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Dinuclear platinum complexes with N,N′-bis(aminoalkyl)-1,4-diaminoanthraquinones as linking ligands. Part I. Synthesis, cytotoxicity, and cellular studies in A2780 human ovarian carcinoma cells

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Abstract

A series of N,N′-bis(aminoalkyl)-1,4-diaminoanthraquinones (aminoalkyl=2-aminoethyl, 3-aminoprop-1-yl and 4-aminobut-1-yl) was functionalized with trans-platinum DNA-binding moieties. Cytotoxicity testing in A2780 human ovarian carcinoma cells revealed high anticancer activity of the formed cationic dinuclear platinum complexes. The cationic dinuclear platinum complexes with the shortest aminoalkyl chain were shown to be the most active, which agrees with the structure–activity relationship found for the corresponding free ligands without platinum. The N,N′-bis(aminoalkyl)-1,4-diaminoanthraquinones partly circumvent cisplatin resistance, whereas their dinuclear platinum complexes were found susceptible to the resistance mechanisms in A2780cisR. The platinum complexes have resistance factors comparable to the control dinuclear complex BBR3005 [{trans-PtCl(NH3)2}2{μ-(NH2(CH2)6NH2)}](NO3)2. The 1,4-diaminoanthraquinone moiety is fluorescent, and thus the cellular processing of the compounds could be monitored by time-lapse digital fluorescence microscopy. The intercalators without platinum were shown to enter the cells within minutes. The platinum complexes enter the cells more slowly. Most likely, the positive charges of the platinum complexes hamper the diffusion through the membrane. Interestingly, the platinum complexes are processed differently than the platinum-free compounds by the cells. After 24 hours the fluorescent platinum complexes are encapsulated in large vesicles in the cytosol. Co-localization of the anthraquinone fluorescence with Lysotracker Green DND-26 shows that these vesicles are acidic compartments, probably lysosomes.

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Fig. 8 A–D

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Abbreviations

AQ2:

N,N′-bis(2-aminoethyl)-1,4-diaminoanthracene-9,10-dione

AQ3:

N,N′-bis(3-aminoprop-1-yl)-1,4-diaminoanthracene-9,10-dione

AQ4:

N,N′-bis(4-aminobut-1-yl)-1,4-diaminoanthracene-9,10-dione

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide

PAQ2:

[{trans-PtCl(NH3)2}2(μ-AQ2)](NO3)2

PAQ3:

[{trans-PtCl(NH3)2}2(μ-AQ3)](NO3)2

PAQ4:

[{trans-PtCl(NH3)2}2(μ-AQ4)](NO3)2

PBS:

phosphate buffered saline

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Acknowledgements

The authors are indebted to the EU for a grant as a Training Host Institute in the EU programme Human Capital and Mobility. Also support and sponsorship by COST Actions D20/0001/00, D20/0002/00 and D20/003/01 (biocoordination chemistry) is kindly acknowledged. The authors wish to thank Johnson Matthey (Reading, UK) for their generous gift of K2PtCl4. This work has been performed under auspices of the joint BIOMAC Research Graduate School of Leiden University and Delft University of Technology.

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Authors and Affiliations

  1. Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA , Leiden, The Netherlands

    Bart A. J. Jansen, Peter Wielaard, Ganna V. Kalayda, Maura Ferrari & Jan Reedijk

  2. Laboratory for Cytochemistry and Cytometry, Department of Molecular Cell Biology, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL , Leiden, The Netherlands

    Chris Molenaar & Hans J. Tanke

  3. Molecular Genetics, Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA , Leiden, The Netherlands

    Jaap Brouwer

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  1. Bart A. J. Jansen
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Correspondence to Jan Reedijk.

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Jansen, B.A.J., Wielaard, P., Kalayda, G.V. et al. Dinuclear platinum complexes with N,N′-bis(aminoalkyl)-1,4-diaminoanthraquinones as linking ligands. Part I. Synthesis, cytotoxicity, and cellular studies in A2780 human ovarian carcinoma cells. J Biol Inorg Chem 9, 403–413 (2004). https://doi.org/10.1007/s00775-004-0539-y

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