Subject: INFO: Conversion of 2',3'-dideoxyadenosine (ddA) and
2',3'-didehydro-2',3'-dideo

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.
Author
Balzarini J; Kruining J; Wedgwood O; Pannecouque C; Aquaro S; Perno CF;
Naesens L; Witvrouw M; Heijtink R; De Clercq E; McGuigan C
Address
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Source
FEBS Lett, 1997 Jun, 410:2-3, 324-8
Abstract
2',3'-Dideoxyadenosine (ddA), 2',3'-didehydro-2',3'-dideoxyadenosine (d4A) and
their lipophilic 5'-monophosphate triester (aryloxyphosphoramidate) pro{*filter*}
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 {*filter*} 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 {*filter*} 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 pro{*filter*} 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.
Language of Publication
English
Unique Identifier
97379333

MeSH Heading (Major)
Adenosine Monophosphate|*AA/CH/PD; Alanine|*AA/CH/PD; Antiviral Agents|CH/*PD;
Dideoxyadenosine|*AA/CH/PD; Hepatitis B Virus|*DE; HIV|*DE
MeSH Heading
Animal; Cell Line; Cells, Cultured; Human; Leukocytes, Mononuclear|CY;
Macrophages|CY; Molecular Structure; Moloney Sarcoma Virus|DE; SIV|DE;
Transfection; Tumor Cells, Cultured

Publication Type - JOURNAL ARTICLE - ISSN - 0014-5793 - Country of Publication
- NETHERLANDS

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