title: [[(Guaninylalkyl)phosphinico]methyl]phosphonic acids. Multisubstrate analogue inhibitors of human erythrocyte purine nucleoside phosphorylase.
abstract: A series of [[(guaninylalkyl)phosphinico]methyl]phosphonic acids, 2, was synthesized and tested as inhibitors of human erythrocyte purine nucleoside phosphorylase (PNPase). The target (phosphinicomethyl)phosphonic acids 2 were synthesized in six or seven steps from alkenylphosphonates 4. The latter were converted to the intermediate alkylmesylates 9 in a series of steps that included (1) conversion of the diethyl phosphonates 4 to the (phosphinoylmethyl)-phosphonates 7 and (2) conversion of the terminal double bond of [(alkenylphosphinoyl)methyl]-phosphonates 7 to the alkylmesylates 9. The pure 9-isomers 2 were obtained by alkylation of 2-amino-6-(2-methoxyethoxy)-9H-purine with alkylmesylates 9 followed by hydrolysis of the protecting groups with concentrated hydrochloric acid and ion exchange chromatography to give 2 as hydrated ammonium salts. The most potent inhibitor of human erythrocyte PNPase, [[[5-(2-amino-1,6-dihydro-6-oxo-9H-purin-9- yl)pentyl]phosphinico]methyl]phosphonic acid (2b), was a multisubstrate analogue inhibitor with a Ki' of 3.1 nM. Optimum PNPase inhibitory activity required the presence of zinc ions in the assay medium. These potent inhibitors of PNPase exhibited only weak activity against human leukemic T-cells in vitro.
authors.affiliation: Division of Organic Chemistry, Burroughs Wellcome Co., Research Triangle Park, North Carolina 27709.
authors.forename: J L
authors.initials: JL
authors.lastname: Kelley
authors.forename: E W
authors.initials: EW
authors.lastname: McLean
authors.forename: R C
authors.initials: RC
authors.lastname: Crouch
authors.forename: D R
authors.initials: DR
authors.lastname: Averett
authors.forename: J V
authors.initials: JV
authors.lastname: Tuttle
mesh_terms: D001667:Binding, Competitive; D002455:Cell Division / Q000187:drug effects; D003849:Deoxyguanosine / Q000494:pharmacology; D004357:Drug Synergism; D004912:Erythrocytes / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D007288:Inosine / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000494:pharmacology*; D010710:Phosphates / Q000378:metabolism / Q000494:pharmacology; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors* / Q000097:blood*; D013379:Substrate Specificity; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D015032:Zinc / Q000494:pharmacology
chemical_list: D063065:Organophosphonates; D010710:Phosphates; D007288:Inosine; D011683:Purine-Nucleoside Phosphorylase; D003849:Deoxyguanosine; D015032:Zinc