Tracking Reactions of Asymmetric Organo-Osmium Transfer Hydrogenation Catalysts in Cancer Cells

Elizabeth M Bolitho; James P C Coverdale; Hannah E Bridgewater; Guy J Clarkson; Paul D Quinn; Carlos Sanchez-Cano; Peter J Sadler

doi:10.1002/anie.202016456

Tracking Reactions of Asymmetric Organo-Osmium Transfer Hydrogenation Catalysts in Cancer Cells

Elizabeth M Bolitho, James P C Coverdale, Hannah E Bridgewater, Guy J Clarkson, Paul D Quinn, Carlos Sanchez-Cano, Peter J Sadler

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Abstract

Most metallodrugs are prodrugs that can undergo ligand exchange and redox reactions in biological media. Here we have investigated the cellular stability of the anticancer complex [OsII [(η6 -p-cymene)(RR/SS-MePh-DPEN)] [1] (MePh-DPEN=tosyl-diphenylethylenediamine) which catalyses the enantioselective reduction of pyruvate to lactate in cells. The introduction of a bromide tag at an unreactive site on a phenyl substituent of Ph-DPEN allowed us to probe the fate of this ligand and Os in human cancer cells by a combination of X-ray fluorescence (XRF) elemental mapping and inductively coupled plasma-mass spectrometry (ICP-MS). The BrPh-DPEN ligand is readily displaced by reaction with endogenous thiols and translocated to the nucleus, whereas the Os fragment is exported from the cells. These data explain why the efficiency of catalysis is low, and suggests that it could be optimised by developing thiol resistant analogues. Moreover, this work also provides a new way for the delivery of ligands which are inactive when administered on their own.

Original language	English
Pages (from-to)	6462-6472
Number of pages	11
Journal	Angewandte Chemie (International ed. in English)
Volume	60
Issue number	12
Early online date	15 Feb 2021
DOIs	https://doi.org/10.1002/anie.202016456
Publication status	Published - 15 Mar 2021
Externally published	Yes

Bibliographical note

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Publisher Copyright:
© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH

Funder

Funding Information:
We thank the Engineering and Physical Sciences Research Council (EPSRC grant no. EP/P030572/1), and Warwick Collaborative Postgraduate Research Scholarship and Diamond Light Source (DLS, Oxford) for a studentship for E.M.B. C.S.C. thanks Gipuzkoa Foru Aldundia (Gipuzkoa Fellows program; grant number 2019‐FELL‐000018‐01/62/2019) for financial support. This work was performed under the Maria de Maeztu Units of Excellence Programme—Grant No. MDM‐2017‐0720 Ministry of Science, Innovation and Universities. We thank I. Bagley for assistance with zebrafish experiments, J. I. Song with cell experiments, S. E. Bakker and I. Hands‐Portsman (Advanced Bioimaging RTP) with plunge‐freezing, A. Catherwood and J. Tod with the freeze‐dryer, J. Barrios‐Rivera and S. Forshaw with GC‐FID, J. Parker and F. Cacho‐Nerin at the I14 beamline, L. Song and J. Morrey with mass spectrometry, I. Prokes with NMR spectroscopy, and M. Wills for stimulating discussions. All synchrotron work was performed at the I14 Beamline (DLS, Oxford) under experiment number sp20552‐1.

Keywords

anticancer catalysts
bioorganometallic chemistry
organo-osmium complexes
transfer hydrogenation
X-ray fluorescence

ASJC Scopus subject areas

Chemistry(all)
Catalysis

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/anie.202016456Licence: CC BY

PublishedFinal published version, 4.46 MBLicence: CC BY

Cite this

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abstract = "Most metallodrugs are prodrugs that can undergo ligand exchange and redox reactions in biological media. Here we have investigated the cellular stability of the anticancer complex [OsII [(η6 -p-cymene)(RR/SS-MePh-DPEN)] [1] (MePh-DPEN=tosyl-diphenylethylenediamine) which catalyses the enantioselective reduction of pyruvate to lactate in cells. The introduction of a bromide tag at an unreactive site on a phenyl substituent of Ph-DPEN allowed us to probe the fate of this ligand and Os in human cancer cells by a combination of X-ray fluorescence (XRF) elemental mapping and inductively coupled plasma-mass spectrometry (ICP-MS). The BrPh-DPEN ligand is readily displaced by reaction with endogenous thiols and translocated to the nucleus, whereas the Os fragment is exported from the cells. These data explain why the efficiency of catalysis is low, and suggests that it could be optimised by developing thiol resistant analogues. Moreover, this work also provides a new way for the delivery of ligands which are inactive when administered on their own.",

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Tracking Reactions of Asymmetric Organo-Osmium Transfer Hydrogenation Catalysts in Cancer Cells

Abstract

Bibliographical note

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Keywords

ASJC Scopus subject areas

UN SDGs

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