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In vitro anti-human immunodeficiency virus and anti-hepatitis B virus activities and pharmacokinetic properties of heterodinucleoside phosphates containing AZT or ddC - Zurich Open Repository and Archive


Peghini, P A; Zahner, R; Kuster, H; Schott, H; Schwendener, R (1998). In vitro anti-human immunodeficiency virus and anti-hepatitis B virus activities and pharmacokinetic properties of heterodinucleoside phosphates containing AZT or ddC. Antiviral Chemistry & Chemotherapy, 9(2):117-126.

Abstract

In vitro activities, against human immunodeficiency virus (HIV)- and hepatitis B virus (HBV)-infected cells, of four amphiphilic heterodinucleoside phosphates containing 3'-azido-2',3'-dideoxythymidine (AZT) or 2',3'-dideoxycytidine (ddC) as antiviral monomers were evaluated. The four compounds were N4-hexadecyl-2'-deoxyribocytidylyl-(3'-->5')-3'-azido-2',3'-deoxyt hymidine (N4-hxddC-AZT), N4-palmitoyl-2'-deoxyribocytidylyl-(3'-->5')-3'-azido-2',3'-deoxyt hymidine (N4-pamdC-AZT), N4-hexadecyl-2'-deoxycytidylyl-(3'-->5')-2',3'-dideoxycytidine (N4-hxddC-ddC) and 2'-deoxythymidylyl-(3'-->5')-N4-palmitoyl-2',3'-dideoxycytidine (dT-N4-pamddC). All four dimers were active against HIV, dT-N4-pamddC being the most active and least toxic. dT-N4-pamddC also exhibited strong antiviral effects against a panel of eight AZT-resistant HIV strains. The ddC-containing heterodimers incorporated in liposomes additionally inhibited HBV replication by 50-80% in HepG2 2.2.15 cells. AZT and the AZT-containing dimers were ineffective. Differences in pharmacokinetic properties between the antiviral monomers and the heterodimers were evaluated using liposomal formulations of 3H-labelled AZT heterodimers as model compounds. The cellular distribution of AZT in H9 cells was predominantly cytoplasmic, whereas the amphiphilic dimers were distributed more evenly throughout the cytoplasm, nuclear membranes and microsomes. Blood levels of the heterodimers decreased at a rate two- to threefold slower than AZT and the areas-under-the-curves were five- to sevenfold higher for N4-pamdC-AZT and N4-hxddC-AZT, respectively. Compared to AZT, the peak levels of the dimers were three to four times higher in blood and five to six times higher in the liver. Analysis of blood samples showed that 34% of N4-pamdC-AZT was metabolized to AZT, whereas only 9% of N4-hxddC-AZT released AZT. Considering the antiviral potency and the favourable pharmacokinetic properties of the heterodimers, these compounds merit further exploration as antiviral drugs.

Abstract

In vitro activities, against human immunodeficiency virus (HIV)- and hepatitis B virus (HBV)-infected cells, of four amphiphilic heterodinucleoside phosphates containing 3'-azido-2',3'-dideoxythymidine (AZT) or 2',3'-dideoxycytidine (ddC) as antiviral monomers were evaluated. The four compounds were N4-hexadecyl-2'-deoxyribocytidylyl-(3'-->5')-3'-azido-2',3'-deoxyt hymidine (N4-hxddC-AZT), N4-palmitoyl-2'-deoxyribocytidylyl-(3'-->5')-3'-azido-2',3'-deoxyt hymidine (N4-pamdC-AZT), N4-hexadecyl-2'-deoxycytidylyl-(3'-->5')-2',3'-dideoxycytidine (N4-hxddC-ddC) and 2'-deoxythymidylyl-(3'-->5')-N4-palmitoyl-2',3'-dideoxycytidine (dT-N4-pamddC). All four dimers were active against HIV, dT-N4-pamddC being the most active and least toxic. dT-N4-pamddC also exhibited strong antiviral effects against a panel of eight AZT-resistant HIV strains. The ddC-containing heterodimers incorporated in liposomes additionally inhibited HBV replication by 50-80% in HepG2 2.2.15 cells. AZT and the AZT-containing dimers were ineffective. Differences in pharmacokinetic properties between the antiviral monomers and the heterodimers were evaluated using liposomal formulations of 3H-labelled AZT heterodimers as model compounds. The cellular distribution of AZT in H9 cells was predominantly cytoplasmic, whereas the amphiphilic dimers were distributed more evenly throughout the cytoplasm, nuclear membranes and microsomes. Blood levels of the heterodimers decreased at a rate two- to threefold slower than AZT and the areas-under-the-curves were five- to sevenfold higher for N4-pamdC-AZT and N4-hxddC-AZT, respectively. Compared to AZT, the peak levels of the dimers were three to four times higher in blood and five to six times higher in the liver. Analysis of blood samples showed that 34% of N4-pamdC-AZT was metabolized to AZT, whereas only 9% of N4-hxddC-AZT released AZT. Considering the antiviral potency and the favourable pharmacokinetic properties of the heterodimers, these compounds merit further exploration as antiviral drugs.

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12 citations in Web of Science®
11 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:1998
Deposited On:29 Jul 2009 13:12
Last Modified:05 Apr 2016 13:18
Publisher:International Medical Press
ISSN:0956-3202
Publisher DOI:https://doi.org/10.1177/095632029800900203
PubMed ID:9875383

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