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New activation mechanism for half-sandwich organometallic anticancer complexes
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Banerjee, Samya, Soldevila-Barreda, Joan J., Wolny, Juliusz A., Wootton, Christopher, Habtemariam, Abraha, Romero-Canelón, Isolda, Chen, Feng, Clarkson, Guy J., Prokes, Ivan, Song, Lijiang, O'Connor, Peter B., Schünemann, Volker and Sadler, P. J. (2018) New activation mechanism for half-sandwich organometallic anticancer complexes. Chemical Science, 9 (12). pp. 3177-3185. doi:10.1039/c7sc05058e
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Official URL: http://doi.org/10.1039/c7sc05058e
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.
| Item Type: | Journal Article | |||||||||||||||||||||||||||||||||
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| Subjects: | R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry R Medicine > RS Pharmacy and materia medica |
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| Divisions: | Faculty of Science > Chemistry | |||||||||||||||||||||||||||||||||
| SWORD Depositor: | Library Publications Router | |||||||||||||||||||||||||||||||||
| Library of Congress Subject Headings (LCSH): | Antineoplastic agents, Organometallic compounds | |||||||||||||||||||||||||||||||||
| Journal or Publication Title: | Chemical Science | |||||||||||||||||||||||||||||||||
| Publisher: | Royal Society of Chemistry (RSC) | |||||||||||||||||||||||||||||||||
| ISSN: | 2041-6539 | |||||||||||||||||||||||||||||||||
| Official Date: | 1 March 2018 | |||||||||||||||||||||||||||||||||
| Dates: |
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| Volume: | 9 | |||||||||||||||||||||||||||||||||
| Number: | 12 | |||||||||||||||||||||||||||||||||
| Page Range: | pp. 3177-3185 | |||||||||||||||||||||||||||||||||
| DOI: | 10.1039/c7sc05058e | |||||||||||||||||||||||||||||||||
| Status: | Peer Reviewed | |||||||||||||||||||||||||||||||||
| Publication Status: | Published | |||||||||||||||||||||||||||||||||
| Publisher Statement: | ||||||||||||||||||||||||||||||||||
| Access rights to Published version: | Open Access | |||||||||||||||||||||||||||||||||
| Funder: | Bruker Analytische Meßtechnik GmbH | |||||||||||||||||||||||||||||||||
| RIOXX Funder/Project Grant: |
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