Synthesis and cytotoxic properties of 4,11-bis[(aminoethyl)amino]anthra[2,3-b]thiophene-5,10-diones, novel analogues of antitumor anthracene-9,10-diones

Andrey E. Shchekotikhin, Valeria A. Glazunova, Lyubov G. Dezhenkova, Yuri N. Luzikov, Yuri B. Sinkevich, Leonid V. Kovalenko, Vladimir N. Buyanov, Jan Balzarini, Fong Chun Huang, Jing Jer Lin, Hsu Shan Huang, Alexander A. Shtil, Maria N. Preobrazhenskaya

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34 Citations (Scopus)

Abstract

We developed the synthesis of a series of thiophene-fused tetracyclic analogues of the antitumor drug ametantrone. The reactions included nucleophilic substitution of methoxy groups in 4,11-dimethoxyanthra[2,3-b]thiophene-5,10-diones with ethylenediamines, producing the derivatives of 4,11-diaminoanthra[2,3-b]thiophene-5,10-dione in good yields. Several compounds showed marked antiproliferative potency against doxorubicin-selected, P-glycoprotein-expressing tumor cells and p53-/- cells. The cytotoxicity of some novel compounds for P-glycoprotein-positive cells is highly dependent on N-substituent at the terminal amino group of ethylenediamine moiety. The cytotoxic potency of selected compounds correlated with their ability to attenuate the functions of topoisomerase I and telomerase, strongly suggesting that these enzymes are the major targets of antitumor activity of anthra[2,3-b]thiophene-5,10-dione derivatives.

Original languageEnglish
Pages (from-to)1861-1869
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number5
DOIs
Publication statusPublished - Mar 1 2009
Externally publishedYes

Keywords

  • Anthra[2,3-b]thiophene-5,10-diones
  • Cytotoxicity
  • Drug resistance
  • Telomerase
  • Topoisomerase I
  • Tumor cells

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

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  • Cite this

    Shchekotikhin, A. E., Glazunova, V. A., Dezhenkova, L. G., Luzikov, Y. N., Sinkevich, Y. B., Kovalenko, L. V., Buyanov, V. N., Balzarini, J., Huang, F. C., Lin, J. J., Huang, H. S., Shtil, A. A., & Preobrazhenskaya, M. N. (2009). Synthesis and cytotoxic properties of 4,11-bis[(aminoethyl)amino]anthra[2,3-b]thiophene-5,10-diones, novel analogues of antitumor anthracene-9,10-diones. Bioorganic and Medicinal Chemistry, 17(5), 1861-1869. https://doi.org/10.1016/j.bmc.2009.01.047