Synthesis and Characterization of 4,11-Diaminoanthra[2,3-b]furan-5,10-diones: Tumor Cell Apoptosis through tNOX-Modulated NAD+/NADH Ratio and SIRT1

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• 作者：Alexander S. Tikhomirov ; Andrey E. Shchekotikhin ; Yi-Hui Lee ; Yi-Ann Chen ; Chia-An Yeh ; Victor V. Tatarskiy Jr. ; Lyubov G. Dezhenkova ; Valeria A. Glazunova ; Jan Balzarini ; Alexander A. Shtil ; Maria N. Preobrazhenskaya ; Pin Ju Chueh
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：December 24, 2015
• 年：2015
• 卷：58
• 期：24
• 页码：9522-9534
• 全文大小：696K
• ISSN：1520-4804

文摘

A series of new 4,11-diaminoanthra[2,3-b]furan-5,10-dione derivatives with different side chains were synthesized. Selected 2-unsubstituted derivatives 11–14 showed high antiproliferative potency on a panel of mammalian tumor cell lines including multidrug resistance variants. Compounds 11–14 utilized multiple mechanisms of cytotoxicity including inhibition of Top1/Top2-mediated DNA relaxation, reduced NAD⁺/NADH ratio through tNOX inhibition, suppression of a NAD⁺-dependent sirtuin 1 (SIRT1) deacetylase activity, and activation of caspase-mediated apoptosis. Here, for the first time, we report that tumor-associated NADH oxidase (tNOX) and SIRT1 are important cellular targets of antitumor anthracene-9,10-diones.