Potential of cycloaddition reactions to generate cytotoxic metal drugs in vitro

Severe general toxicity issues blight many chemotherapeutics utilized in the treatment of cancers, resulting in the need for more selective drugs able to exert their biological activity at only the required location(s). Toward this aim, we report the development of an organometallic ruthenium compound, functionalized through a η6-bound arene ligand with a bicyclononyne derivative, able to participate in strain-promoted cycloaddition reactions with tetrazines. We show that combination of the ruthenium compound with a ditetrazine in biological media results in the in situ formation of a dinuclear molecule that is more cytotoxic toward cancer cells than the starting mononuclear ruthenium compound and tetrazine components. Such an approach may be extended to in vivo applications to construct a cytotoxic metallodrug at a tumor site, providing a novel approach toward the turn-on cytotoxicity of metallodrugs in the treatment of cancer

Ruthenium(ii) and osmium(ii) 1,2,3-triazolylidene organometallics: a preliminary investigation into the biological activity of ‘click’ carbene complexes

Taking advantage of the facile and versatile synthetic properties of 'click' 1,2,3-triazolylidene N-heterocyclic carbenes (tzNHC's), a range of new organometallic Ru(II) and Os(II) arene complexes containing functionalised tzNHC ligands, [M(eta(6)-p-cymene)(tzNHC)Cl-2] [M = Ru(II), Os(II)], have been synthesised and fully characterised, including the X-ray crystal structure of one of the Os(II) complexes. The tzNHC ligands remain coordinated to the metal centres under relevant physiological conditions, and following binding to the model protein, ubiquitin. The in vitro cytotoxicity of the compounds towards human ovarian cancer cells is dependent on the substituent on the tzNHC ligand but is generally <50 mu M and in some cases <1 mu M, whilst still retaining a high degree of selectivity towards cancer cells over healthy cells (1.85 mu M in A2780 ovarian cancer cells versus 435 mu M in human embryonic kidney cells in one case)