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.