Abstract
Stable five-coordinate Pt(II) complexes have been highlighted as a promising and original platform for the development of new cytotoxic drugs. Their interaction with proteins has been scarcely studied. Here, the reactivity of the five-coordinate Pt(II) compound [Pt(I)(Me) (dmphen)(olefin)] (Me = methyl, dmphen = 2,9-dimethyl-1,10-phenanthroline, olefin = dimethylfumarate) with the model proteins hen egg white lysozyme (HEWL) and bovine pancreatic ribonuclease (RNase A) has been investigated by X-ray crystallography and electrospray ionization mass spectrometry. The X-ray structures of the adducts of RNase A and HEWL with [Pt(I)(Me)(dmphen)(olefin)] are not of very high quality, but overall data indicate that, upon reaction with RNase A, the compound coordinates the side chain of His105 upon releasing the iodide ligand, but retains the pentacoordination. On the contrary, upon reaction with HEWL, the trigonal bi-pyramidal Pt geometry is lost, the iodide and the olefin ligands are released, and the metal center coordinates the side chain of His15 probably adopting a nearly square-planar geometry. This work underlines the importance of the combined use of crystallographic and mass spectrometry techniques to characterize, in detail, the protein–metallodrug recognition process. Our findings also suggest that five-coordinate Pt(II) complexes can act either retaining their uncommon structure or functioning as prodrugs, i.e., releasing square-planar platinum complexes as bioactive species.
Highlights
Cisplatin (cis-diamminedichloridoplatinum(II)) and its second-generation analogues are among the most used anticancer drugs [1,2,3]
We have studied the reaction of a five-coordinate Pt(II) compound with two model proteins through a combined electrospray ionization mass spectra (ESI MS)/X-ray crystallography approach [50,51]
Our experiments show that complex I can react with proteins, leading to different products
Summary
Cisplatin (cis-diamminedichloridoplatinum(II)) and its second-generation analogues are among the most used anticancer drugs [1,2,3]. Direct Pt interactions with proteins play an important role in these adverse effects [8,9,10,11,12] To overcome these side effects, structurally and functionally unique metallodrugs have been designed [1]. These include trans-configured complexes [13], Pt(IV) compounds [14,15], polynuclear complexes [16], photoactivatable complexes [17], and even five-coordinate (trigonal bi-pyramidal) complexes of general formula [Pt(X)(Y)(N–N)(olefin)] (X = halide; Y = alkyl, aryl, or halide) [18,19]
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