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Sequence-dependent attack on peptides by photoactivated platinum anticancer complexes

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Abstract

Octahedral platinum(IV) complexes such as trans,trans,trans-[Pt(N3)2(OH)2(pyridine)2] (1) are stable in the dark, but potently cytotoxic to a range of cancer cells when activated by UVA or visible light, and active in vivo. Photoactivation causes the reduction of the complex and leads to the formation of unusual Pt(II) lesions on DNA. However, radicals are also generated in the excited state resulting from photoactivation (J. S. Butler, J. A. Woods, N. J. Farrer, M. E. Newton and P. J. Sadler, J. Am. Chem. Soc., 2012, 134, 16508–16511). Here we show that once photoactivated, 1 also can interact with peptides, and therefore proteins are potential targets of this candidate drug. High resolution FT-ICR MS studies show that reactions of 1 activated by visible light with two neuropeptides Substance P, RPKPQQFFGLM-NH2 (SubP) and [Lys]3-Bombesin, pEQKLGNQWAVGHLM-NH2 (K3-Bom) give rise to unexpected products, in the form of both oxidised and platinated peptides. Further MS/MS analysis using electron-capture dissociation (ECD) dissociation pathways (enabling retention of the Pt complex during fragmentation), and EPR experiments using the spin-trap DEPMPO, show that the products generated during the photoactivation of 1 depend on the amino acid composition of the peptide. This work reveals the multi-targeting nature of excited state platinum anticancer complexes. Not only can they target DNA, but also peptides (and proteins) by sequence dependent platination and radical mechanisms.

Graphical abstract: Sequence-dependent attack on peptides by photoactivated platinum anticancer complexes

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Publication details

The article was received on 03 Dec 2017, accepted on 01 Feb 2018 and first published on 12 Feb 2018


Article type: Edge Article
DOI: 10.1039/C7SC05135B
Citation: Chem. Sci., 2018, Advance Article
  • Open access: Creative Commons BY license
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    Sequence-dependent attack on peptides by photoactivated platinum anticancer complexes

    C. A. Wootton, C. Sanchez-Cano, A. F. Lopez-Clavijo, E. Shaili, M. P. Barrow, P. J. Sadler and P. B. O'Connor, Chem. Sci., 2018, Advance Article , DOI: 10.1039/C7SC05135B

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