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Sequence-dependent attack on peptides by photoactivated platinum anticancer complexes
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Wootton, Christopher, Sanchez-Cano, Carlos, Lopez-Clavijo, Andrea F., Shaili, Evyenia, Barrow, Mark P., Sadler, P. J. and O'Connor, Peter B. (2018) Sequence-dependent attack on peptides by photoactivated platinum anticancer complexes. Chemical Science, 9 . pp. 2733-2739. doi:10.1039/C7SC05135B ISSN 2041-6520.
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Official URL: https://doi.org/10.1039/C7SC05135B
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 multitargeting 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.
Item Type: | Journal Article | ||||||||||||||||||
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Subjects: | Q Science > QD Chemistry R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||||||||||||||||
Library of Congress Subject Headings (LCSH): | Antineoplastic agents, Peptides | ||||||||||||||||||
Journal or Publication Title: | Chemical Science | ||||||||||||||||||
Publisher: | Royal Society of Chemistry | ||||||||||||||||||
ISSN: | 2041-6520 | ||||||||||||||||||
Official Date: | 12 February 2018 | ||||||||||||||||||
Dates: |
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Volume: | 9 | ||||||||||||||||||
Page Range: | pp. 2733-2739 | ||||||||||||||||||
DOI: | 10.1039/C7SC05135B | ||||||||||||||||||
Status: | Peer Reviewed | ||||||||||||||||||
Publication Status: | Published | ||||||||||||||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||||||||||||||
Copyright Holders: | Royal Society of Chemistry | ||||||||||||||||||
Date of first compliant deposit: | 19 February 2019 | ||||||||||||||||||
Date of first compliant Open Access: | 20 February 2019 | ||||||||||||||||||
RIOXX Funder/Project Grant: |
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