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

FEBS Letters

Heijtink, Rudolf⁴  De Clercq, Erik³  Pannecouque, Christophe³  Wedgwood, Orson¹  McGuigan, Christopher¹  Kruining, Johannes⁴  Naesens, Lieve³  Balzarini, Jan³  Aquaro, Stefano²  Perno, Carlo-Federico²  Witvrouw, Myriam³ 

[1] Welsh School of Pharmacy, University of Wales, Cardiff CF1 3XF, UK;University of Rome ‘Tor Vergata’, 00135 Rome, Italy;Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium;Erasmus University Rotterdam, 3000 DR Rotterdam, Netherlands

关键词: HIV;    HBV;    Reverse transcriptase;    Nucleoside analogues;    AIDS;    Hepatitis;    Prodrugs;   

DOI  :  10.1016/S0014-5793(97)00616-9

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

2′,3′-Dideoxyadenosine (ddA), 2′,3′-didehydro-2′,3′-dideoxyadenosine (d4A) and their lipophilic 5′-monophosphate triester (aryloxyphosphoramidate) prodrugs were evaluated for their anti-retrovirus and anti-hepatitis B virus activity in various cell culture models. The aryloxyphosphoramidate derivatives of ddA (Cf 1093) and d4A (Cf 1001) showed markedly superior (100–1000-fold) efficacies than the parent drugs against human immunodeficiency virus type 1 (HIV-1), HIV-2, simian immunodeficiency virus (SIV), Moloney murine sarcoma virus (MSV) and human hepatitis B virus (HBV) replication regardless of the cell type in which the virus replication was studied (i.e., human T-lymphocyte CEM, MT-4, Molt/4 and C8166 cells, peripheral blood lymphocytes (PBL), monocyte/macrophages (M/M), murine embryo fibroblasts and human hepatocyte cells). Also the selectivity index (ratio of cytotoxic concentration/antivirally 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 d4A in established laboratory cell lines. Also Cf 1001 had a selectivity index of 400–650 in HIV-1-infected PBL and M/M, respectively. Both Cf 1001 and Cf 1093 were equally efficient as 3TC (lamivudine) in inhibiting HBV replication in hepatocytes, and rank among the most potent HIV and HBV inhibitors reported so far in cell culture.

【 授权许可】

Unknown