New activation mechanism for half-sandwich organometallic anticancer complexes

Abstract

The Cp ^<i>x</i> C-H protons in certain organometallic Rh^III half-sandwich anticancer complexes [(η⁵-Cp ^<i>x</i> )Rh(<i>N</i>,<i>N</i>')Cl]⁺, where Cp ^<i>x</i> = Cp*, phenyl or biphenyl-Me₄Cp, and <i>N</i>,<i>N</i>' = bipyridine, dimethylbipyridine, or phenanthroline, can undergo rapid sequential deuteration of all 15 Cp* methyl protons in aqueous media at ambient temperature. DFT calculations suggest a mechanism involving abstraction of a Cp* proton by the Rh-hydroxido complex, followed by sequential H/D exchange, with the Cp* rings behaving like dynamic molecular 'twisters'. The calculations reveal the crucial role of p_π orbitals of <i>N</i>,<i>N</i>'-chelated ligands in stabilizing deprotonated Cp ^<i>x</i> ligands, and also the accessibility of Rh^I-fulvene intermediates. They also provide insight into why biologically-inactive complexes such as [(Cp*)Rh^III(en)Cl]⁺ and [(Cp*)Ir^III(bpy)Cl]⁺ do not have activated Cp* rings. The thiol tripeptide glutathione (γ-l-Glu-l-Cys-Gly, GSH) and the activated dienophile <i>N</i>-methylmaleimide, (NMM) did not undergo addition reactions with the proposed Rh^I-fulvene, although they were able to control the extent of Cp* deuteration. We readily trapped and characterized Rh^I-fulvene intermediates by Diels-Alder [4+2] cyclo-addition reactions with the natural biological dienes isoprene and conjugated (9<i>Z</i>,11<i>E</i>)-linoleic acid in aqueous media, including cell culture medium, the first report of a Diels-Alder reaction of a metal-bound fulvene in aqueous solution. These findings will introduce new concepts into the design of organometallic Cp* anticancer complexes with novel mechanisms of action.