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.
|Autori interni:||LA MOTTA, CONCETTINA|
DA SETTIMO PASSETTI, FEDERICO
|Autori:||BUTINI STEFANIA; GEMMA SANDRA; BRINDISI MARGHERITA; BORRELLI GIUSEPPE; LOSSANI ANDREA; PONTE ANNA MARIA; TORTI ANDREA; MAGA GIOVANNI; MARINELLI LUCIANA; LA PIETRA VALERIA; FIORINI ISABELLA; LAMPONI STEFANIA; CAMPIANI GIUSEPPE; ZISTERER DANIELA M; NATHWANI SEEMA-MARIA; SARTINI STEFANIA; LA MOTTA CONCETTINA; DA SETTIMO PASSETTI F; NOVELLINO ETTORE; FOCHER FEDERICO|
|Titolo:||Non-nucleoside inhibitors of human adenosine kinase: synthesis, molecular modeling, and biological studies|
|Anno del prodotto:||2011|
|Digital Object Identifier (DOI):||10.1021/jm101438u|
|Appare nelle tipologie:||1.1 Articolo in rivista|