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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 ISSN 2041-6539.

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Official URL: http://doi.org/10.1039/c7sc05058e

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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.

Item Type: Journal Article
Subjects: R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
R Medicine > RS Pharmacy and materia medica
Divisions: Faculty of Science, Engineering and Medicine > 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:
DateEvent
1 March 2018Published
18 February 2018Accepted
Volume: 9
Number: 12
Page Range: pp. 3177-3185
DOI: 10.1039/c7sc05058e
Status: Peer Reviewed
Publication Status: Published
Reuse Statement (publisher, data, author rights):
Access rights to Published version: Open Access (Creative Commons)
Date of first compliant deposit: 14 May 2018
Date of first compliant Open Access: 14 May 2018
Funder: Bruker Analytische Meßtechnik GmbH
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
247450European Research Councilhttp://dx.doi.org/10.13039/501100000781
EP/F034210/1[EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266
UNSPECIFIEDUniversity of Warwickhttp://dx.doi.org/10.13039/501100000741
Scholarship Alexander von Humboldt-Stiftunghttp://dx.doi.org/10.13039/100005156
UNSPECIFIEDRoyal Societyhttp://dx.doi.org/10.13039/501100000288
Newton International FellowshipScience and Education Research Board (SERB)UNSPECIFIED
StudentshipChina Scholarship Councilhttp://dx.doi.org/10.13039/501100004543
Warwick Collaborative StudentshipBruker Analytische Meßtechnik GmbHhttp://viaf.org/viaf/268533260
NANOKABundesministerium für Bildung und Forschunghttp://dx.doi.org/10.13039/501100002347
Action CM1105European Cooperation in Science and Technologyhttp://dx.doi.org/10.13039/501100000921

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