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Issue 12, 2018
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New activation mechanism for half-sandwich organometallic anticancer complexes

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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.

Graphical abstract: New activation mechanism for half-sandwich organometallic anticancer complexes

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Publication details

The article was received on 25 Nov 2017, accepted on 18 Feb 2018 and first published on 01 Mar 2018


Article type: Edge Article
DOI: 10.1039/C7SC05058E
Citation: Chem. Sci., 2018,9, 3177-3185
  • Open access: Creative Commons BY license
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    New activation mechanism for half-sandwich organometallic anticancer complexes

    S. Banerjee, J. J. Soldevila-Barreda, J. A. Wolny, C. A. Wootton, A. Habtemariam, I. Romero-Canelón, F. Chen, G. J. Clarkson, I. Prokes, L. Song, P. B. O'Connor, V. Schünemann and P. J. Sadler, Chem. Sci., 2018, 9, 3177
    DOI: 10.1039/C7SC05058E

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