Catalytic anticancer metallodrugs active at low doses could minimize side-effects, introduce novel mechanisms of action that combat resistance and widen the spectrum of anticancer-drug activity. Here we use highly stable chiral half-sandwich organometallic Os(II) arene sulfonyl diamine complexes, [Os(arene)(TsDPEN)] (TsDPEN, N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine), to achieve a highly enantioselective reduction of pyruvate, a key intermediate in metabolic pathways. Reduction is shown both in aqueous model systems and in human cancer cells, with non-toxic concentrations of sodium formate used as a hydride source. The catalytic mechanism generates selectivity towards ovarian cancer cells versus non-cancerous fibroblasts (both ovarian and lung), which are commonly used as models of healthy proliferating cells. The formate precursor N-formylmethionine was explored as an alternative to formate in PC3 prostate cancer cells, which are known to overexpress a deformylase enzyme. Transfer-hydrogenation catalysts that generate reductive stress in cancer cells offer a new approach to cancer therapy.
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We thank the European Research Council (grant no. 247450 and no. 324594), Science City (Advantage West Midlands and the European Regional Development Fund), Warwick Collaborative Postgraduate Research Scholarship and Bruker Daltonics (studentship for J.P.C.C.), Engineering and Physical Research Council/Cancer Research UK (grant no. C53561/A19933) for support, and EU COST Action CM1105 for stimulating discussions. Some reduced precursors for dimer synthesis were kindly provided by K. T. Bhayat and R. Needham. We thank L. Song and P. Aston for assistance with mass spectrometry, A. Knight, H. E. Bridgewater and J. I. Song for assistance with cell experiments and I. Prokes for assistance with NMR spectroscopy.
The authors declare no competing financial interests.
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Coverdale, J., Romero-Canelón, I., Sanchez-Cano, C. et al. Asymmetric transfer hydrogenation by synthetic catalysts in cancer cells. Nature Chem 10, 347–354 (2018). https://doi.org/10.1038/nchem.2918
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