Stabilization of Triam(m)inechloridoplatinum Complexes by Oxidation to PtIV

Abstract

PtIV analogues of the active end groups {PtClN3} of multinuclear Pt anticancer drugs have been investigated. The crystal structure of trans,mer-[PtCl(OH)2(dien)]Cl shows that the bond lengths are similar to those in the dihydroxidoplatinum(iv) analogue of cisplatin. The axial ligands are shown to be the predominant influence on reduction potentials with the dihydroxido complex trans,mer-[PtCl(OH)2(NH3)3]Cl being the most resistant to reduction. X-ray absorption near-edge spectroscopy is shown to be suitable for monitoring the oxidation state of these complexes and reveals that trans,mer-[PtCl(OH)2(NH3)3]+ survives for more than 2 h in cancer cells.

The use of X-ray absorption and synchrotron based micro-X-ray fluorescence spectroscopy to investigate anti-cancer metal compounds in vivo and in vitro

“…Hambley et al 54 presented a method whereby the ratio a/b of the absorbance maximum at the white line a and the post edge minimum b is linearly related to the content of Pt(IV), which was used to determine the percentage of Pt(IV) present in an unknown sample. Daly et al 55 applied this concept of the Pt(IV)/Pt(II) ratio determination to determine the extent of reduction of the triamine platinum complexes 9 (Fig. 2) and 10 ( Fig.…”

Synchrotron Radiation Spectroscopic Techniques as Tools for the Medicinal Chemist: Microprobe X-Ray Fluorescence Imaging, X-Ray Absorption Spectroscopy, and Infrared Microspectroscopy

“…[33,74] So too did the ratio of the intensity of the white line peak to the post-edge region. [33,74] In recent efforts to try to combat cisplatin resistance, Hambley and coworkers [75] , since the latter complex had been withdrawn from phase II clinical trials due to side effects (despite earlier promise). [75] Human ovarian A2780 carcinoma cells were treated with the Pt(IV) drug and analysis of the XANES spectra with respect to the standard curve, prepared from the ratio of the peak height to the post-edge intensity for known ratios of Pt(II) to Pt(IV), was performed.…”

“…[33,74] In recent efforts to try to combat cisplatin resistance, Hambley and coworkers [75] , since the latter complex had been withdrawn from phase II clinical trials due to side effects (despite earlier promise). [75] Human ovarian A2780 carcinoma cells were treated with the Pt(IV) drug and analysis of the XANES spectra with respect to the standard curve, prepared from the ratio of the peak height to the post-edge intensity for known ratios of Pt(II) to Pt(IV), was performed. It was found that 38% of the drug had reduced to Pt(II) in the first 2 h while most of the drug (87%) had converted to Pt(II) within 24 h. They concluded that the improved intracellular stability of the triammine complex highlights the importance of preparation and testing of the Pt(IV) polynuclear complex.…”

“…Bulk XAS has also been used for the development of controlled release drug delivery systems by confirming the integrity of drugs in the delivery agent; a specific example being the use of XAS to confirm that the structure of cisplatin did not alter following its incorporation into poly(ethylene oxide) gel. [73] Hambley and coworkers [33,[74][75] used bulk XAS to determine the ability of Pt-treated cancer cells to reduce Pt(IV) complexes to the potentially more active Pt(II) anti-cancer agents. Predictably, the position of the edge assisted in the differentiation (2.2 eV difference)…”

Foreword to the 39th International Conference on Coordination Chemistry Bioinorganic Research Front

“…The use of synchrotron radiation as a tool for imaging metals within cells is covered in two different papers using distinct techniques. Trevor Hambley (Sydney) and coworkers, [5] using X-ray absorption near-edge spectroscopy, have developed a way of extracting information about the relative proportions of Pt(II) and Pt(IV) within cells. Pt(II) complexes comprise the most thoroughly investigated metal-based anticancer drugs to date but their side effects, linked to reactions with other biomolecules, have led to new approaches including the use of more chemically inert Pt(IV) analogues.…”