Dimethylsulfoxide complexes

The solubility of ruthenium complexes can be highly improved by substituting the NH3 ligands by dimethylsulfoxide (DMSO) molecules. The initial in vitro and in vivo studies with DMSO complexes were performed by Mestroni, Alessio

Ruthenium Complexes that Mimic Platinum Drugs

SO(CH3)2

SO(CH3)2

SO(CH3)2

SO(CH3)2

SO(CH3)2

SO(CH3)2

Figure 19.3 Dimethyl-sulfoxide complexes. (a) ci's-[RuII(DMSO)4Cl2] and the corresponding aqua species, (b) trans-[RuII(DMSO)4Cl2] and the corresponding aqua species, (c) Na{trans-[Rum(DMSO)(Im)Cl4r} (NAMI) and its imidazolium salt (NAMI-A)

and co-workers on the cis- and trans-[RuII(DMSO)4Cl2] complexes (Figure 19.3a and 3b).25'26

Although both isomers were shown to be able to coordinate N7 positions of guanine residues of DNA, different studies have shown that trans-[RuII(DMSO)4Cl2]

binds much more rapidly to DNA than the ci's-isomer. ' Moreover, only monoadducts of the cis-isomer on DNA are observed, whereas the trans-complex, similarly to cisplatin, is able to form DNA biadducts leading to intra- and inter-strand cross-links.25,30 The difference of behavior between the two isomers has been explained by differences in the DMSO coordination sites. Indeed, in the trans-[RuII(DMSO)4Cl2], the four DMSO ligands are coordinated via the S atom whereas the cis-isomer contains three S-bonded DMSO molecules and the fourth one is coordinated via the oxygen atom. In solution, due to the important trans labilizing effect induced by a S-bonded DMSO on another DMSO ligand, the cis-[RuII(DMSO)4Cl2] loses rapidly its O-bonded DMSO in preference to an aqua molecule, whereas the trans-isomer loses two DMSO ligands

(Figure 19.3). After this first step, both isomers slowly lose one chloride ligand, resulting in a species containing three reactive groups in the case of the transisomer but containing only two reactive sites in the case of the cis-isomer (Figure 19.3).29 Moreover, the reaction of the complex on DNA is facilitated thanks to a weaker steric hindrance in the case of the trans compound which contains less remaining DMSO ligands than the cis-isomer.

cis- And trans-[RuII(DMSO)4Cl2] have been tested in vitro and in vivo against different tumor cells, and the trans-isomer was shown to be almost 16 times more active than the cis-isomer, confirming a mechanism including DNA binding.28,31,32 On the other hand, if trans-[RuII(DMSO)4Cl2] is less active than cisplatin against P388 leukemia for example, the reverse tendency is observed when the ruthenium complex is tested against a Pt-resistant P388 leukemia tumor line.31 Moreover, trans-[RuII(DMSO)4Cl2] presents a good anti-meta-static activity that is particularly interesting since metastatic cancers are particularly difficult to cure.32,33

The encouraging results obtained with trans- [RuII(DMSO)4Cl2] are at the origin of the search for other trans-DMSO ruthenium complexes as anti-cancer agents. The more promising compounds of this kind are the Rura complexes Na{trans-[RuIII(DMSO)(Im)Cl4]} (NAMI) and its imidazolium salt NAMI-A (Figure 19.3c) which is a more stable and reproducible solid than NAMI. (NAMI has two DMSO molecules of crystallization that can be randomly replaced by water or acetone molecules of the crystallization solvent.)34,35 NAMI-A is currently being tested in clinical phase I studies and presents an interesting anti-metastatic activity on a broad range of tumors among which is lung metastasis.35 37 Such a complex could be particularly useful in minimizing the growth of undetected micro-metastases following surgery or radiotherapy.

However, the mechanism by which NAMI and NAMI-A exert their anti-metastatic activity is not yet elucidated, but could require in vivo reduction. It has been shown that NAMI loses two of its chloride ligands and is transformed into the corresponding, more reactive, aqua species that can bind to various biomolecules among which is DNA.38 NAMI is also able to inhibit DNA and RNA polymerases, but not to form significant DNA interstrand cross-links.6,39 Thus, the anti-metastatic activity of NAMI and NAMI-A seems to arise from other mechanisms than in the case of cisplatin, such as protein-DNA cross-links for example.39 41

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