Abstract
AbstractMost 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.
Highlights
Transition metal catalysts have potential as therapeutic agents to treat cancer and other diseases.[1]
Angewandte Chemie International Edition published by Wiley-VCH GmbH
We introduced halogen tags (R1 or R2) into chiral Phdiphenylethylene (Ph-DPEN) ligands by coupling phenylsulfonyl chlorides carrying Br, I, or F in para or meta positions to 1S,2S or 1R,2R diphenylethylenediamine
Summary
Angewandte Chemie International Edition published by Wiley-VCH GmbH 3fold more efficient (in turnover frequency, TOF) and more stable (over one month under normal atmospheric conditions) than its industrially-used RuII analogue.[3] once inside cells, and in presence of the non-toxic hydride donor formate, this complex catalyses the enantioselective reduction of pyruvate, an essential precursor in cell metabolism, to natural L-lactate or unnatural D-lactate, depending on the chirality of the catalyst.[1f]. Chelated DPEN ligand to be tracked in cells using the halide label These experiments shed new light on the chemistry of these organometallic catalysts in cells, and will aid the design of next-generation catalytic drugs
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