Synthesis of the 2-chloro analogues of 3'-deoxyadenosine, 2',3'-dideoxyadenosine, and 2',3'-didehydro-2',3'-dideoxyadenosine as potential antiviral agents.

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 synthesized 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 microM, 2-ClddAdo inhibited reverse transcriptase (RT) production by 97%, while 2',3'-dideoxyadenosine (ddAdo) gave greater than 99% inhibition. In growth assays against uninfected T4+ cells, however, 100 microM 2-ClddAdo gave 23% inhibition while 100 microM ddAdo was nontoxic. At a nontoxic concentration of 20 microM, RT production was 75% inhibited by ddAdo but only 43% 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 microM, where there was only 75% inhibition of RT production. Because of the decreased therapeutic index of 2-ClddeAdo relative to 2-ClddAdo and ddAdo, greater than 90% inhibition of viral protein synthesis at a noncytotoxic concentration could not be achieved. In growth assays with cultured human T and B lymphocytes, 100 microM 2-chlorocordycepin gave 60-70% growth inhibition, while the IC50 against mouse fibroblasts was only 30 microM. The high cytotoxicity of 2-chlorocordycepin precluded consideration of this compound as an antiviral agent.