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Synthesis, structure and biological evaluation of ruthenium(III) complexes of triazolopyrimidines with anticancer properties

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Abstract

Six novel ruthenium(III) complexes of general formula [RuCl3(L)3] (1,3,5) and [RuCl3(H2O)(L)2] (2,4,6), where L stands for three different triazolopyrimidine-derived ligands, are reported. The compounds have been structurally characterized (IR, EPR, SCXRD), and their magnetic moments have been determined. The single-crystal X-ray diffraction study revealed a slightly distorted octahedral geometry of the Ru(III) complexes with mer configuration in 1 and 5, and fac configuration in 3. In 2 and 4, three chloride ions are in mer configuration and the two triazolopyrimidines are oriented trans mutually with the water molecule playing the role of the sixth ligand. All complexes have been thoroughly screened for their in vitro cytotoxicity against human breast cancer cell line MCF-7, human cervical cancer cell line HeLa, and L929 murine fibroblast cells, uncovering among others that the most lipophilic complexes 5 and 6, containing the bulky ligand dptp (5,7-diphenyl-1,2,4-triazolo[1,5-a]pyrimidine), display high cytotoxic activity against MCF-7, and HeLa cells. Moreover, it was also revealed that during the interaction of the complexes 1–6 with the cancer MCF-7 cell line, reactive oxygen species are released intracellularly, which could indicate that they are involved in cell apoptosis. Furthermore, extensive studies have been carried out to reveal the mechanism by which complexes 1–6 interact with DNA, albumin, and apotransferrin. The biological studies were complemented by detailed kinetic studies of the hydrolysis of the complexes in the pH range 5–8, to determine the stability of the complexes in solution.

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Six novel ruthenium(III) complexes with triazolopyrimidine derivatives demonstrated the potential for use as anticancer agents by maintaining the toxic effect on MCF-7 and HeLa cells.

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Acknowledgements

Financial support from the National Science Center (NCN) Poland through Grant Etiuda no. 2013/08/T/ST5/00391 (to M.F.) is gratefully acknowledged. M. F. is thankful to J. Masternak, DSc PhD from the Jan Kochanowski University in Kielce for magnetic measurements and Prof. Juan M. Salas from the University of Granada for support and advice during the internship. His extraordinary personality and great mentoring will forever remain in my memory.

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Authors and Affiliations

  1. Institute of Low Temperature and Structure Research, PAS, Okólna 2, 50-422, Wrocław, Poland

    Marzena Fandzloch

  2. Faculty of Chemistry, University of Wrocław, F. Joliot-Curie 14, 50-383, Wrocław, Poland

    Marzena Fandzloch & Julia Jezierska

  3. Faculty of Chemistry, Nicolaus Copernicus University in Toruń, Gagarina 7, 87-100, Toruń, Poland

    Liliana Dobrzańska, Joanna Wiśniewska & Iwona Łakomska

  4. Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University in Toruń, Lwowska 1, 87-100, Toruń, Poland

    Tomasz Jędrzejewski

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  1. Marzena Fandzloch
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775_2019_1743_MOESM1_ESM.doc

Supplementary material 1 (DOC 1487 kb) [Table S1 presented selected bond lengths and angles for 1–4, representation (Fig. S1) and crystal data for 5, Fig. S2 and Fig. S3 with concentration-dependent effect of the ruthenium complexes 1–6 on the viability of L929 fibroblasts and MCF-7 cells or HeLa in comparison to both cell lines stimulated with cisplatin, and Fig. S4 presented a summary of the concentration-dependent impact of ruthenium complexes 1–6, cisplatin and NAMI-A on cell viability and intracellular ROS production]. See https://doi.org/10.1039/x0xx00000x

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Fandzloch, M., Dobrzańska, L., Jędrzejewski, T. et al. Synthesis, structure and biological evaluation of ruthenium(III) complexes of triazolopyrimidines with anticancer properties. J Biol Inorg Chem 25, 109–124 (2020). https://doi.org/10.1007/s00775-019-01743-5

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