title: Simplified analogues of immucillin-G retain potent human purine nucleoside phosphorylase inhibitory activity.
abstract: A set of deazaguanine derivatives 1-3 targeting human purine nucleoside phosphorylase (hPNP) have been designed and synthesized. The new compounds are characterized by the presence of a structurally simplified "azasugar" motif to be more easily accessible by chemical synthesis than previous inhibitors. In the enzymatic assays, some of the new derivatives proved to be able to inhibit hPNP at low nanomolar concentration, thereby showing the same inhibitory potency in vitro as immucillin-H (IMH). Molecular docking experiments revealed a binding mode to hPNP essentially identical to that of IMH. As a result, the lower in vivo activity exhibited by 1d, compared with that exhibited by IMH, might be ascribed to differences in the pharmacokinetic, rather than pharmacodynamic, profile between these compounds. Derivatives 1a, 1d, and 2c emerged as the most active compounds within this new set and may represent interesting leads in the search for novel hPNP inhibitors.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. De Gasperi 2, 53100 Siena, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Semeraro
authors.forename: Andrea
authors.initials: A
authors.lastname: Lossani
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
authors.forename: Chiara
authors.initials: C
authors.lastname: Ghiron
authors.forename: Reinaldo
authors.initials: R
authors.lastname: Alvarez
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Manetti
authors.forename: Claudia
authors.initials: C
authors.lastname: Mugnaini
authors.forename: Silvia
authors.initials: S
authors.lastname: Valensin
authors.forename: Federico
authors.initials: F
authors.lastname: Focher
authors.forename: Federico
authors.initials: F
authors.lastname: Corelli
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; D011744:Pyrimidinones; D011758:Pyrroles; D011759:Pyrrolidines; C113100:immucillin G; D011683:Purine-Nucleoside Phosphorylase