Asymmetric transfer hydrogenation by synthetic catalysts in cancer cells

Abstract

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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Figure 1: Synthesis of osmium(II) arene sulfonamide catalysts 18.
Figure 2: Catalytic reduction of pyruvate to lactate in aqueous solution by [Os(p-cymene)(TsDPEN)] (2) using formate as a hydride source.
Figure 3: Potentiation of the antiproliferative activity of the osmium p-cymene complex S,S-2 or biphenyl complex S,S-7.
Figure 4: The enantioselectivity for the transfer hydrogenation (reduction) of pyruvate to afford selectively D-lactate is conserved in cells.

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Acknowledgements

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.

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All the authors were involved with the design and interpretation of the experiments and with the writing of the manuscript. Chemical and biological experiments were carried out by J.P.C.C., I.R.-C., C.S.-C. and A.H. G.J.C. carried out the X-ray crystallography. All the authors have given approval to the final version of the manuscript.

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Correspondence to Peter J. Sadler.

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The authors declare no competing financial interests.

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Crystallographic data for compound RR-7. (CIF 1656 kb)

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Crystallographic data for compound SS-7. (CIF 1132 kb)

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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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