Platinum and Ruthenium

Platinum anticancer agents have been used extensively during the last 35 years in chemotherapy. The drugs target and interact with DNA in cells and thus prevent cell division. The cytotoxic effect is most serious on rapidly dividing cells, i.e., in addition to cancer cells there are also the cells of normal bone marrow, gut, skin epithelium, and mucosa. The lack of high selectivity of the Pt drugs is one of its main problems and thus constitutes a major challenge in developing new pharmaceuticals.

FIGURE 10.10 Coenzyme B12. The prosthetic group in vitamin B12. Besides coordinating to four corrin nitrogen atoms (blue), the cobalt(III) ion is also bound to an axial ligand, nitrogen from a benzimidazole group (not shown). The vacant sixth position is a binding site for substrates and is indicated with a stick pointing upward. A phosphate group (orange) is seen in the lower right corner. The coordinates are taken from the Protein Data Bank (1CB7).

FIGURE 10.11 Platinum anticancer agents. Cisplatin (A). Oxaliplatin (B).

However, the drugs are partly selective toward cancer cells as they are more effective against proliferating cell than resting cells, where no DNA replication may occur over long periods of time.

Despite extensive research, only three platinum drugs have succeeded in reaching the market in the Western World while a fourth (satraplatin) is expected to be released in 2008. The relevant drugs are shortly introduced in the following text. For details concerning platinum interactions with proteins, biochemical pathways, and cancer type specific activities we refer to Chapter 23.

Cisplatin (cis-diamminedichloroplatinum(II); cis-DDP; Figure 10.11A), the first platinum anticancer agent to be used clinically, was discovered serendipitously in 1970 as an inhibitor of E. coli cell division. The two ammine ligands represent nonleaving groups and the chloride ions constitute exchangeable groups, which can be replaced by other ligands (nucleophiles). The second and third generation analogues to cis-DDP have been developed by simple substitution of the ammine ligands or chloride leaving groups of cisplatin. In "carboplatin" [cis-diammine-1,1-cyclobutanedicarboxyl-atoplatinum(II)], the two chloride ions have been substituted with less labile carboxylato groups. Carboplatin shows less toxic side effects than cisplatin and has now replaced the latter in many clinical situations.

In the third generation analogues of cisplatin, "oxaliplatin" [(diaminocyclohexane) oxalato-platinum(II); cf. Figure 10.11B] and "satraplatin" [bis(aceto)amminedichloro-(cyclohexylamine) platinum(IV)] all ligands have been replaced by more bulky ligands. They are effective in cells that show resistance to cisplatin. The unique feature of satraplatin is that platinum is present in the +4 oxidation state (compared to the more cytotoxic +2 oxidation state in the remaining platinum anticancer drugs). As a consequence it will undergo fewer reactions en route that make the drug suitable as an oral agent, which will potentially improve the quality of life millions of cancer patients.

Presumably, platinum agents mainly cross the cell membranes as uncharged molecules by passive diffusion, but studies indicate that active transport via Cu transporters are also involved. Once inside the cell, the compounds hydrolyze, i.e., cis- and carboplatin form the same positively charged di-aqua species [Pt(NH3)2(H2O)2]2+. This ligand exchange is essential as the aquated and positively charged molecules are very reactive toward nucleophilic centers in biomolecules. Thus, the aqua-platinum complex favors binding to the N7 atoms of the imidazole rings of guanosine (G) (Figure 10.12) and adenosine (A). Three different types of purine base adducts can be formed in DNA, all involving coordination to G: monadducts d(Gp), intrastrand crosslinks (1,2-d(GpG), 1,2-d(GpA), 1,3-d(GpXpGp)), and interstrand crosslinks like d(GpG). Platinum crosslinks cause bending of the double helix of DNA and thus induce changes in the secondary structure of DNA. Oxaliplatin, with its bulky and hydrophobic ligand causes a larger bend than cis- and carboplatin. In almost all cases of pt-DNA binding, the metal alone cannot be held responsible for binding and stability, but hydrogen bonding between the ligand and DNA is an additional factor, thus making the pt drugs "active complexes."

It is generally assumed that the cytotoxicity of platinum compounds is due to the ability of the cross-links to block DNA replication and/or prevent transcription, as polymerase enzymes cannot pass the lesions. The 1,2-intrastrand crosslink may be responsible for the cytotoxicity of cisplatin. In the trans-isomer, this crosslink cannot be established in line with the smaller cytotoxicity of this complex. Additionally, high mobility group (HMG) proteins recognize and bind to DNA at the 1,2-intrastrand crosslink. The HMG binding prevents the NER system (nucleotide excision repair system, which normally removes impaired DNA sequences) in removing the platinum adducts.

FIGURE 10.12 Platinum complex with DNA. Platinum (blue) is seen coordinated to two neighboring guanosine molecules in the DNA string. Nitrogen is blue, oxygen red, and phosphorus orange. The coordinates are taken from the Protein Data Bank (1A84).

It should be noted that most platinum containing agents bind to proteins rather than DNA and that the degree of platinum cytotoxicity cannot be explained by inhibition of DNA synthesis alone. Thus, other mechanisms such as direct binding and damage of proteins or other biomolecules may also be of significance in triggering apoptosis or necrosis. Currently, research is focused on the development of platinum (and ruthenium) anticancer drugs with other targets than DNA and on combination therapies.

In the last few years, the search for effective anticancer compounds based on other metal centers than Pt has been intensified and particularly anticancer drugs based on ruthenium are making progress in clinical trials. Two ruthenium-based anticancer drugs, NAMI-A (Imidazolium trans-[tetrachloro(DMSO)(imidazole)ruthenate(III)] and KP1019 (Indazolium trans-[tetrachlorobis (1H-indazole)ruthenate-(III); cf. Figure 10.13], are scheduled to enter phase 2 trials in the near future.

Both NAMI-A and KP1019 are prodrugs that have Ru present in the +3 oxidation state and are activated by reduction. The "activation by reduction" mechanism may contribute to the lower toxicity of Ru(III) compounds compared with Pt-based anticancer compounds. However, the lower toxicity may also be due to its ability to mimic iron in the binding to biological molecules such as albumin and transferrin. Binding of ruthenium to transferrin allows for effective uptake of Ru-based drugs into cancer cells, as transferrin receptors are generally overexpressed in rapidly dividing cells.

The first Ru-based anticancer drugs were designed to target DNA, similarly to cisplatin. However, NAMI-A and KP1019 belong to a newer generation of Ru-based drugs that do not target primary tumors and DNA, but instead target metastases cells and proteins. A recent approach is design of Ru-drugs with multiple modes of activity by combining Ru with an active targeted ligand. Some examples are the Ru-SERMs complexes (selective estrogen receptor modulators) that target both hormone-dependent and -independent breast tumors and RAPTA complexes designed to inhibit Glutathione-S-Transferases (GST), a cytosolic detoxification enzyme associated with drug resistance.

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