title: Intracellular metabolism of the new antiviral compound 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine.
abstract: 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine [HPMP-5-azaC], the 5-azacytosine analogue of cidofovir (HPMPC), represents a new acyclic nucleoside phosphonate with pronounced activity against DNA viruses, and a selectivity index superior to that of cidofovir. Here we investigated the intracellular metabolic pathway of [6-(3)H]-HPMP-5-azaC. By comparing the metabolism in mouse lymphosarcoma S49-wild type (S49-WT) and mutant cells deficient for dCMP deaminase, we identified the mono- and diphosphate metabolites generated from HPMP-5-azaC and its deaminated product HPMP-5-azaU. In human lung carcinoma A549 cells, the relative formation of the deaminated metabolites was only 6%, implying that deamination plays a minor role in the overall metabolism of HPMP-5-azaC. The diphosphorylated metabolite of HPMP-5-azaC accounted for 60% of the total radioactivity, and reached intracellular levels which were 60-fold higher in absolute value than the corresponding diphosphate levels obtained with cidofovir. Consequently to its increased activation, HPMP-5-azaC showed about 45-fold higher incorporation into cellular DNA than cidofovir. Herpes-, pox- or adenovirus infection had no marked influence on the metabolism of HPMP-5-azaC. The HPMP-5-azaC-diphosphate metabolite was shown to have long intracellular stability (half-life: 63h), suggesting that infrequent administration of HPMP-5-azaC should be possible. HPMP-5-azaC represents a new acyclic nucleoside phosphonate compound with promising anti-DNA virus activity and a favorable metabolic profile that is characterized by low sensitivity to catabolic deamination and a high rate of phosphorylation and DNA incorporation.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium. lieve.naesens@rega.kuleuven.be
authors.forename: Lieve
authors.initials: L
authors.lastname: Naesens
authors.forename: Graciela
authors.initials: G
authors.lastname: Andrei
authors.forename: Ivan
authors.initials: I
authors.lastname: Votruba
authors.forename: Marcela
authors.initials: M
authors.lastname: Krecmerová
authors.forename: Antonín
authors.initials: A
authors.lastname: Holý
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Robert
authors.initials: R
authors.lastname: Snoeck
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism*; D045744:Cell Line, Tumor; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004261:DNA Replication; D004267:DNA Viruses / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D004355:Drug Stability; D005260:Female; D018259:Herpesvirus 1, Human / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms; D008228:Lymphoma, Non-Hodgkin; D051379:Mice; D008815:Mice, Inbred Strains; D063065:Organophosphonates / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; D004273:DNA, Neoplasm; D063065:Organophosphonates; C039854:5-azacytosine; D003596:Cytosine; D000077404:Cidofovir