title: Synthesis and biological evaluation of 1,1-difluoro-2-(tetrahydro-3-furanyl)ethylphosphonic acids possessing a N9-purinylmethyl functional group at the ring. a new class of inhibitors for purine nucleoside phosphorylases.
abstract: 1,1-Difluoro-2-(tetrahydro-3-furanyl)ethylphosphonic acids cis-3 and trans-3 possessing a N9-purinylmethyl functionality at the ring were synthesized and tested as "multi-substrate analogue" inhibitors for purine nucleoside phosphorylases. Radical cyclization of allyic alpha,alpha-difluorophosphonate (E)-7 was applied to construct the alpha,alpha-difluorophosphonate-functionalized tetrahydrofuranyl moiety. The IC50 values of cis-3 and trans-3 for human erythrocyte PNP-catalyzed phosphorylation of inosine were determined to be 88 and 320 nM, respectively. The stereochemistry of the inhibitors was found to affect significantly the inhibitory potency.
authors.affiliation: School of Pharmacy, Tokyo University of Pharmacy & Life Science, Hachioji, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yokomatsu
authors.forename: Y
authors.initials: Y
authors.lastname: Hayakawa
authors.forename: K
authors.initials: K
authors.lastname: Suemune
authors.forename: T
authors.initials: T
authors.lastname: Kihara
authors.forename: S
authors.initials: S
authors.lastname: Soeda
authors.forename: H
authors.initials: H
authors.lastname: Shimeno
authors.forename: S
authors.initials: S
authors.lastname: Shibuya
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D004912:Erythrocytes / Q000201:enzymology; D017611:Fluorine Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D005663:Furans / Q000138:chemical synthesis* / Q000494:pharmacology; D006093:Gram-Positive Asporogenous Rods / Q000201:enzymology; D006801:Humans; D007288:Inosine / Q000378:metabolism; D015394:Molecular Structure; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000494:pharmacology; D010766:Phosphorylation; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D011687:Purines / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: C401622:1,1-difluoro-2-(tetrahydro-3-furanyl)ethylphosphonic acid; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D017611:Fluorine Compounds; D005663:Furans; D063065:Organophosphonates; D011687:Purines; D007288:Inosine; D011683:Purine-Nucleoside Phosphorylase