title: Phosphonylmethoxyethyl purine derivatives, a new class of anti-human immunodeficiency virus agents.
abstract: A study of the structure-activity relationship of a series of newly synthesized phosphonylmethoxyalkyl purine and pyrimidine derivatives revealed that several adenine derivatives substituted at the N9 position by a 2-phosphonylmethoxyethyl (PME) group inhibited human immunodeficiency virus (HIV)-induced cytopathogenicity and HIV antigen expression in vitro at concentrations significantly below the toxicity threshold for the host cells. In terms of anti-HIV potency in MT-4 cells, the PME 2,6-diaminopurine derivative (50% effective dose [ED50], 1 microM) ranked first, followed by the PME adenine derivative (ED50, 2 microM [MT-4]) and the PME 2-monoaminopurine derivative (ED50, 45 microM). Antiretroviral activity was also demonstrated in ATH8 and H9 cells, which were de novo infected with HIV, and extended to C3H mouse fibroblasts infected with Moloney murine sarcoma virus. Unlike 2',3'-dideoxyadenosine, these compounds were not found to be degraded by deaminases derived from bovine intestine.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: Pauwels
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: D
authors.initials: D
authors.lastname: Schols
authors.forename: M
authors.initials: M
authors.lastname: Baba
authors.forename: J
authors.initials: J
authors.lastname: Desmyter
authors.forename: I
authors.initials: I
authors.lastname: Rosenberg
authors.forename: A
authors.initials: A
authors.lastname: Holy
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D003588:Cytopathogenic Effect, Viral; D006678:HIV / Q000187:drug effects*; D006681:HLA-D Antigens / Q000032:analysis; D006801:Humans; D006868:Hydrolysis; D051379:Mice; D008809:Mice, Inbred C3H; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D011687:Purines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D009053:Sarcoma Viruses, Murine / Q000187:drug effects; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D006681:HLA-D Antigens; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D011687:Purines; D011743:Pyrimidines; C050127:9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine; D000225:Adenine