Ruthenium arenes

A. General Features of Ruthenium-Arene Anticancer Drugs 24... 

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).

Other active areas of research into the anticancer properties of ruthenium(II) complexes, include, amongst several other examples, the related work on RAPTA ruthenium-arene... 

Fig. 12. (a) General structure of the half-sandwich, piano-stool ruthenium—arene complexes (b) X and Y are commonly occupied by a bidentate ligand L giving a monofunctional complex (c) tethering of a monodentate ligand to the arene results in a bifunctional complex. 

We have also recently explored some ruthenium-arene complexes that depart markedly from the general structure described above. For instance, full-sandwich ruthenium complexes have been synthesized, in which the positions X, Y, and Z are taken by an rj6-arene ring of a biologically active ligand, such as aspartame, to assess the influence of a metal complex as a modulating substituent on the properties of the bioactive ligand (66). 

Fig. 14. Dynamic chiral recognition of 9-ethylguanine by chiral ruthenium-arene complex 9.

A convenient and easily accessible way to quantify hydrophobicity is the determination of the octanolAvater partition coefficient (log P) and we have determined the hydrophobicity of 13 selected ruthenium-arene complexes (71). As expected, hydrophobicity increases with an increase of the size of the coordinated arene ring, but decreases significantly when the chloride is replaced by neutral ligands such as pyridine and 4-cyanopyridine. The latter observation is somewhat counter intuitive at first inspection, but correlates with replacement of anionic chloride to yield a dicationic complex. The hydrophobicity... 

Fig. 15. Trends illustrating the influence of the arene, the chelate, and the leaving group on the cytotoxicity and cross-resistance of ruthenium-arene complexes developed in the Sadler lab. The complexes are not cross-resistant with cisplatin.

Aquation. The principal reactivity of our family of ruthenium-arene complexes is the exchange of the leaving group Z, usually a... 

Loss of Coordinated Arene. We previously stated that the arene ligand in ruthenium(II)-arene complexes is relatively inert towards displacement under physiological conditions. While this is generally true, there are a few exceptions to this rule and this type of reactivity can be used to advantage. Weakly bound arenes, for instance, can be thermally displaced, a property convenient for the synthesis of ruthenium-arene complexes that are not readily available through more common synthetic routes. This way, the reaction of a precursor dimer, [RuCl2(etb)]2 (etb, ethylbenzoate) (68), with either 3-phenyl-1-propylamine or... 

Alternatively, arene displacement can also be photo- rather than thermally-induced. In this respect, we studied the photoactivation of the dinuclear ruthenium-arene complex [ RuCl (rj6-indane) 2(p-2,3-dpp)]2+ (2,3-dpp, 2,3-bis(2-pyridyl)pyrazine) (21). The thermal reactivity of this compound is limited to the stepwise double aquation (which shows biexponential kinetics), but irradiation of the sample results in photoinduced loss of the arene. This photoactivation pathway produces ruthenium species that are more active than their ruthenium-arene precursors (Fig. 18). At the same time, free indane fluoresces 40 times more strongly than bound indane, opening up possibilities to use the arene as a fluorescent marker for imaging purposes. The photoactivation pathway is different from those previously discussed for photoactivated Pt(IV) diazido complexes, as it involves photosubstitution rather than photoreduction. Importantly, the photoactivation mechanism is independent of oxygen (see Section II on photoactivatable platinum drugs) (83). 

Fig. 19. The combination of (a) a strong stereospecific hydrogenbonding interaction of the C60 carbonyl of 9-EtG with an en NH in [Ru(r 6-dha)(en)(9-EtG)]+ and (b) a strong ti-ti arene-nucleobase stacking interaction is responsible for the high preference of G over A observed for such ruthenium—arene complexes.

This work provides important evidence for elucidating the cytotoxic effect of the ruthenium-arene complexes and the influence of the arene thereon, for instance with respect to excision repair of DNA lesions and DNA destabilization. It also established two different classes of Ru(II) arene anticancer drugs, i.e. those bearing an arene that has the possibility to intercalate and those that do not. This distinction is important as we will see further differences in DNA binding interactions for these two classes (vide infra). 

Further experiments focused therefore on [RuCl(en)(r 6-tha)]+ (12) and [RuCl(rj6-p-cym)(en)]+ (22), which represent the two different classes, and their conformational distortion of short oligonucleotide duplexes. Chemical probes demonstrated that the induced distortion extended over at least seven base pairs for [RuCl(rj6-p-cym)(en)]+ (22), whereas the distortion was less extensive for [RuCl(en)(rj6-tha)]+ (12). Isothermal titration calorimetry also showed that the thermodynamic destabilization of the duplex was more pronounced for [RuCl(r 6-p-cym)(en)]+ (22) (89). DNA polymerization was markedly more strongly inhibited by the monofunctional Ru(II) adducts than by monofunctional Pt(II) compounds. The lack of recognition of the DNA monofunctional adducts by HMGB1, an interaction that shields cisplatin-DNA adducts from repair, points to a different mechanism of antitumor activity for the ruthenium-arenes. DNA repair activity by a repair-proficient HeLa cell-free extract (CFE) showed a considerably lower level of damage-induced DNA repair synthesis (about six times) for [RuCl(en)(rj6-tha)] + compared to cisplatin. This enhanced persistence of the adduct is consistent with the higher cytotoxicity of this compound (89). 

Histidine residues are, however, generally regarded as major possible binding sites for ruthenium-arene complexes in proteins. To model this interaction, we also studied the reaction of [RuCl(en)(rj6-bip)]+ (10) with L-histidine at 310 K in aqueous solution (91). The reaction was quite sluggish and did not reach equilibrium until 24 h at 310 K, by which time only about 22% of the complex had reacted. Two isomeric imidazole-bound histidine adducts could be discerned, with more or less equal binding of Ne... 

Fig. 22. Remarkable activation-by-ligand-oxidation pathways for the reaction of ruthenium-arenes with thiolates. (a) Reaction of [Ru (r 6-bip)(en)(OH2)]+ with GSH (b) direct synthesis of ruthenium-arene sulfenato complexes (c) the air-stable thiolato complexes are oxidized in the presence of the antioxidant GSH.

We started this section by stating that the advent of bioorganometallics provides the medicinal chemist with access to new types of reactivity and therefore with new opportunities for anticancer drug design. Our studies on the ruthenium-arene... 

Fig. 24. Comparison between the osmium- and ruthenium-arenes, exemplified by the respective [M(ri6-bip)Cl(en)]+ complexes. Although the crystal structures show the complexes to be isostructural with similar M-Cl bond lengths (a), the properties of the complexes are quite different, illustrated by the differences in hydrolysis rate h1/2), pAa, and 5 -GMP binding (the black box denotes the amount of OP03-bound 5 -GMP) (b).

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