Synthesis of the 2-Chloro Analogues of 3'-Deoxyadenosine, 2',3'-Dideoxyadenosine, and 2',3'-Didehydro-2',3'-dideoxyadenosine as Potential Antiviral Agents

Article abstract of DOI:10.1021/jm00125a031

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.