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標題: 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
作者: Tikhomirov, Alexander S
Shchekotikhin, Andrey E
Lee, Yi-Hui
Chen, Yi-Ann
Yeh, Chia-An
Tatarskiy, Victor V
Dezhenkova, Lyubov G
Glazunova, Valeria A
Balzarini, Jan
Shtil, Alexander A
Preobrazhenskaya, Maria N
Chueh, Pin Ju
關鍵字: Animals;Anthracenes;Antineoplastic Agents;Cell Line, Tumor;Drug Screening Assays, Antitumor;Humans;Mice;NAD;NADH, NADPH Oxidoreductases;Sirtuin 1;Structure-Activity Relationship;Apoptosis
Project: Journal of medicinal chemistry, Volume 58, Issue 24, Page(s) 9522-34.
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.
DOI: 10.1021/acs.jmedchem.5b00859
Appears in Collections:生物醫學研究所

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