New antitumor anthra[2,3-b]furan-3-carboxamides: Synthesis and structure-activity relationship

Eur J Med Chem. 2018 Mar 25:148:128-139. doi: 10.1016/j.ejmech.2018.02.027.

Alexander S Tikhomirov ¹, Chia-Yang Lin ², Yulia L Volodina ³, Lyubov G Dezhenkova ⁴, Victor V Tatarskiy ³, Dominique Schols ⁵, Alexander A Shtil ⁶, Punit Kaur ⁷, Pin Ju Chueh ⁸, Andrey E Shchekotikhin ⁹

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.
2 Institute of Biomedical Sciences, National Chung Hsing University, Taichung 40227, Taiwan.
3 Blokhin National Medical Research Center of Oncology, 24 Kashirskoye Shosse, Moscow 115478, Russia.
4 Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia.
5 Rega Institute for Medical Research, K.U. Leuven, 3000 Leuven, Belgium.
6 Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia; Blokhin National Medical Research Center of Oncology, 24 Kashirskoye Shosse, Moscow 115478, Russia; ITMO University, 49 Kronverksky Avenue, 197101 Saint-Petersburg, Russia.
7 Biophysics, All India Institute of Medical Sciences, New Delhi 110029, India.
8 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. Electronic address: pjchueh@dragon.nchu.edu.tw.
9 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.

PMID: 29459273 DOI: 10.1016/j.ejmech.2018.02.027

Abstract

Chemical modifications of the anthraquinone scaffold are aimed at optimization of this exceptionally productive class of antitumor drugs. In particular, our previously reported anthra[2,3-b]furan-3-carboxamides demonstrated a high cytotoxic potency in Cell Culture and in vivo. In this study, we expanded our series of anthra[2,3-b]furan-3-carboxamides by modifying the key functional groups and dissected the structure-activity relationship within this chemotype. The majority of new compounds inhibited the growth of mammalian tumor cell lines at submicromolar to low micromolar concentrations. We found that 4,11-hydroxy groups as well as the carbonyl moiety in the carboxamide fragment were critical for cytotoxicity whereas the substituent at the 2-position of anthra[2,3-b]furan was not. Importantly, the new derivatives were similarly potent against wild type cells and their variants resistant to doxorubicin due to P-glycoprotein (Pgp) expression or p53 inactivation. The most cytotoxic derivatives 6 and 9 attenuated plasmid DNA relaxation by Topoisomerase 1. Finally, we demonstrated that 6 and 9 at 1 μM induced intracellular oxidative stress, accumulation in G2/M phase of the cell cycle, and Apoptosis in gastric carcinoma cell lines regardless of their p53 status. These results further substantiate the potential of anthra[2,3-b]furan-3-carboxamides as antitumor drug candidates.

Keywords

Anthra[2,3-b]furan-3-carboxamides; Antiproliferative activity; Apoptosis; Multidrug resistance; Reactive oxygen species; Topoisomerase 1; р53.

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