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
Gause Institute of New Antibiotics , 11 Bolshaya Pirogovskaya Street, Moscow 119021, Russia.
Mendeleyev University of Chemical Technology , 9 Miusskaya Square, Moscow 125190, Russia.
J Med Chem. 2015 Dec 24;58(24):9522-34. doi: 10.1021/acs.jmedchem.5b00859. Epub 2015 Dec 15.
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.
合成了一系列具有不同侧链的新型4,11-二氨基蒽[2,3-b]呋喃-5,10-二酮衍生物。选定的2-未取代衍生物11-14对包括多药耐药变体在内的一组哺乳动物肿瘤细胞系显示出高抗增殖效力。化合物11-14利用多种细胞毒性机制，包括抑制Top1/Top2介导的DNA松弛、通过抑制tNOX降低NAD(+)/NADH比值、抑制NAD(+)依赖性沉默调节蛋白1（SIRT1）脱乙酰酶活性以及激活半胱天冬酶介导的细胞凋亡。在此，我们首次报道肿瘤相关NADH氧化酶（tNOX）和SIRT1是抗肿瘤蒽-9,10-二酮的重要细胞靶点。
