The family of diazido Pt(IV) complexes trans, trans, trans-[Pt(N3)2(OH)2(Am1)(Am2)] where Am – amine, e.g. pyridine, are non-toxic to cancer cells in the dark but potently antiproliferative when irradiated with UVA, blue or green light [1]. The mechanism of action of low-spin d6 organometallic Ru(II), Os(II) arene and Ir(III) cyclopentadienyl anticancer complexes [(arene/Cp)M(XY)(Z)]n+ is strongly dependent on the nature of the arene/Cp, the chelating ligand XY (e.g. C, N or O donors) and the monodentate ligand X (e.g. halide or pyridine derivative). Their attack on target sites can depend not only on affinities and rates of binding to nucleophilic sites, but also on coupling to redox-active centres in cells, sometimes with catalytic behaviour [2]. Metal complexes have the potential advantage over conventional anticancer agents of multi-targeting and polypharmacology [3], and the ability to overcome cisplatin and oxaliplatin resistance, a major clinical problem. However, successful phenotypic screening leads to the challenge of identifying the specific target sites in cells. For this, new experimental approaches are needed. We are exploring not only the use of transcriptomics and genomics for identifying biological pathways involved in activity, but also especially the use of ultra-high resolution Fourier transform mass spectrometry (FT-ICR MS) [4], which is revealing unexpected binding sites and modifications of peptides, proteins and DNA. We thank the ERC, EPSRC, BBSRC, WCPRS and Bruker Daltonics for support, and all our collaborators. [1] Zhao, Y.; Farrer, N.J.; Li, H.; Butler, J.S.; McQuitty, R.J.; Habtemariam, A.; Wang, F.; Sadler, P.J. Angew. Chem. Int. Ed. 2013, 52, 13633-13637. [2] Noffke, A.L.; Habtemariam, A.; Pizarro, A.M.; Sadler, P.J. Chem. Commun. 2012, 48, 5219-5246 [3] Romero-Canelón, I.; Sadler, P.J. Inorg. Chem. 2013, 52, 12276–12291. [4] Wills, R.H.;Habtemariam, A.; Lopez-Clavijo, A.F.; Barrow, M.P.; Sadler, P.J.; O’Connor, P.B. J. Am. Soc. Mass Spectrom. 2014, 25, 662-672.

Unusual modifications of protein and DNA targets by precious metal photoactivated and organometallic anticancer agents

249th National Meeting (2015)

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Unusual modifications of protein and DNA targets by precious metal photoactivated and organometallic anticancer agents<br />