New activation mechanism for half-sandwich organometallic anticancer complexes

Abstract

The Cpx C-H protons in certain organometallic RhIII half-sandwich anticancer complexes [(η5-Cpx)Rh(N,N′)Cl]+, where Cpx = Cp∗, phenyl or biphenyl-Me4Cp, and N,N′ = 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 pπ orbitals of N,N′-chelated ligands in stabilizing deprotonated Cpx ligands, and also the accessibility of RhI-fulvene intermediates. They also provide insight into why biologically-inactive complexes such as [(Cp∗)RhIII(en)Cl]+ and [(Cp∗)IrIII(bpy)Cl]+ do not have activated Cp∗ rings. The thiol tripeptide glutathione (γ-l-Glu-l-Cys-Gly, GSH) and the activated dienophile N-methylmaleimide, (NMM) did not undergo addition reactions with the proposed RhI-fulvene, although they were able to control the extent of Cp∗ deuteration. We readily trapped and characterized RhI-fulvene intermediates by Diels-Alder [4+2] cyclo-addition reactions with the natural biological dienes isoprene and conjugated (9Z,11E)-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.