Of platinum compounds

Table 2. Lytic effects of platinum compounds on E.coli Tau strain (3)...

After this brief introduction, the chapter will focus on solvolysis reactions and acid-base equilibria of various platinum compounds and on species distribution of isomeric [PtCl2(NH3)2] in aqueous solution in Section 2. Binding of platinum compounds to monomeric nucleobase derivatives will be discussed in Section 3, while Section 4 pays attention to the reactions of Pt-nucleobase complexes with different nucleophiles. And finally, the interactions of Pt with DNA and defined oligonucleotides will be discussed in Section 5. 

The availability of different metal ion binding sites in 9-substituted purine and pyrimidine nucleobases and their model compounds has been recently reviewed by Lippert [7]. The distribution of metal ions between various donor atoms depends on the basicity of the donor atom, steric factors, interligand interactions, and on the nature of the metal. Under appropriate reaction conditions most of the heteroatoms in purine and pyrimidine moieties are capable of binding Pt(II) or Pt(IV) [7]. In addition, platinum binding also to the carbon atoms (e.g. to C5 in 1,3-dimethyluracil) has been established [22]. However, the strong preference of platinum coordination to the N7 and N1 sites in purine bases and to the N3 site in pyrimidine bases cannot completely be explained by the negative molecular electrostatic potential associated with these sites [23], Other factors, such as kinetics of various binding modes and steric factors, appear to play an important role in the complexation reactions of platinum compounds. 

Antitumor Activities of Platinum Compounds Against L1210 in Vivo... 

In a review of explosions involving derivatives of gold, silver and platimmi, reactions of ammonia with gold and silver compoimds, and of hydrogen in presence of platinum compounds are emphasised. 

During the past decades a vast amount of evidence has been obtained that points to interactions of platinum compounds with DNA in the tumor cell as the origin for cytotoxic action. The most important observations are as follows ... 

Initially these hypotheses directed almost all attention to platinum-DNA interactions in the studies concerning the working mechanism of cis-Pt. However, it cannot be excluded that other cis-Pt-induced processes at the cellular level might attribute to the ultimate cell killing. In this respect the natural immune response should be mentioned. It appears, however, that an ever-increasing amount of research is focused on the interactions of platinum compounds with DNA. 

Binding of Platinum Compounds to Monomeric Nucleic Acid Fragments. 65... 

Investigations on the working mechanism of cisplatin have been carried out during the last decade by a variety of research groups, involving chemists, biochemists, biologists and medical researchers17. Early studies already made it clear that reaction of platinum compounds with nucleic adds play an important role in the mechanism of action. The present review deals with the status of this field, with special attention to platinum-DNA interactions. 

In the field of new platinum compounds the recently described ascorbato-Pt compounds look very promising125,126). In the study of platinum compounds with nucleobases... 

Recent investigations of Kumada et al.69 3 694) show that the catalytic action of platinum compounds leads to rearrangements of pentamethyldisilane and tetramethyldisilane to higher silanes ... 

Platinum-based compounds are commonly used as cancer treatment agents. Pharmacokinetic studies of these antitumor drugs require ultratrace analysis. Electrothermal vaporization ICP-MS provides low detection limits for small samples [256]. High-performance liquid chromatography with ICP-MS detection allows speciation of platinum compounds in tissues [256]. LA-ICP-MS can be used to study the distribution of platinum in tissues and tumors [256]. Natural levels of Pt are below typical quadrupole ICP-MS detection limits [257]. 

A substantial body of literature documents the side effects of platinum compounds. The nephrotoxicity of the parent compound cisplatin almost led to its abandonment, until Cvitkovic et al. introduced aggressive hydration, which prevented the development of acute renal failure [2] [3], As noted above, the toxicity of cisplatin was a driving force both in the search for less toxic analogues and for more effective treatments for its side effects, especially nausea and vomiting. 

Research in the last decade has made clear that the toxic side effects of platinum compounds have an exciting molecular basis. It has stimulated the research activities dealing with Pt compounds and rescue agents (usually S-donor ligands) and especially the study of the reactions of these compounds in combination with other cellular components and their complicated cell-wall transport. 

Methods for Screening the Potential Antitumor Activity of Platinum Compounds in Combinatorial Libraries... 

Both pyridine (pyr) and quinoline (quin) compounds are efficient cross-linking agents but not potent cytotoxic agents. Interstrand cross-linking is thus not by itself a sufficient requirement for cytotoxicity. These results were also of considerable interest because the mononuclear precursors were found to be similar in cytotoxicity to cisplatin itself, violating the classical structure-activity relationship of platinum compounds. Yet incorporation into the dinuclear structure did not produce active compounds ... 

At the preclinical level, oral antitumor activity has been observed with two other classes of platinum compound, the PtIV monocarboxylate, C(5)-OHP-C1, and the first Ptn complex to exhibit oral activity, the sterically hindered AMD473. Now licenced to Zeneca, AMD473 exhibited promising circumvention of acquired cisplatin resistance against both in vitro and in vivo preclinical models. Together with the drug s favourable pharmacokinetic and toxicology profile in rodents (myelosuppression was dose-limit-... 

The success of cisplatin and carboplatin in treating cancer, combined with the intrinsic and acquired resistance of many tumors to traditional platinum chemotherapy, has generated considerable interest in developing next-generation platinum drugs. Since the discovery of the antitumor activity of cisplatin, researchers have reported the synthesis, characterization, and antitumor activity of thousands of platinum compounds [1] [2]. The previous two chapters in this section describe the promising activity of novel multi-nuclear Ptn and orally active PtIV complexes [3] [4],... 

In vitro methods are not widely used to predict the antitumor activity of platinum compounds. Until it is determined what factors render a specific platinum-DNA adduct cytotoxic, the in vitro screens for platinum drugs will be limited. Because a good platinum drug must form DNA adducts, preliminary screening methods have been employed which measure DNA binding alone as a measure of potential antitumor activity. In one such study [13], the DNA binding of palladium and platinum complexes having inter-... 

Although the platinum-amino-acid complexes do not show much promise as cytotoxic agents, these results demonstrated the utility of in vitro screening methods to survey the DNA-binding properties of platinum compounds in a combinatorial manner. Assuming that HMG-domain proteins are involved in the cisplatin mechanism of action, then screening based on the Pt-... 

Cossa G, Gatti L, Zunino F, Perego P (2009) Strategies to improve the efficacy of platinum compounds. Curr Med Chem 16 2355-2365... 

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