Platinum chemistry

The cell-killing effects of cisplatin (and carboplatin) appear to be due to the formation of various stable bifunctional adducts on DNA, which then block replication or inhibit transcription. Supportive evidence for DNA as the critical target for the antitumour activity of cisplatin is provided by observations that cells from patients with diseases where DNA repair processes are deficient e.g. Xeroderma pigmentosum) are hypersensitive to cisplatin. In addition, correlations have been shown between levels of platinum-DNA adducts in peripheral blood cells (leukocytes) and disease response in patients receiving cisplatin or carboplatin.  

---

Works developed by Navarro and coworkers for the palladium and stabilized ylides complexes have been extended to the platinum chemistry (Scheme 25) [97,98]. 

In platinum chemistry, cleavage of bis(silyl) compounds by HCl may be used [Eqs. (58), (59)] to generate monosilyl complexes 63). 

Thus we shall be concerned with properties that furnish information about the nature of the ligands, the oxidation state of the metal, and the geometry of the field of ligands. Techniques such as radio-isotope tracer studies, neutron-activation analysis, and electron microscopy are powerful methods for locating a metal within constituents of the cell and are particularly suited to heavy-metal rather than organic drugs but since they do not provide information about the chemical environment of the metal they will not concern us here. After each section below we shall give an example, not necessarily from platinum chemistry, where the method has been used with success in biochemistry. 

There is a protein, metallothionine, which is found in kidney and which binds cadmium and zinc very effectively. This may well be related to the bacterial protein. We see that biological systems have developed highly selective ways of countering the influence of poisonous metals. The protection involves the interaction between a selected protein and a given metal. We can now return to platinum chemistry. 

Metal chemical shifts have not found extensive use in relation to structural problems in catalysis. This is partially due to the relatively poor sensitivity of many (but not all) spin 1=1/2 metals. The most interesting exception concerns Pt, which is 33.7% abundant and possesses a relatively large magnetic moment. Platinum chemistry often serves as a model for the catalytically more useful palladium. Additionally, Pt NMR, has been used in connection with the hydrosilyla-tion and hydroformylation reactions. In the former area, Roy and Taylor [82] have prepared the catalysts Pt(SiCl2Me)2(l,5-COD) and [Pt()i-Cl)(SiCl2Me)(q -l,5-COD)]2 and used Pt methods (plus Si and NMR) to characterize these and related compounds. These represent the first stable alkene platinum silyl complexes and their reactions are thought to support the often-cited Chalk-Harrod hydrosilylation mechanism. 

It appears that one of these rate constants (kc or kt) is 10 times as large as the other and anyone who has worked in platinum chemistry will say, of course, that chloride has a greater trans effect than ammonia. These are both weak trans directors, but one would expect the fast reaction site to be the cw-chlorides in other words, the chloride which is trans to a chloride, the cis-diaquo isomer, is the one which should be formed rapidly. 

The complex PtCl2 is an extremely useful precursor in platinum chemistry.10b The labile benzonitrile ligands can be easily and quantatively replaced by neutral ligands (e.g., amines, phosphines, etc.). On the other hand, the chloride ligands can be substituted by nucleophiles of which an example is given below. 

Among the less common oxidation states those of I and III have the most significance. Complexes of platinum(III) have been of interest for many years because of their intermediacy in substitution reactions of platinum(II) and (IV). More recently binuclear platinum(I) and (III) complexes have been isolated, and the chemistry of these new complexes will be of increasing interest in platinum chemistry. Platinum forms strong homometallic bonds giving rise to multimetallic chain compounds and cluster complexes. The increasing use of X-ray crystallography, and 31P and 19 PtNMR will allow systematic studies to be made on these multimetallic platinum complexes. 

Four comprehensive sources are available for platinum chemistry, three of which are written in the English language. The companion volume Comprehensive Organometallic Chemistry has a chapter devoted to platinum, and three books are of primary importance to readers with an interest in the coordination chemistry of platinum. The books by Belluco5 and Muraveiskaya6 are restricted to the organometallic and coordination chemistry of platinum, and Hartley s book is entitled, The Chemistry of Platinum and Palladium .7 It is assumed that readers will use these sources in conjunction with this chapter. For earlier literature this... 

