Metal-based anticancer drugs

Fig. 2. Ligand substitution as a prodrug strategy for metallochem-otherapeutics (a) general scheme of prodrug activation by ligand substitution hydrolysis of a metal—halide bond is a typical activation pathway of metal-based anticancer drugs, as exemplified by the activation of cisplatin (b) and a ruthenium—arene complex (c).

Substituted titanocene dichlorides have potential application as metal-based anticancer drugs, and therefore, the cytotoxic activity of members of all four... 

Because of the severe side effects, the restricted tumour spectrum and the acquired or intrinsic resistance, alternative metal-based anticancer drugs are being actively pursued. Ruthenium compounds containing Ru or Ru are considered to be suitable candidates two mthenium(III) complexes have entered clinical trials, trans-[RuCl4(DMSO)(Im)]ImH (NAMI-A, where Im = imidazole) and trans-[RuCl4(Ind)2]IndH (KP1019, where Ind = indazole). This is the mthenium complex, their stmctures are presented in Figure 22.9. There are two... 

We have examined a class of gold(III) complexes using an integrated approach to the search for new metal-based anticancer drugs. This incorporates inorganic medicinal chemistry, in vitro screening, in vivo human tumour xenograft models and mechanistic studies. 

Cisplatin, as described earlier, is a heavy metal-based anticancer drug with absolutely no chemical features. 

Hannon MJ. Metal-based anticancer drugs from a past anchored in platinum chemistry to a post-genomic future of diverse chemistry and biology. Pure Appl Chem. 2007 79 2243-61. 

Molecular mechanics and dynamics studies of metal-nucleotide and metal-DNA interactions to date have been limited almost exclusively to modeling the interactions involving platinum-based anticancer drugs. As with metal-amino-acid complexes, there have been surprisingly few molecular mechanics studies of simple metal-nucleotide complexes that provide a means of deriving reliable force field parameters. A study of bis(purine)diamine-platinum(II) complexes successfully reproduced the structures of such complexes and demonstrated how steric factors influenced the barriers to rotation about the Pt(II)-N(purine) coordinate bonds and interconversion of the head-to-head (HTH) to head-to-tail (HTT) isomers (Fig. 12.4)[2011. In the process, force field parameters for the Pt(II)/nucleotide interactions were developed. A promising new approach involving the use of ab-initio calculations to calculate force constants has been applied to the interaction between Pt(II) and adenine[202]. 

Topics not included here or appearing in more length elsewhere include book-length discussions of concepts and summaries,toxic metal ions in the environment and nervous system, " and cisplatin as an anticancer agent (see Platinum-based Anticancer Drugs). An element by element discussion of toxicity appears in a convenient handbook. ... 

MM studies on metal-nueleotide and metal-DNA interactions are dominated by platinum-based anticancer drugs. There have been numerous studies on the interaetion of cisplatin, cis-[PtCl2(NH3)2] with DNA foeusing on the intrastrand adduct between adjaeent guanine bases. 

In our group, a major part of our research is devoted to the design of new anticancer drugs. Our recent efforts towards the discovery of new platinum-, ruthenium- and osmium-based anticancer agents provide the topic for this account and a section is devoted to each metal. We focus on recent results from our lab in the context of other developments and related research in this field (hence our coverage of the field is focused on these areas and is not comprehensive). 

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