CONVERSION OF 2',3'-DIDEOXYADENOSINE (DDA) AND 2',3'-DIDEHYDRO-2',3'-DIDEOXYADENOSINE (D4A) TO THEIR CORRESPONDING ARYLOXYPHOSPHORAMIDATE DERIVATIVES MARKEDLY POTENTIATES THEIR ACTIVITY AGAINST HUMAN-IMMUNODEFICIENCY-VIRUS AND HEPATITIS-B VIRUS

2',3'-Dideoxyadenosine (ddA), 2',3'-didehydro-2',3'-dideoxyadenosine ( d4A) and their lipophilic 5'-monophosphate triester (aryloxyphosphoram idate) prodrugs were evaluated for their anti-retrovirus and anti-hepa titis B virus activity in various cell culture models, The aryloxyphos phoramidate derivatives of ddA (Cf 1093) and d4A (Cf 1001) showed mark edly superior (100-1000-fold) efficacies than the parent drugs against human immunodeficiency virus type 1 (HIV-1), HIV-2, simian immunodefi ciency virus (SIV), Moloney murine sarcoma virus (MSV) and human hepat itis B virus (HBV) replication regardless of the cell type in which th e virus replication was studied (i.e., human T-lymphocyte GEM, MT-4, M olt/4 and C8166 cells, peripheral blood lymphocytes (PBL), monocyte/ma crophages (M/M), murine embryo fibroblasts and human hepatocyte cells) , Also the selectivity index (ratio of cytotoxic concentration/antivir ally effective concentration) of both aryloxyphosphoramidate prodrugs was markedly increased, In particular the d4A prodrug Cf 1001 showed a selectivity index of 300-3000 as compared with 2-3 for the parental d 4A in established laboratory cell lines, Also Cf 1001 had a selectivit y index of 400-650 in HIV-l-infected PBL and M/M, respectively, Both C f 1001 and Cf 1093 were equally efficient as 3TC (lamivudine) in inhib iting HBV replication in hepatocytes, and rank among the most potent H IV and HBV inhibitors reported so far in cell culture. (C) 1997 Federa tion of European Biochemical Societies.