Discovery of antitumor anthra[2,3-b]furan-3-carboxamides: Optimization of synthesis and evaluation of antitumor properties

Eur J Med Chem. 2016 Apr 13:112:114-129. doi: 10.1016/j.ejmech.2016.01.050.

Andrey E Shchekotikhin ¹, Lyubov G Dezhenkova ², Vladimir B Tsvetkov ³, Yuri N Luzikov ², Yulia L Volodina ⁴, Victor V Tatarskiy Jr ⁴, Anastasia A Kalinina ⁴, Michael I Treshalin ², Helen M Treshalina ⁴, Vladimir I Romanenko ⁴, Dmitry N Kaluzhny ⁵, Michael Kubbutat ⁶, Dominique Schols ⁷, Yves Pommier ⁸, Alexander A Shtil ⁹, Maria N Preobrazhenskaya ²

Affiliations

1 Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia; Mendeleyev University of Chemical Technology, 9 Miusskaya Square, Moscow 125190, Russia. Electronic address: shchekotikhin@mail.ru.
2 Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia.
3 Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences, 29 Leninsky Avenue, 119991 Moscow, Russia; Institute for Physical-Chemical Medicine, 1A M. Pirogovskaya Street, Moscow 119435, Russia.
4 Federal State Budgetary Scientific Institution «N.N. Blokhin Cancer Research Center» of the Ministry of Health of the Russian Federation, 24 Kashirskoye Shosse, Moscow 115478, Russia.
5 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow 119991, Russia.
6 ProQinase GmbH, Breisacher Str. 117, 79106 Freiburg, Germany.
7 Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium.
8 Developmental Therapeutics Branch, National Cancer Institute, NIH, 37 Convent Drive, 37-5068, Bethesda, MD 20892, USA.
9 Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia; Federal State Budgetary Scientific Institution «N.N. Blokhin Cancer Research Center» of the Ministry of Health of the Russian Federation, 24 Kashirskoye Shosse, Moscow 115478, Russia.

PMID: 26890118 DOI: 10.1016/j.ejmech.2016.01.050

Abstract

Anthraquinones and their analogues, in particular heteroarene-fused anthracendiones, are prospective scaffolds for new compounds with improved antitumor characteristics. We herein report the use of a 'scaffold hopping' approach for the replacement of the core structure in the previously discovered hit compound naphtho[2,3-f]indole-5,10-dione 2 with an alternative anthra[2,3-b]furan-5,10-dione scaffold. Among 13 newly synthesized derivatives the majority of 4,11-dihydroxy-2-methyl-5,10-dioxoanthra[2,3-b]furan-3-carboxamides demonstrated a high antiproliferative potency against a panel of wild type and drug resistant tumor cell lines, a property superior over the reference drug doxorubicin or lead naphtho[2,3-f]indole-5,10-dione 2. At low micromolar concentrations the selected derivative of (R)-3-aminopyrrolidine 3c and its stereoisomer (S)-3-aminopyrrolidine 3d caused an apoptotic cell death preceded by an arrest in the G2/M phase. Studies of intracellular targets showed that 3c and 3d formed stable intercalative complexes with the duplex DNA as determined by spectral analysis and molecular docking. Both 3c and 3d attenuated Topoisomerase 1 and 2 mediated unwinding of the supercoiled DNA via a mechanism different from conventional DNA-enzyme tertiary complex formation. Furthermore, 3d decreased the activity of selected human protein kinases in vitro, indicating multiple targeting by the new chemotype. Finally, 3d demonstrated an antitumor activity in a model of murine intraperitoneally transplanted P388 leukemia, achieving the increase of animal life span up to 262% at tolerable doses. Altogether, the 'scaffold hopping' demonstrated its productivity for obtaining new perspective antitumor drug candidates.

Keywords

Anthra[2,3-b]furan-3-carboxamides; Antitumor activity; Circumvention of multidrug resistance; Cytotoxicity; DNA ligands; Protein kinase inhibitors; Topoisomerase inhibitors.

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