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

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• 作者：Stefania Butini ; Sandra Gemma ; Margherita Brindisi ; Giuseppe Borrelli ; Andrea Lossani ; Anna Maria Ponte ; Andrea Torti ; Giovanni Maga ; Luciana Marinelli ; Valeria La Pietra ; Isabella Fiorini ; Stefania Lamponi ; Giuseppe Campiani ; Daniela M. Zisterer ; Seema-Maria Nathwani ; Stefania Sartini ; Concettina La Motta ; Federico Da Settimo ; Ettore Novellino ; Federico Focher
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：March 10, 2011
• 年：2011
• 卷：54
• 期：5
• 页码：1401-1420
• 全文大小：1450K
• 年卷期：v.54,no.5(March 10, 2011)
• ISSN：1520-4804

文摘

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鈭?b>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.