N‐Acetylmethionine and Biotin as Photocleavable Protective Groups for Ruthenium Polypyridyl Complexes

Abstract

Over the last decades the large therapeutic success of cisplatin-like anticancer drugs, combined to its recognized limitations (such as acquired resistance and general toxicity), have stimulated the scientific community to find other metal-based drugs with anticancer properties. Ruthenium-based molecules, and among them those containing polypyridyl ligands, have emerged as a vast family of active compounds. However, clinical studies have shown that general toxicity remains an important issue, and ruthenium-based chemotherapy is still a heavy burden for the cancer patient. Although several mechanisms might explain their anticancer properties in vivo, the thermal aquation of ruthenium–chloride bonds, followed by coordination to DNA 16–18] and/or proteins is, like for platinum-based anticancer drugs, a highly plausible mode of action (see Figure 1, route 1). 21] However, as thermal breaking of Ru!Cl bonds in aqueous solution might happen anywhere in a human body, this mechanism is thought to be the basis of both antitumor activity and general toxicity. Our analysis that the Ru!Cl coordination bond is too weak to provide good selectivity towards cancer cells, led us to look for protective groups, that is, ligands that would hold more strongly to ruthenium than chlorides, but that could also be cleaved in a controlled way in vivo. In the ideal case, such ligands would avoid the formation of aqua complexes, and thus prevent the coordination of competing biological ligands in vivo. Thioether ligands are ideal candidates because ruthenium(II) likes binding to their soft sulfur atom. Secondly, unlike nitrogen-based ligands, thioethers are only weakly basic in water, which might make their ruthenium complexes less sensitive to pH changes. Finally, visible-light irradiation leads to the controlled release of thioether ligands, which feature might be used to deliver locally the cytotoxic form of the ruthenium complex at the desired location (Figure 1, route 2). The use of light to cure cancer, which has notably led to the clinical development of photodynamic therapy, has also been proposed as an interesting development in metal-based anticancer drug research, in which the presence of oxygen is not required. To investigate this concept, we selected two monodentate thioether ligands of natural origin: N-acetyl-l-methionine and d-biotin, and synthesized their ruthenium complexes [Ru ACHTUNGTRENNUNG(terpy) ACHTUNGTRENNUNG(bpy)(N-acetyl-l-methionine)]Cl2 (compound [3]Cl2) and [RuACHTUNGTRENNUNG(terpy)ACHTUNGTRENNUNG(bpy) ACHTUNGTRENNUNG(d-biotin)]Cl2 (compound [4]Cl2, see Scheme 1). The synthesis is straightforward: it does not require any silver salts to remove the chloride anions, but simply requires mixing in water, at 80 8C and in the dark, the chlorido complex [Ru ACHTUNGTRENNUNG(terpy) ACHTUNGTRENNUNG(bpy)Cl]Cl (compound[1]Cl, see Scheme 1) and one equivalent of the thioether ligand. The course of the reaction can be nicely monitored using H NMR spectroscopy, since each different ruthenium species present in solution gives a distinct A6 [a] R. E. Goldbach, I. Rodriguez-Garcia, S. Bonnet Leiden Institute of Chemistry, Gorlaeus Laboratories Leiden University, P.O. Box 9502 2300 RA Leiden (The Netherlands) E-mail : bonnet@chem.leidenuniv.nl [b] J. H. v. Lenthe Theoretical Chemistry Group Debye Institute for Nanomaterial Science Faculty of Science, Utrecht University Padualaan 8, 3584 CH Utrecht (The Netherlands) [c] M. A. Siegler Small Molecule X-ray Facility Department of Chemistry, Johns Hopkins University Baltimore, MD 21218 (USA) Supporting information for this article (including synthetic procedures, full characterization and high-resolution ES-MS spectra of complexes [3]Cl2 and [4]Cl2; notations for the assignments of the NMR spectra and H NMR spectra; X-ray crystallography resolution method and data; ferrioxalate actinometry, quantum yield measurement procedures, H NMR and kinetic data for irradiation experiments; calculation procedure and x,y,z coordinates for the DFT-minimized species [3A] , [3B] , [4A], and [4B]) is available on the WWW under http://dx.doi.org/10.1002/chem.201101541. Figure 1. One of the modes of action of ruthenium polypyridyl anticancer drugs (reaction 1), and a new photochemotherapy strategy using analogous complexes “protected” by thioethers ligands and “deprotected” by visible light irradiation (reaction 2).