F10, and CCRF-CEM tumor cell lines and for antiviral activity against HIV-1 and HBV.
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
Camplo,Charvet-Faury,Borel,Turin,Hantz,Trabaud,Niddam,Mourier,Graciet,Chermann,Kraus
, p. 539 - 546 (2007/10/03)
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.
Synthesis and anti-human immunodeficiency virus type 1 activities of new peptido-nucleoside analogues
Camplo,Niddam,Barthelemy,Faury,Mourier,Simon,Charvet,Trabaud,Graciet,Chermann,Kraus
, p. 789 - 800 (2007/10/03)
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.
Inhibition of human immunodeficiency virus type 1 replication by phosphonoformate- and phosphonoacetate-2',3'-dideoxy-3'-thiacytidine conjugates
Charvet,Camplo,Faury,Graciet,Mourier,Chermann -,Kraus
, p. 2216 - 2223 (2007/10/02)
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.
Asymmetric Synthesis and Biological Evaluation of β-L-(2R,5S)- and α-L-(2R,5R)-1,3-Oxathiolane-Pyrimidine and -Purine Nucleosides as Potential Anti-HIV Agents
Jeong, Lak S.,Shinazi, Raymond F.,Beach, J. Warren,Kim, Hea O.,Nampalli, Satyanarayana,et al.
, p. 181 - 195 (2007/10/02)
In order to study the structure-acivity relationships of L-oxathiolanyl nucleosides as potential anti-HIV agents, a series of enantiomerically pure L-oxathiolanyl pyrimidine and purine nucleosides were synthesized and evaluated for anti-HIV-1 activity in human peripheral blood mononuclear (PBM) cells.The key intermediate 8 was synthesized starting from L-gulose via 1,6-thiaanhydro-L-gulopyranose.The acetate 8 was condensed with thymine, 5-substituted uracils and cytosines, 6-chloropurine, and 6-chloro-2-fluoropurine to give pyrimidine and purine nucleosides.Upon evaluation of these final nucleosides, the 5-fluorocytosine derivative 51 was found to be the most potent compound among those tested.In the case of 5-substituted cytosine analogues, the antiviral potency was found to be in the following decreasing order: cytosine (β-isomer) > 5-iodocytosine (β-isomer) > 5-fluorocytosine (α-isomer) > 5-methylcytosine (α-isomer) > 5-methylcytosine (β-isomer) > 5-bromocytosine (β-isomer) > 5-chlorocytosine (β-isomer).Among the thymine, uracil, and 5-substituted uracil derivatives, thymine (α-isomer) and uracil (β-isomer) derivatives exhibited moderate anti-HIV activity.In the purine series, the antiviral potency is found to be in the following decreasing order: adenine (β-isomer) > 6-chloropurine (β-isomer) > 6-chloropurine (α-isomer) > 2-NH2-6-Cl-purine (β-isomer) > guanine (β-isomer) > N6-methyladenine (α-isomer) > N6-methyladenine (β-isomer).The cytotoxicity was also determined in human PBM cells as well as Vero cells.None of the synthesized nucleosides was toxic up to 100 μ in PBM cells.
