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2017 | 64 | 1 | 41-48
Article title

Anticancer activity of new molecular hybrids combining 1,4-naphthalenedione motif with phosphonic acid moiety in hepatocellular carcinoma HepG2 cells

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EN
Abstracts
EN
Structural motifs found in naturally occurring compounds are frequently used by researchers to develop novel synthetic drug candidates. Some of these new agents are hybrid molecules which are designed through a concept of combining more than one functional element. In this report, anticancer activity of new synthetic molecular hybrids, substituted 3-diethoxyphosphorylnaphtho[2,3-b]furan-4,9-diones and 3-diethoxyphosphorylbenzo[f]indole-4,9-diones, which integrate natural 1,4-naphtalenedione scaffold, present in several anticancer agents, with pharmacophoric phosphonate moiety, were tested against hepatocellular cell line HepG2. Cytotoxicity was examined using MTT assay. Two most potent compounds, furandione 8a and benzoindoldione 12a, which reduced the number of viable HepG2 cells with the IC50 values of 4.13 µM and 5.9 µM, respectively, were selected for further research. These compounds decreased the mRNA expression levels of several genes: Bcl-2, angiogenic vascular endothelial growth factor (VEGF), c-Fos, caspase-8 and increased the expression of Bax, caspase-3 and -9, c-Jun, p21, p53, as determined by quantitative real-time PCR. The ability of these compounds to induce apoptosis and DNA damage was studied by flow cytometry. The obtained data showed that the new compounds inhibited cell viability by increasing apoptosis and decreasing angiogenesis. Compound 8a was a much stronger apoptosis inducer as compared with 12a and strongly activated the intrinsic pathway of apoptosis, associated with the loss of mitochondrial membrane potential and changes in Bax/Bcl-2 ratio. These findings show that the synthetic hybrids combining 1,4-naphthalenedione system and phosphonic acid moiety display potential to be further explored in the development of new anticancer agents.
Publisher

Year
Volume
64
Issue
1
Pages
41-48
Physical description
Dates
published
2017
received
2016-02-09
revised
2016-09-13
accepted
2016-09-15
(unknown)
2016-11-04
Contributors
  • Department of Biomolecular Chemistry, Faculty of Medicine, Medicinal University of Lodz, Łódź, Poland
  • Department of Biomolecular Chemistry, Faculty of Medicine, Medicinal University of Lodz, Łódź, Poland
  • Central Scientific Laboratory, Division of Public Health, Faculty of Health Sciences, Medical University of Lodz, Łódź, Poland
  • Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Łódź, Poland
  • Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Łódź, Poland
author
  • Department of Biomolecular Chemistry, Faculty of Medicine, Medicinal University of Lodz, Łódź, Poland
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Document Type
Publication order reference
Identifiers
YADDA identifier
bwmeta1.element.bwnjournal-article-abpv64p41kz
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