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 languageEnglish
Pages (from-to)6462-6472
Number of pages11
JournalAngewandte Chemie
Volume60
Issue number12
Early online date15 Feb 2021
DOIs
Publication statusPublished - 15 Mar 2021

Keywords

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

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