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Tracking reactions of asymmetric organo-osmium transfer hydrogenation catalysts in cancer cells
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Bolitho, Elizabeth, Coverdale, James P. C., Bridgewater, Hannah E., Clarkson, Guy J., Quinn, Paul D., Sanchez-Cano, Carlos and Sadler, Peter J. (2021) Tracking reactions of asymmetric organo-osmium transfer hydrogenation catalysts in cancer cells. Angewandte Chemie International Edition, 60 (12). pp. 6462-6472. doi:10.1002/anie.202016456
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Official URL: https://doi.org/10.1002/anie.202016456
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.
| Item Type: | Journal Article | ||||||||||||
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| Subjects: | R Medicine > RM Therapeutics. Pharmacology R Medicine > RS Pharmacy and materia medica |
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||||||||||
| Library of Congress Subject Headings (LCSH): | Pharmaceutical chemistry, Organometallic chemistry, Prodrugs, Transition metal catalysts, Metal catalysts -- Therapeutic use, Antineoplastic agents -- Research | ||||||||||||
| Journal or Publication Title: | Angewandte Chemie International Edition | ||||||||||||
| Publisher: | Wiley-Blackwell Publishing Ltd. | ||||||||||||
| ISSN: | 1433-7851 | ||||||||||||
| Official Date: | 15 March 2021 | ||||||||||||
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| Volume: | 60 | ||||||||||||
| Number: | 12 | ||||||||||||
| Page Range: | pp. 6462-6472 | ||||||||||||
| DOI: | 10.1002/anie.202016456 | ||||||||||||
| Status: | Peer Reviewed | ||||||||||||
| Publication Status: | Published | ||||||||||||
| Access rights to Published version: | Open Access | ||||||||||||
| RIOXX Funder/Project Grant: |
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