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New minor groove covering DNA binding mode of dinuclear Pt(II) complexes with various pyridine-linked bridging ligands and dual anticancer-antiangiogenic activities

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Abstract

New anticancer platinum(II) compounds simultaneously targeting tumor cells and tumor-derived neoangiogenesis, with new DNA interacting mode and large therapeutic window are appealing alternative to improve efficacy of clinical platinum chemotherapeutics. Herein, we describe three novel dinuclear [{Pt(en)Cl}2(μ-L)]2+ complexes with different pyridine-like bridging ligands (L), 4,4′-bipyridine (Pt1), 1,2-bis(4-pyridyl)ethane (Pt2) and 1,2-bis(4-pyridyl)ethene (Pt3), which highly, positively charged aqua derivatives, [{Pt(en)(H2O)}2(μ-L)]4+, interact with the phosphate backbone forming DNA-Pt adducts with an unique and previously undescribed binding mode, called a minor groove covering. The results of this study suggested that the new binding mode of the aqua-Pt(II) complexes with DNA could be attributed to the higher anticancer activities of their chloride analogues. All three compounds, particularly complex [{Pt(en)Cl}2(μ-4,4′-bipy)]Cl2·2H2O (4,4′-bipy is 4,4′-bipyridine) (Pt1), overcame cisplatin resistance in vivo in the zebrafish–mouse melanoma xenograft model, showed much higher therapeutic potential than antiangiogenic drug sunitinib malate, while effectively blocking tumor neovascularization and melanoma cell metastasis. Overall therapeutic profile showed new dinuclear Pt(II) complexes could be novel, effective and safe anticancer agents. Finally, the correlation with the structural characteristics of these complexes can serve as a useful tool for developing new and more effective anticancer drugs.

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Acknowledgements

This work has been financially supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia, (Grant No 172023, 172036, 172035 and 173048) and the Serbian Academy of Sciences and Arts (Strategic projects programme—Grant agreement No. 01-2019-F65 and Project No. F128). We thank D. Urankar and J. Kljun (University of Ljubljana) for HRMS measurements. We are also immensely grateful to Prof. Dr. Miloš Djuran, from the Serbian Academy of Sciences and Arts, who provided insight and expertise that greatly assisted us in our research. Numerical simulations were run on the PARADOX supercomputing facility at Scientific Computing Laboratory of the Institute of Physics Belgrade.

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Correspondence to Aleksandar Pavić, Goran V. Janjić or Snežana Rajković.

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Franich, A.A., Živković, M.D., Ilić-Tomić, T. et al. New minor groove covering DNA binding mode of dinuclear Pt(II) complexes with various pyridine-linked bridging ligands and dual anticancer-antiangiogenic activities. J Biol Inorg Chem 25, 395–409 (2020). https://doi.org/10.1007/s00775-020-01770-7

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