Unexpected arene ligand exchange results in the oxidation of an organoruthenium anticancer agent: the first X-ray structure of a protein–Ru(carbene) adduct

Abstract

The first X-ray structures of adducts formed between a RuII(N-heterocyclic carbene)(η6-p-cymene) compound and a protein are reported. Coordination to the protein induced the cleavage of the cymene ligand and EPR spectroscopy demonstrated the oxidation of the Ru centre.

High-resolution crystal structures of a “half sandwich”-type Ru(II) coordination compound bound to hen egg-white lysozyme and proteinase K

“…Although this binding site was suggested to be weaker, as the complex was refined with 0.5 occupancy, this observation provides evidence that most likely the ligand-induced charge of the Ru fragments can modulate the selectivity of the metalation site. In a later work, the same group presented the first X-ray structure of a Ru-carbene adduct of HEWL using [Ru II (η 6 -p-cymene)(dmb)Cl 2 ] (dmb = 1,3-dimethylbenzimidazol-2-ylidene), where three distinct binding sites were identified [33]. In the first site, {RuCl 2 (dmb)(OH x )} was coordinated to both side-chains of Arg14 and His15, whereas at the second site, an adduct of {RuCl 2 (dmb) (OH x ) 2 } with the side-chain amine of Lys33 was formed.…”

“…In the first site, {RuCl 2 (dmb)(OH x )} was coordinated to both side-chains of Arg14 and His15, whereas at the second site, an adduct of {RuCl 2 (dmb) (OH x ) 2 } with the side-chain amine of Lys33 was formed. A third site was identified with a {RuCl(OH x ) 4 } fragment displaying weak interactions with the carbonyl oxygen of Ala107 [33]. Although the overall charge of the Ru adducts could not be unambiguously determined (the metal center has been shown to be oxidized upon exchange of the arene ligand, and the nature of the coordinated H 2 O vs OH − has not been determined), and thus, no correlation between fragment's charge and site selectivity can be extracted; these results clearly show that different fragments target diverse sites.…”

“…tenfold faster hydrolysis rate than RAED-C under the same conditions [30]. The nature of protein-ruthenium adducts at the atomic level has been elucidated by crystallographic studies, which highlight the role and importance of the Ru ligands, and provide clues about a general mode of Ru binding [31][32][33]. With the aim to obtain structural information on the proteinbinding mode of these Ru(II) coordination compounds, and towards a better understanding of their mode of action, we studied the crystal structures of the protein adducts formed upon reaction of RuTE-Cl with hen egg-white lysozyme (HEWL) and proteinase K (PK).…”

“…HEWL (EC 3.2.1.17) is a 129-amino acid residue enzyme (14.3 kDa) and has been extensively employed as a model protein due to its stability over a wide range of conditions. More importantly, HEWL has been employed in several structural studies of metal-based complexes, including ruthenium anticancer compounds [32,[34][35][36], thus allowing for direct comparisons. PK from the mold Tritirachium album Limber (EC 3.4.21.64) is a commonly used, broad-spectrum protease that belongs to the subtilisin peptidase family S8 [37].…”

Synthesis, structure and anticancer properties of new biotin- and morpholine-functionalized ruthenium and osmium half-sandwich complexes

“…Metal-arene coordination is well known to stabilize halfsandwich complexes, and increase lipophilicity [10]. Recent developments further highlighted the importance of the metal-arene: the p-cymene can be released to form new complexes via an original pathway [51] and this may play a role in the interaction with proteins [52]. We thus sought to explore the nature of the metal-arene bond.…”