Quantitative measurement of the reduction of platinum(iv) complexes using X-ray absorption near-edge spectroscopy (XANES)

Abstract

The platinum(II) drugs cisplatin, carboplatin and oxaliplatin are usefully employed against a range of malignancies, but toxicities and resistance have spurred the search for improved analogs. This has included investigation of the platinum(IV) oxidation state, which provides greater kinetic inertness. It is generally accepted that Pt(IV) complexes must be reduced to Pt(II) for activation. As such, the ability to monitor reduction of Pt(IV) complexes is critical to guiding the design of candidates, and providing mechanistic understanding. Here we report in full that the white line height of X-ray absorption near-edge spectra (XANES) of Pt complexes, normalized to the post-edge minima, can be used to quantitatively determine the proportion of each oxidation state in a mixture. A series of Pt(IV) complexes based on the Pt(II) complexes cisplatin and transplatin were prepared with chlorido, acetato or hydroxido axial ligands, and studies into their reduction potential and cytotoxicity against A2780 human ovarian cancer cells were performed, demonstrating the relationship between reduction potential and cytotoxicity. Analysis of white line height demonstrated a clear and consistent difference between Pt(II) (1.52 ± 0.05) and Pt(IV) (2.43 ± 0.19) complexes. Reduction of Pt(IV) complexes over time in cell growth media and A2780 cells was observed by XANES, and shown to correspond with their reduction potentials and cytotoxicities. We propose that this method is useful for monitoring reduction of metal-based drug candidates in complex biological systems.

Reduction of ormaplatin and cis-diamminetetrachloroplatinum(iv) by ascorbic acid and dominant thiols in human plasma: kinetic and mechanistic analyses

“…24,[29][30][31][32][33][34][35] In this work, we report a kinetic investigation of the reduction of [Pt(dach)Cl 4 ], cis-[Pt(NH 3 ) 2 Cl 4 ], and cis,cis,trans-[Pt(NH 3 ) 2 Cl 2 Br 2 ] by Asc, and the "observed activation parameters" (vide infra) at physiological pH (7.40); cis-[Pt(NH 3 ) 2 Cl 4 ], and cis,cis,trans-[Pt(NH 3 ) 2 Cl 2 Br 2 ] are the cisplatin prodrugs. 41,42 The structures of these Pt(IV) prodrugs and ascorbic acid are illustrated in Scheme 1. In addition, we studied the reduction of [Pt(dach)Cl 4 ] and cis-[Pt(NH 3 ) 2 Cl 4 ] by Asc in a much wider pH range.…”

A Single‐Site Platinum CO Oxidation Catalyst in Zeolite KLTL: Microscopic and Spectroscopic Determination of the Locations of the Platinum Atoms

“…[15] The white line intensity and XANES features of the as-prepared sample at approximately 11 580 eV nearly match those of Pt II tetraamine complexes. [15] The white line intensity increased during oxidation (Supporting Information, Figure S3), indicating an increase in the number of oxygen donor atoms without a change in the platinum oxidation state, [16,17] corresponding to the unchanged edge energy [18] and the increase from 2 to 3 of the PtÀO coordination number representing oxygen atoms bonded to Pt after the oxidation (Table 1).…”

Characterization of the mechanism of reduction of trans-diamminetetrachloroplatinum(IV) by l-cysteine and dl-homocysteine

“…Therefore, the development of a new generation of platinum anticancer drugs is of great interest in order to minimize the toxic effects of such drugs and also to broaden the spectrum of treatable cancers. This process has involved the design and synthesis of numerous Pt(IV) compounds [2,[4][5][6][7][8][9]. Although Pt(IV) anticancer drugs usually have two ammines/amines in cis positions in their equatorial planes similar to cisplatin and other Pt(II) drugs [2,[4][5][6], some Pt(IV) complexes with two ammines/amines in trans positions in their equatorial planes also show anticancer activities [7][8][9].…”

“…Contrary to their inert behaviors toward substitution, Pt(IV) anticancer drugs can be reduced readily to their Pt(II) counterparts and they are thus often referred to as prodrugs [1,2,[4][5][6][7][8][9]. Some dominant small molecule reductants in plasma [10] such as L-cysteine, glutathione, and ascorbic acid are believed to be responsible for the reduction of Pt(IV) anticancer prodrugs [11][12][13][14][15].…”

“…Trans-[Pt(NH 3 ) 2 Cl 4 ] was chosen as a representative for the class of Pt(IV) anticancer active compounds bearing a transdiammine configuration in the equatorial plane [7]. To the best of our knowledge, the kinetic and mechanistic aspects of the reduction of Pt(IV) anticancer prodrugs with a transdiammine configuration in their equatorial planes by thiolcontaining compounds have not been studied before [11][12][13][14][15][16][17][18][19][20].…”