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Synthesis, Molecular Structure, DNA/Protein Binding, Cytotoxicity, Apoptosis, Reactive Oxygen Species, and Mitochondrial Membrane Potential of Dibenzoxanthenes Derivatives

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Abstract

Two dibenzoxanthene isomers 3 and 4 were synthesized and characterized. The crystal structures of the two compounds were solved by single-crystal X-ray diffraction. Binding of two compounds with calf thymus DNA (CT DNA) and BSA (bovine serum albumin) has been thoroughly investigated by UV–Vis and fluorescence spectroscopy. The DNA-binding constants were determined to be 2.51 (±0.09) × 103 for compound 3 and 4.55 (±0.10) × 103 for compound 4. Two compounds can cleave pBR322 DNA upon irradiation. Significant nuclear damages of BEL-7402 cells were observed with compound treatment in a comet assay. The cytotoxicity in vitro was investigated by MTT method. These compounds have been found to induce nuclear condensation and fragmentation in BEL-7402 cells. The two compounds can enhance intracellular reactive oxygen species and decrease the mitochondrial membrane potential. The compounds activated caspase-3 and caspase-7, down-regulated the expression levels of anti-apoptotic protein Bcl-2, and up-regulated the expression levels of pro-apoptotic protein Bax. These compounds induce apoptosis of BEL-7402 cells through an ROS-mediated mitochondrial dysfunction pathway.

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Acknowledgments

This work was supported by the Priority Academic Program Development of Guangdong Higher Education Institutions (2013LYM0047), the High-Level Personnel Project in 2013 of Guangdong Province, and the Joint Nature Science Fund of the Department of Science and Technology and the First Affiliated Hospital of Guangdong Pharmaceutical University (No. GYFYLH201315).

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Authors and Affiliations

  1. College of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, People’s Republic of China

    Hui-Hui Yang, Bing-Jie Han, Wei Li, Yun-Jun Liu & Xiu-Zhen Wang

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  1. Hui-Hui Yang
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  2. Bing-Jie Han
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  3. Wei Li
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  4. Yun-Jun Liu
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Correspondence to Yun-Jun Liu or Xiu-Zhen Wang.

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Yang, HH., Han, BJ., Li, W. et al. Synthesis, Molecular Structure, DNA/Protein Binding, Cytotoxicity, Apoptosis, Reactive Oxygen Species, and Mitochondrial Membrane Potential of Dibenzoxanthenes Derivatives. J Membrane Biol 248, 951–965 (2015). https://doi.org/10.1007/s00232-015-9847-0

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