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Formation of platinated GG cross-links on DNA by photoactivation of a platinum(IV) azide complex

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Abstract

Platinum(II) diam(m)ine complexes such as cisplatin are effective anticancer drugs but have accompanying side effects. We are exploring the design of platinum complexes with low toxicity that could be photoactivated selectively at the target site. We show here that the Pt(IV) azide complex cis,trans-[Pt(en)(N3)2(OH)2] is unreactive towards DNA until irradiated with visible light. Transcription mapping studies of a 212-bp fragment of pSP73KB plasmid DNA treated with cis,trans-[Pt(en)(N3)2(OH)2] and irradiated with visible light showed that the platination sites were similar to those observed for cisplatin, and were mainly in GG sequences. HPLC analysis of enzymatic digests of an irradiated sample of a 40-bp DNA duplex treated with the same complex also revealed preferential formation of GG cross-links. Since such DNA lesions are thought to be responsible for the induction of apoptosis in cancer cells by platinum drugs, the use of unreactive photoactivatable platinum pro-drugs may become an effective strategy for the design of a new generation of platinum anticancer complexes.

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Acknowledgements

We thank the EPSRC, Wellcome Trust and EC COST D20 for their support for this work. This work was also supported in part by the Grant Agency of the Academy of Sciences of the Czech Republic (grants A5004101 and KJB5004301). We thank Dr. Phil Müller for his advice on synthesis and for valuable discussions.

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Authors and Affiliations

  1. School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh , EH9 3JJ, UK

    Fiona S. Mackay & Peter J. Sadler

  2. Institute of Biophysics, Academy of Sciences of the Czech Republic, 61265 , Brno, Czech Republic

    Jana Kašpárková & Viktor Brabec

Authors
  1. Jana Kašpárková
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  2. Fiona S. Mackay
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  3. Viktor Brabec
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  4. Peter J. Sadler
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Corresponding authors

Correspondence to Viktor Brabec or Peter J. Sadler.

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Kašpárková, J., Mackay, F.S., Brabec, V. et al. Formation of platinated GG cross-links on DNA by photoactivation of a platinum(IV) azide complex. J Biol Inorg Chem 8, 741–745 (2003). https://doi.org/10.1007/s00775-003-0474-3

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  • DOI: https://doi.org/10.1007/s00775-003-0474-3

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