title: 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.
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.
authors.affiliation: Gause Institute of New Antibiotics , 11 Bolshaya Pirogovskaya Street, Moscow 119021, Russia.|Mendeleyev University of Chemical Technology , 9 Miusskaya Square, Moscow 125190, Russia.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Tikhomirov
authors.affiliation: Gause Institute of New Antibiotics , 11 Bolshaya Pirogovskaya Street, Moscow 119021, Russia.|Mendeleyev University of Chemical Technology , 9 Miusskaya Square, Moscow 125190, Russia.
authors.forename: Andrey E
authors.initials: AE
authors.lastname: Shchekotikhin
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University , Taichung 40227, Taiwan.
authors.forename: Yi-Hui
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University , Taichung 40227, Taiwan.
authors.forename: Yi-Ann
authors.initials: YA
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University , Taichung 40227, Taiwan.
authors.forename: Chia-An
authors.initials: CA
authors.lastname: Yeh
authors.affiliation: Blokhin Cancer Center , 24 Kashirskoye Shosse, Moscow 115478, Russia.
authors.forename: Victor V
authors.initials: VV
authors.lastname: Tatarskiy
authors.affiliation: Gause Institute of New Antibiotics , 11 Bolshaya Pirogovskaya Street, Moscow 119021, Russia.
authors.forename: Lyubov G
authors.initials: LG
authors.lastname: Dezhenkova
authors.affiliation: Blokhin Cancer Center , 24 Kashirskoye Shosse, Moscow 115478, Russia.
authors.forename: Valeria A
authors.initials: VA
authors.lastname: Glazunova
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven , 3000 Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.affiliation: Blokhin Cancer Center , 24 Kashirskoye Shosse, Moscow 115478, Russia.|National University of Science and Technology "MISIS", 4 Leninsky Avenue, Moscow 119991, Russia.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Shtil
authors.affiliation: Gause Institute of New Antibiotics , 11 Bolshaya Pirogovskaya Street, Moscow 119021, Russia.
authors.forename: Maria N
authors.initials: MN
authors.lastname: Preobrazhenskaya
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University , Taichung 40227, Taiwan.|Graduate Institute of Basic Medicine, China Medical University , Taichung 40402, Taiwan.|Department of Medical Research, China Medical University Hospital , Taichung 40402, Taiwan.|Department of Biotechnology, Asia University , Taichung 41354, Taiwan.
authors.forename: Pin Ju
authors.initials: PJ
authors.lastname: Chueh
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D009243:NAD / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000873:Anthracenes; D000970:Antineoplastic Agents; D009243:NAD; D009247:NADH, NADPH Oxidoreductases; C431909:tumor-associated NADH oxidase; D056564:Sirtuin 1