Non-Nucleoside Inhibitors of Human Adenosine Kinase: Synthesis, Molecular Modeling, and Biological Studies

作者：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 Federico; Novellino Ettore; Focher Federico

来源：Journal of Medicinal Chemistry, 2011, 54(5): 1401-1420.

DOI：10.1021/jm101438u

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.

• 出版日期2011-3-10