title: Synthesis and biological evaluation of 9-(5',5'-difluoro-5'-phosphonopentyl)guanine derivatives for PNP-inhibitors.
abstract: 9-(5',5'-Difluoro-5'-phosphonopentyl)guanine (DFPP-G) and its hypoxanthine analogue (DFPP-H) were modified by introducing a methyl group to all possible positions of the linker connecting a purine and difluoromethylenephosphonic acid moiety to evaluate the effects of the methyl group on inhibition against purine nucleoside phosphorylase. The methyl group on the linker affected the inhibition in a positional-dependent manner. Inhibitory potency of alpha-methyl and beta-methyl-substituted analogues of DFPP-H increased by about 600- to 1000-fold upon converting to cyclopropane nucleotide analogue (+/-)-4.
authors.affiliation: School of Pharmacy, Tokyo University of Pharmacy and Life Science, Japan.
authors.forename: Sadao
authors.initials: S
authors.lastname: Hikishima
authors.forename: Machiko
authors.initials: M
authors.lastname: Isobe
authors.forename: Satoru
authors.initials: S
authors.lastname: Koyanagi
authors.forename: Shinji
authors.initials: S
authors.lastname: Soeda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimeno
authors.forename: Shiroshi
authors.initials: S
authors.lastname: Shibuya
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yokomatsu
mesh_terms: D004002:Clodronic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D003521:Cyclopropanes / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D005459:Fluorides / Q000737:chemistry* / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D007042:Hypoxanthines / Q000138:chemical synthesis* / Q000494:pharmacology; D007700:Kinetics; D008745:Methylation; D010756:Phosphoric Acids / Q000737:chemistry* / Q000494:pharmacology; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: C509941:9-(5',5'-difluoro-5'-phosphonopentyl)guanine; D003521:Cyclopropanes; D004791:Enzyme Inhibitors; D007042:Hypoxanthines; D010756:Phosphoric Acids; D004002:Clodronic Acid; C041121:difluoromethylene diphosphonate; C081381:difluorophosphoric acid; D006147:Guanine; D011683:Purine-Nucleoside Phosphorylase; D005459:Fluorides