Issue 12, 2018

New activation mechanism for half-sandwich organometallic anticancer complexes


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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Article information

Article type
Edge Article
25 Nov 2017
18 Feb 2018
First published
01 Mar 2018
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2018,9, 3177-3185

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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