title: 9-[(Phosphonoalkyl)benzyl]guanines. Multisubstrate analogue inhibitors of human erythrocyte purine nucleoside phosphorylase.
abstract: A series of 9-[(phosphonoalkyl)benzyl]guanines was synthesized and tested for inhibition of human erythrocyte purine nucleoside phosphorylase (PNPase). Inhibitors of PNPase should be T-cell selective, immunosuppressive agents with potential clinical utility in the treatment of a wide variety of disorders in which T-lymphocytes are pathogenic. An initial set of six analogues of the weak PNPase inhibitor 9-benzylguanine (2) contained a phosphonic acid group linked to the ortho, meta, or para position of the aryl moiety via two- or three-atom spacers. These compounds allowed us to probe for a favorable interaction with the phosphate-binding domain. Several additional meta phosphonoalkyl substituents were examined in an effort to optimize the spacer. The two most potent compounds, [[3-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methyl] benzyl]oxy]-methylphosphonic acid (3f) and [[3-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-methyl)methyl] benzyl]-thio]methylphosphonic acid (3j), were inhibitors of PNPase with Ki's of 5.8 and 1.1 nM, respectively. These inhibitors displayed competitive kinetics with respect to inosine and inorganic phosphate, which showed that these compounds possess binding determinants for both the purine- and phosphate-binding domains of the enzyme, characteristics that are consistent with 3f and 3j being multisubstrate analogue inhibitors of PNPase. The potency of 9-benzylguanine (2) was enhanced more than 6000-fold by linking a phosphonic acid residue with a (methylthio)methyl spacer to the meta position of 2 to give 3j, which illustrates the potent enzyme inhibitory properties available to multisubstrate analogue inhibitors.
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: J A
authors.initials: JA
authors.lastname: Linn
authors.forename: E W
authors.initials: EW
authors.lastname: McLean
authors.forename: J V
authors.initials: JV
authors.lastname: Tuttle
mesh_terms: D001593:Benzyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D004912:Erythrocytes / Q000201:enzymology*; D006147:Guanine / Q000031:analogs & derivatives*; D006801:Humans; D007700:Kinetics; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000494:pharmacology*; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D001593:Benzyl Compounds; D063065:Organophosphonates; D006147:Guanine; D011683:Purine-Nucleoside Phosphorylase