Reversible activation dynamics of Tethered Osmium(II) half-sandwich complexes for biological applications

Zusammenfassung

Novel osmium(II) arene compounds of general formulae [Os(η6-areneZ)(XY)(Z’)]n+ (open) and [Os(η6:κ1-areneZ)(XY)]n+ (closed) are presented in this Thesis. The areneZ functionalized ligand is hemilabile, and has the capability to not only 6-bind the osmium centre but also to form a -bond with the metal, affording a tether ring; XY is a chelating bidentate ligand; and Z’ (when Z is not binding to Os) is present as a labile monodentate ligand. The Z donor group located in the arene offers two reversible functionalities: (i) binding to the Os(II) centre to form a closed tether-ring complex (inactive form) or (ii) dissociation from the Os(II) centre —as a pendant arm— to afford an open-tether complex (active form). We have explored the reactivity profile of tethered osmium(II) arene complexes for their development as scaffolds to generate reversible activatable metallo(pro)drugs. Structural modifications of the building blocks constituting the Os(II) complexes can fine-tune the activation of the Os–Z bond by varying (i) the functionalization in the hemilabile arene ligand (carboxylic acids, alcohols, amines and sulfonamides) as well as the length and structural tension of the tether ring, (ii) the chelating ligand (aliphatic or aromatic N,N-; N,O-- or N,C--bidentate ligands), and (iii) the monodentate ligand in open-tether complexes of formula [Os(η6-areneZ)(XY)(Z’)]n+ (mostly chlorido but also iodido and pyridine). Following an introduction to the field of metals in medicine in Chapter 1, Chapter 2 presents the design, synthesis, and characterization of the different hemilabile ligands used throughout this Thesis. Chapter 2 provides valuable information regarding how both length and rigidity of the tethering arm, together with the nature of the donor atom, are important features that play a key role in the activation of the Os–Z(tether) bond. Chapter 2 also introduces the synthesis of the dimer precursors of the target monomers studied in this Thesis, as well as the first examples of Os(II) tethered half-sandwich compounds bearing carboxylate hemilabile ligands. As an introduction to the aqueous and cytotoxic studies, some pKa and IC50 data are also included. In Chapter 3, we investigated in depth the family of compounds bearing a hemilabile alcohol in the tether arm, in their open- and closed-tethered form, [Os(η6-C6H5(CH2)3OH)(XY)Cl]n+ and [Os(η6:κ1-C6H5(CH2)3OH)(XY)]n+, respectively, bearing different XY chelating ligands. Despite of the inefficiency and/or low reactivity of water-mediated processes reported in the literature for Os-arenes complexes and the consequent formation of inert osmium hydroxo bridges, we achieve successful interconversion of Os–chlorido into Os–aqua species, showing an entirely new reactivity profile. We unveil that the deprotonated aqua adduct, that is, the hydroxido adduct (Os–OH), in fact triggers intramolecular rearrangement culminating in the binding of the pendant alcohol-oxygen to the metal centre (reversible formation of a closed tether complex), and thus, protects the complex towards irreversible inactivation. This is achieved by introducing a terminal alcohol functionality attached to the arene ligand, which can bind the osmium centre. Moreover, this family of compounds was proved successful in carrying out transfer hydrogenation reactions inside cells. Chapter 4 is focused on Os(II) complexes bearing a nitrogen (either from an amine or a sulfonamide) in the pendant arm from the arene to form the Os-tethered structure. Three subfamilies of compounds are synthesised, characterised and their speciation in water solutions is investigated. Several biological studies are carried out with these complexes; not only the cytotoxic activity and intracellular accumulation is assessed but, importantly, the capacity to modulate the internal pH in cancer cells is also evaluated. The latter represent an entirely new set of experiments developed for organometallic complexes. These experiments have been possible thanks to the collaboration with Prof. Diane Barber (UCSF) who invited me to stay in her laboratories in San Francisco (USA) for three months (placement supported by an individually awarded EMBO travel grant). Finally, Chapter 5 contains a selection of tethered osmium(II) half-sandwich compounds using different hemilabile ligands (most of them used as building blocks in Chapters 2–4) yet using the same XY chelating ligand, phenylpyridine. The selection of the latter is based on the high potency that this ligand provides Os(II) half-sandwich compounds with. We determine the IC50 values as well as their speciation in aqueous and DMSO solutions with unexpected results, as the complexes are unreactive towards pure DMSO yet readily react with this solvent when hydrolysed.