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Characterising the atypical 5′-CG DNA sequence specificity of 9-aminoacridine carboxamide Pt complexes

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Abstract

In this study, the DNA sequence specificity of four DNA-targeted 9-aminoacridine carboxamide Pt complexes was compared with cisplatin, using two specially constructed plasmid templates. One plasmid contained 5′-CG and 5′-GA insert sequences while the other plasmid contained a G-rich transferrin receptor gene promoter insert sequence. The damage profiles of each compound on the different DNA templates were quantified via a polymerase stop assay with fluorescently labelled primers and capillary electrophoresis. With the plasmid that contained 5′-CG and 5′-GA dinucleotides, the four 9-aminoacridine carboxamide Pt complexes produced distinctly different damage profiles as compared with cisplatin. These 9-aminoacridine complexes had greatly increased levels of DNA damage at CG and GA dinucleotides as compared with cisplatin. It was shown that the presence of a CG or GA dinucleotide was sufficient to reveal the altered DNA sequence selectivity of the 9-aminoacridine carboxamide Pt analogues. The DNA sequence specificity of the Pt complexes was also found to be similarly altered utilising the transferrin receptor DNA sequence.

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Abbreviations

CE-LIF:

Capillary electrophoresis with laser-induced-fluorescence detection

Cisplatin:

cis-Diamminedichloridoplatinum(II)

9AmAcPtCl2 :

Dichlorido(N-2-[(2-aminoethyl)amino]-ethyl)-9-aminoacridine-4-carboxamide)platinum(II)

7-Methoxy-9AmAcPtCl2 :

Dichlorido(N-2-[(2-aminoethyl)amino]-ethyl)-7-methoxy-9-aminoacridine-4-carboxamide)platinum(II)

7-Fluoro-9AmAcPtCl2 :

Dichlorido(N-2-[(2-aminoethyl)amino]-ethyl)-7-fluoro-9-aminoacridine-4-carboxamide)platinum(II)

9-Ethanolamine-AcPtCl2 :

Dichlorido(N-2-[(2-aminoethyl)amino]-ethyl)-9-ethanolamine-acridine-4-carboxamide)platinum(II)

DMF:

Dimethylformamide

NER:

Nucleotide excision repair

TFRC:

Transferrin receptor

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Acknowledgments

Support of this work by the University of New South Wales, Science Faculty Research Grant Scheme, is gratefully acknowledged.

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Authors and Affiliations

  1. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, 2052, Australia

    Hieronimus W. Kava, Anne M. Galea, Farhana Md. Jamil, Yue Feng & Vincent Murray

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  1. Hieronimus W. Kava
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  2. Anne M. Galea
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  3. Farhana Md. Jamil
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  4. Yue Feng
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  5. Vincent Murray
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Corresponding author

Correspondence to Vincent Murray.

Electronic supplementary material

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775_2014_1144_MOESM1_ESM.pdf

Supplementary Figure 1: Electropherograms showing DNA adduct formation caused by cisplatin and the four analogues with the T7.TFRC.G10 plasmid. The relative fluorescence intensity is shown on the y-axis while the DNA fragment size (in nucleotides) is on the x-axis. The peaks indicate the intensity of DNA adduct binding of the Pt compound at the indicated DNA sequence sites on the DNA template. The telomere T7 region is shown T1-T7, left to right. The TFRC insert region includes 5′-GG, 5′-CGGGGG and 5′-GGGGG sequence elements. A) The DMF negative control; B) Treatment with 1.0 μM cisplatin; C) 0.1 μM 9AmAcPtCl2; D) 3.0 μM 7-methoxy-9AmAcPtCl2; E) 0.1 μM 7-fluoro-9AmAcPtCl2 and F) 0.1 μM 9-ethanolamine-9AcPtCl2. (PDF 1272 kb)

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Kava, H.W., Galea, A.M., Md. Jamil, F. et al. Characterising the atypical 5′-CG DNA sequence specificity of 9-aminoacridine carboxamide Pt complexes. J Biol Inorg Chem 19, 997–1007 (2014). https://doi.org/10.1007/s00775-014-1144-3

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  • DOI: https://doi.org/10.1007/s00775-014-1144-3

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