Infrared and Raman spectra are useful, of course, in determining the symmetry of poly(nitrile) complexes. An example is dichlorobis(benzonitrile)platinum, a versatile starting material in platinum chemistry. There is a dispute in the literature as to whether it has a cis or trans configuration. (There is a general agreement that the corresponding Pd complex is trans.) It has recently been shown by X-ray structure analysis that both cis and trans complexes exist, and their vibrational spectra have been discussed.21... 

Carbon-bonded [-diketonate ligands, in which the metal is bonded to the central carbon, i.e. that flanked by two acetyl groups, are rather common in palladium and platinum chemistry and were first demonstrated in K[Pt(Cl)(C-MeC0CHC0Me)(0,0-MeC0CHC0Me)] (Figure 4).54... 

The intermediacy of B—H— -metal linkages in the formation of direct boron-metal a bonds is well illustrated by studies in carbaboranetungsten-platinum chemistry. The reaction between the salts [PtH(Me2CO)(PEt3)2]-... 

Higher Oxidation State Organopalladium and Platinum Chemistry... 

As clearly written in several chapters of this volume, the story of cisplatin is indeed a success story, given the numerous patients that have been completely cured after cisplatin (or carboplatin) treatment of cancer [1], This chapter will deal with a special aspect of platinum chemistry, namely its re-... 

So, in principle, we have to consider three types of species, all competing for cisplatin, namely, the rescue agents, the peptides and proteins, and the DNA. Although, at present, much highly relevant information is available about Pt-DNA binding, information of other aspects of in vivo platinum chemistry has become recently available [18-20], A review devoted towards the interaction of (new, active, and some relevant inactive) platinum compounds (in model fluids in vitro and in vivo) with cellular components (DNA peptides) and additives (rescue agents) is highly relevant and timely, and the most important results available will be discussed below. 

More recent evidence has been gained that shows that the formation of dimeric Ptm species may be a relatively common, although overlooked, feature of platinum chemistry and, also in the case of monomeric Pt11 species, might play an important role in redox reactions. A mechanistic interpretation of their formation will be proposed. 

At the time MBBMA was written, little was known of the chemistry of compounds containing the Pt2+ central unit, which is isoelectronic with the Rh2+ unit. The scope of this area of platinum chemistry, and some that are closely related, has increased enormously in the past few years. 

Such coupling is not unexpected in nickel, palladium and platinum chemistry, and it takes place in the presence of donor ligands such as CO, PPh, as demonstrated in the coupling of two allyl groups (Equation (65)). 

The organometallic chemistry of palladium is one of the most extensive and varied fields of transition metal organometallic chemistry. In many respects, the chemistry of palladium parallels that of platinum, as one would expect from its place in the periodic table. However, where a given compound might be a stable species in platinum chemistry. 

In 1926, Chernyaev introduced the concept of the trans effect in platinum chemistry. In reactions of square-planar Pt(II) compounds, ligands trans to chloride are more easily replaced than those trans to ligands such as ammonia chloride is said to have a stronger trans effect than ammonia. When coupled with the fact that chloride itself is more easily replaced than ammonia, this trans effect allows the formation of isomeric... 

The source of trans stereoselectivity for Co—H addition reactions to acetylenes while olefins are generally cis is unclear. Cis237 and trans238 additions of acetylenes are known in platinum chemistry, and radical intermediates are thought to play a role in some insertions.239 Cis additions indicate concerted insertion reactions, while trans additions are indicative of radical pathways. Sterically demanding acetylenes can lead to a reversal of regio- and stereochemistry.208... 

This chapter describes the clinical properties of cisplatin, and of its analogues that have undergone extensive clinical trials (particularly carboplatin), platinum chemistry relating to mechanism of action, the mechanisms of tumour resistance to cisplatin and their circumvention. 

---