TY - JOUR
T1 - Tracking reactions of asymmetric organo‐osmium transfer hydrogenation catalysts in cancer cells
AU - Bolitho, Elizabeth M.
AU - Coverdale, James P. C.
AU - Bridgewater, Hannah E.
AU - Clarkson, Guy J.
AU - Quinn, Paul D.
AU - Sanchez‐Cano, Carlos
AU - Sadler, Peter J.
PY - 2021/3/15
Y1 - 2021/3/15
N2 - 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.
AB - 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.
KW - anticancer catalysts
KW - bioorganometallic chemistry
KW - organo-osmium complexes
KW - transfer hydrogenation
KW - x-ray fluorescence
UR - http://www.scopus.com/inward/record.url?scp=85101430844&partnerID=8YFLogxK
U2 - 10.1002/ange.202016456
DO - 10.1002/ange.202016456
M3 - Article
SN - 0044-8249
VL - 60
SP - 6462
EP - 6472
JO - Angewandte Chemie
JF - Angewandte Chemie
IS - 12
ER -
