114849-58-0Relevant articles and documents
Azido/Tetrazole Tautomerism in 2-Azidoadenine β -D-Pentofuranonucleoside Derivatives
Lioux, Thierry,Gosselin, Gilles,Mathe, Christophe
, p. 3997 - 4002 (2007/10/03)
The β-D-ribofuranoside derivative of 2-azidoadenine and its 2′-deoxy-, 2′,3′-dideoxy- and 2′,3′ -dideoxy-2′,3′-didehydro counterparts have been synthesized. All these compounds were obtained through the preparation of their 2-chloro precursors. These were converted into their 2-hydrazino derivatives, which upon treatment with sodium nitrate in acid medium gave the target nucleosides. The azido/tetrazole tautomerism observed in such nucleoside analogues was studied in detail. The compounds were also tested for their activity against HIV and HBV, but did not show significant antiviral effects. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.
Method for treating HBV infections with L-2',3'-didehydro-dideoxy-5-fluorocytidine
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, (2008/06/13)
The present invention relates to the surprising discovery that certain dideoxynucleoside analogs which contain a dideoxy ribofuranosyl moiety having an L-configuration (as opposed to the naturally occurring D- configuration) exhibit unexpected activity against Hepatitis B virus (HBV). In particular, the compounds according to the present invention show potent inhibition of the replication of the virus in combination with very low toxicity to the host cells (i.e., animal or human tissue). Compounds according to the present invention exhibit primary utility as agents for inhibiting the growth or replication of HBV, HIV and other retroviruses, most preferably HBV.
Synthesis of the 2-Chloro Analogues of 3'-Deoxyadenosine, 2',3'-Dideoxyadenosine, and 2',3'-Didehydro-2',3'-dideoxyadenosine as Potential Antiviral Agents
Rosowsky, Andre,Solan, Vishnu C.,Sodroski, Joseph G.,Ruprecht, Ruth M.
, p. 1135 - 1140 (2007/10/02)
2-Chloro-3'-deoxyadenosine (2-chlorocordycepin), 2-chloro-2',3'-dideoxyadenosine (2-ClddAdo), and 2-chloro-2',3'-didehydro-2',3'-dideoxyadenosine (2-ClddeAdo) were synthsized from 2-chloroadenosine (2-ClAdo) as candidate antiretroviral agents on the basis that 2-chloro substitution would prevent enzymatic deamination and increase efficacy relative to 2',3'-dideoxyadenosine (ddAdo).Reduction of 2-chloro-5'-(4,4'-dimethoxytrityl)-2',3'-O-thiocarbonyladenosine with n-Bu3SnH, followed by detritylation with AcOH, unexpectedly gave a mixture of 2-chlorocordycepin and 2-chloroadenine.Treatment of the crude n-Bu3SnH reduction product with 1,1'- thiocarbonyldiimidazole, followed by another cycle of n-Bu3SnH reduction and detritylation with silica gel afforded 2-ClddAdo and a byproduct identified as 2-chloro-2',3'-O-methyleneadenosine.Treatment of 2-chloro-5'-O-(4,4'-dimethoxytrityl)-2',3'-thiocarbonyladenosine with 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine followed by silica gel detritylation afforded 2-ClddeAdo. 2-ClddAdo and 2-ClddeAdo were tested for activity against human immunodeficiency virus (HIV) in a cultured human T4+ lymphocyte cell line.At a concentration of 100 μM, 2-ClddAdo inhibited reverse transcriptase (RT) production by 97percent, while 2',3'-dideoxyadenosine (ddAdo) gave >99percent inhibition.In growth assays against uninfected T4+ cells, however, 100 μM 2-ClddAdo gave 23percent inhibition while 100 μM ddAdo was nontoxic.At a nontoxic concentration of 20 μM, RT production was 75percent inhibited by ddAdo but only 43percent inhibited by 2-ClddAdo.Thus, a 2-chloro substituent increased host cell toxicity but decreased antiretroviral activity.The unsaturated analogue 2-ClddeAdo was more cytotoxic than 2-ClddAdo, and antiviral effects could not be measured above 20 μM, where was only 75percent inhibition of RT production.Because of the decreased therapeutic index of 2-ClddeAdo relative to 2-ClddAdo and ddAdo, >90percent inhibition of viral protein synthesis at a nontoxic concentration could not be achieved.In growth assays with cultured human and B lymphocytes, 100 μM 2-chlorocordycepin gave 60-70percent growth inhibition, while the IC50 against mouse fibroblasts was only 30 μM.The high cytotoxicity of 2-chlorocordycepin precluded consideration of this compound as an antiviral agent.