title: 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.
abstract: 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.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: J
authors.initials: J
authors.lastname: Kruining
authors.forename: O
authors.initials: O
authors.lastname: Wedgwood
authors.forename: C
authors.initials: C
authors.lastname: Pannecouque
authors.forename: S
authors.initials: S
authors.lastname: Aquaro
authors.forename: C F
authors.initials: CF
authors.lastname: Perno
authors.forename: L
authors.initials: L
authors.lastname: Naesens
authors.forename: M
authors.initials: M
authors.lastname: Witvrouw
authors.forename: R
authors.initials: R
authors.lastname: Heijtink
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: C
authors.initials: C
authors.lastname: McGuigan
mesh_terms: D000249:Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000409:Alanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D016048:Dideoxyadenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006678:HIV / Q000187:drug effects*; D006515:Hepatitis B virus / Q000187:drug effects*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008264:Macrophages / Q000166:cytology; D015394:Molecular Structure; D008980:Moloney murine sarcoma virus / Q000187:drug effects; D015302:Simian Immunodeficiency Virus / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D019380:Anti-HIV Agents; D000998:Antiviral Agents; C107505:Cf 1001; C107506:Cf 1093; D000249:Adenosine Monophosphate; D016048:Dideoxyadenosine; C075923:2'3'-didehydro-2'3'-dideoxyadenosine; C021008:2',5'-dideoxyadenosine; D000409:Alanine