2. Academic Validation
  3. 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

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

  • J Med Chem. 2015 Dec 24;58(24):9522-34. doi: 10.1021/acs.jmedchem.5b00859.
Alexander S Tikhomirov 1 2,  Andrey E Shchekotikhin 1 2,  Yi-Hui Lee 3,  Yi-Ann Chen 3,  Chia-An Yeh 3,  Victor V Tatarskiy Jr 4,  Lyubov G Dezhenkova 1,  Valeria A Glazunova 4,  Jan Balzarini 5,  Alexander A Shtil 4 6,  Maria N Preobrazhenskaya 1,  Pin Ju Chueh 3 7 8 9
Affiliations

Affiliations

  • 1 Gause Institute of New Antibiotics , 11 Bolshaya Pirogovskaya Street, Moscow 119021, Russia.
  • 2 Mendeleyev University of Chemical Technology , 9 Miusskaya Square, Moscow 125190, Russia.
  • 3 Institute of Biomedical Sciences, National Chung Hsing University , Taichung 40227, Taiwan.
  • 4 Blokhin Cancer Center , 24 Kashirskoye Shosse, Moscow 115478, Russia.
  • 5 Rega Institute for Medical Research, Katholieke Universiteit Leuven , 3000 Leuven, Belgium.
  • 6 National University of Science and Technology "MISIS", 4 Leninsky Avenue, Moscow 119991, Russia.
  • 7 Graduate Institute of Basic Medicine, China Medical University , Taichung 40402, Taiwan.
  • 8 Department of Medical Research, China Medical University Hospital , Taichung 40402, Taiwan.
  • 9 Department of Biotechnology, Asia University , Taichung 41354, Taiwan.
PMID: 26633734 DOI: 10.1021/acs.jmedchem.5b00859
Abstract

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.

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