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  3. Anticancer properties of new synthetic hybrid molecules combining naphtho[2,3-b]furan-4,9-dione or benzo[f]indole-4,9-dione motif with phosphonate subunit

Anticancer properties of new synthetic hybrid molecules combining naphtho[2,3-b]furan-4,9-dione or benzo[f]indole-4,9-dione motif with phosphonate subunit

  • Eur J Med Chem. 2016 Sep 14:120:51-63. doi: 10.1016/j.ejmech.2016.05.002.
Katarzyna Gach 1,  Jakub Modranka 2,  Jacek Szymański 3,  Dorota Pomorska 1,  Urszula Krajewska 4,  Marek Mirowski 4,  Tomasz Janecki 5,  Anna Janecka 6
Affiliations

Affiliations

  • 1 Department of Biomolecular Chemistry, Faculty of Medicine, Medicinal University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland.
  • 2 Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924, Lodz, Poland.
  • 3 Central Scientific Laboratory, Division of Public Health, Faculty of Health Sciences, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland.
  • 4 Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Medical University of Lodz, Muszynskiego 1, 90-151, Lodz, Poland.
  • 5 Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924, Lodz, Poland. Electronic address: tomasz.janecki@p.lodz.pl.
  • 6 Department of Biomolecular Chemistry, Faculty of Medicine, Medicinal University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland. Electronic address: anna.janecka@umed.lodz.pl.
PMID: 27187858 DOI: 10.1016/j.ejmech.2016.05.002
Abstract

In this paper we report an efficient and general synthesis of substituted 3-diethoxyphosphorylnaphtho [2,3-b]furan-4,9-diones and 3-diethoxyphosphorylbenzo [f]indole-4,9-diones which integrate the natural 1,4-naphtalenedione scaffold, present in several Anticancer agents with the phosphonate moiety. The cytotoxicity of such hybrid molecules was tested against two leukemia cell lines, HL-60 and NALM-6 and against a breast adenocarcinoma MCF-7 cell line. Selected compounds were also tested on normal human cells: HUVEC and MCF-10A. In general, naphthofuran-4,9-diones showed much higher cytotoxic activity (IC50 values below 10 μM) than benzoindole-4,9-diones. The most promising 2-(2-chlorophenyl)-3-diethoxyphosphorylnaphtho [2,3-b]furan-4,9-dione, with the highest cytotoxic activity in the MTT test, was chosen for further evaluation of its Anticancer potential. This compound, tested on HL-60 and MCF-7 cells inhibited cell proliferation, generated DNA damage and induced Apoptosis. The suggested mechanism of its cytotoxic activity was the generation of intracellular Reactive Oxygen Species and the induction of mitochondrial membrane potential dissipation.

Keywords

Apoptosis; Cytotoxicity; Hybrid molecules; Naphthofurandiones; Phosphonate moiety.

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