New activation mechanism for half-sandwich organometallic anticancer complexes

The Cp(x) C–H protons in certain organometallic Rh(III) half-sandwich anticancer complexes [(η(5)-Cp(x))Rh(N,N′)Cl](+), where Cp(x) = Cp*, phenyl or biphenyl-Me(4)Cp, 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 p(π) orbitals of N,N′-chelated ligands in stabilizing deprotonated Cp(x) 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 N-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 (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.