title: Non-nucleoside inhibitors of human adenosine kinase: synthesis, molecular modeling, and biological studies.
abstract: Adenosine kinase (AK) catalyzes the phosphorylation of adenosine (Ado) to AMP by means of a kinetic mechanism in which the two substrates Ado and ATP bind the enzyme in a binary and/or ternary complex, with distinct protein conformations. Most of the described inhibitors have Ado-like structural motifs and are nonselective, and some of them (e.g., the tubercidine-like ligands) are characterized by a toxic profile. We have cloned and expressed human AK (hAK) and searched for novel non-substrate-like inhibitors. Our efforts to widen the structural diversity of AK inhibitors led to the identification of novel non-nucleoside, noncompetitive allosteric modulators characterized by a unique molecular scaffold. Among the pyrrolobenzoxa(thia)zepinones (4a-qq) developed, 4a was identified as a non-nucleoside prototype hAK inhibitor. 4a has proapoptotic efficacy, slight inhibition of short-term RNA synthesis, and cytostatic activity on tumor cell lines while showing low cytotoxicity and no significant adverse effects on short-term DNA synthesis in cells.
authors.affiliation: European Research Centre for Drug Discovery and Development, NatSynDrugs, Università di Siena, 53100 Siena, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Butini
authors.forename: Sandra
authors.initials: S
authors.lastname: Gemma
authors.forename: Margherita
authors.initials: M
authors.lastname: Brindisi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Borrelli
authors.forename: Andrea
authors.initials: A
authors.lastname: Lossani
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Ponte
authors.forename: Andrea
authors.initials: A
authors.lastname: Torti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Valeria
authors.initials: V
authors.lastname: La Pietra
authors.forename: Isabella
authors.initials: I
authors.lastname: Fiorini
authors.forename: Stefania
authors.initials: S
authors.lastname: Lamponi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Zisterer
authors.forename: Seema-Maria
authors.initials: SM
authors.lastname: Nathwani
authors.forename: Stefania
authors.initials: S
authors.lastname: Sartini
authors.forename: Concettina
authors.initials: C
authors.lastname: La Motta
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Federico
authors.initials: F
authors.lastname: Focher
mesh_terms: D000248:Adenosine Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000494:Allosteric Regulation; D000495:Allosteric Site; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D010077:Oxazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012313:RNA / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C558526:6-ethyl-6-(4-((phenylthio)methyl)phenyl)-6,7-dihydrobenzo(b)pyrrolo(1,2-d)(1,4)oxazepin-7-one; D000970:Antineoplastic Agents; D010077:Oxazepines; D011758:Pyrroles; D011994:Recombinant Proteins; D012313:RNA; D004247:DNA; D000248:Adenosine Kinase