title: Antiretrovirus activity of a novel class of acyclic pyrimidine nucleoside phosphonates.
abstract: A novel class of acyclic nucleoside phosphonates has been discovered in which the base consists of a pyrimidine preferably containing an amino group at C-2 and C-4 and a 2-(phosphonomethoxy)ethoxy (PMEO) or a 2-(phosphonomethoxy)propoxy (PMPO) group at C-6. The 6-PMEO 2,4-diaminopyrimidine (compound 1) and 6-PMPO 2,4-diaminopyrimidine (compound 11) derivatives showed potent activity against human immunodeficiency virus (HIV) in the laboratory (i.e., CEM and MT-4 cells) and in primary (i.e., peripheral blood lymphocyte and monocyte/macrophage) cell cultures and pronounced activity against Moloney murine sarcoma virus in newborn NMRI mice. Their in vitro and in vivo antiretroviral activity was comparable to that of reference compounds 9-[(2-phosphonomethoxy)ethyl]adenine (adefovir) and (R)-9-[(2-phosphonomethoxy)-propyl]adenine (tenofovir), and the enantiospecificity of (R)- and (S)-PMPO pyrimidine derivatives as regards their antiretroviral activity was identical to that of the classical (R)- and (S)-9-(2-phosphonomethoxy)propyl purine derivatives. The prototype PMEO and PMPO pyrimidine analogues were relatively nontoxic in cell culture and did not markedly interfere with host cell macromolecular (i.e., DNA, RNA, or protein) synthesis. Compounds 1 and 11 should be considered attractive novel pyrimidine nucleotide phosphonate analogues to be further pursued for their potential as antiretroviral agents in the clinical setting.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium. jan.balzarini@rega.kuleuven.ac.be
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: C
authors.initials: C
authors.lastname: Pannecouque
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: S
authors.initials: S
authors.lastname: Aquaro
authors.forename: C-F
authors.initials: CF
authors.lastname: Perno
authors.forename: H
authors.initials: H
authors.lastname: Egberink
authors.forename: A
authors.initials: A
authors.lastname: Holý
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D024882:Drug Resistance, Viral; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051379:Mice; D009154:Mutation; D063065:Organophosphonates / Q000494:pharmacology; D011742:Pyrimidine Nucleotides / Q000494:pharmacology*; D014412:Tumor Virus Infections / Q000517:prevention & control
chemical_list: D019380:Anti-HIV Agents; D063065:Organophosphonates; D011742:Pyrimidine Nucleotides