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Cytotoxic platinum(II) complexes derived from saccharinate and phosphine ligands: synthesis, structures, DNA cleavage, and oxidative stress-induced apoptosis

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Abstract

A series of the structurally related platinum(II) saccharinate (sac) complexes with alkylphenylphosphines, namely cis-[Pt(sac)2(PPh2Me)2]·DMSO (1), cis-[Pt(sac)2(PPhMe2)2] (2), cis-[Pt(sac)2(PPh2Et)2] (3), and cis-[Pt(sac)2(PPhEt2)2]·2DMSO (4), were synthesized and fully characterized; their structures were determined by X-ray crystallography. All the complexes were investigated for their anticancer potentials on three human cancer cells including A549 (lung), MCF-7 (breast), and HCT116 (colon) in addition to a noncancerous human bronchial epithelial cells (BEAS-2B). Specifically, 1 and 3 showed significant cytotoxic effects against MCF-7 and HCT116 cell lines in comparison to cisplatin, and were considered as the most potent ones in the series. The cytotoxic complexes were found to cleave DNA efficiently. In addition, the binding interactions of the complexes with DNA were confirmed by enzyme inhibition and molecular docking studies. Complexes 1 and 3 were capable of inducing apoptosis and arrested the cell cycle at the DNA synthesis (S) phase in MCF-7 cells. Furthermore, 1 and 3 caused the excessive generation of reactive oxygen species (ROS), leading to mitochondrial dysfunction and double-strand DNA breaks.

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Acknowledgements

The financial support from TUBITAK (project no. 215Z230) is gratefully acknowledged. We thank Prof. Dr. Ismail Ozdemir for collecting the NMR data.

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Authors and Affiliations

  1. Department of Chemistry, Faculty of Arts and Sciences, Uludag University, 16059, Bursa, Turkey

    Ceyda Icsel & Veysel T. Yilmaz

  2. Research Center for Translational Medicine (KUTTAM), Koc University, 34450, Istanbul, Turkey

    Buse Cevatemre

  3. Department of Physics, Faculty of Sciences, Dokuz Eylul University, 35210, Izmir, Turkey

    Muhittin Aygun

  4. Department of Medicinal Biochemistry, Faculty of Medicine, University of Istinye, 34010, Istanbul, Turkey

    Engin Ulukaya

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  1. Ceyda Icsel
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  2. Veysel T. Yilmaz
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  5. Engin Ulukaya
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Correspondence to Veysel T. Yilmaz.

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775_2019_1736_MOESM1_ESM.pdf

Crystallographic and structure refinement data, FT-IR spectra, NMR spectra (1H, 13C and 31P), ESI-MS spectra, stability data in DMSO and saline, Annexin-V positivity in MCF-7 cells, cell cycle progression of MCF-7 cells, ROS generation in MCF-7 cells, mitochondrial membrane depolarization in MCF-7 cells and formation of DNA double-strand breaks in MCF-7 cells treated with the IC90 doses of 1 (17.4 μM), 3 (4.5 μM) and cisplatin (28.0 μM) for different time intervals. (PDF 899 kb)

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Icsel, C., Yilmaz, V.T., Cevatemre, B. et al. Cytotoxic platinum(II) complexes derived from saccharinate and phosphine ligands: synthesis, structures, DNA cleavage, and oxidative stress-induced apoptosis. J Biol Inorg Chem 25, 75–87 (2020). https://doi.org/10.1007/s00775-019-01736-4

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  • DOI: https://doi.org/10.1007/s00775-019-01736-4

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