Asymmetric transfer hydrogenation by synthetic catalysts in cancer cells

• Published in: Nature chemistry 2018-03, Vol.10 (3), p.347-354
• Main Authors: Coverdale, James P. C., Romero-Canelón, Isolda, Sanchez-Cano, Carlos, Clarkson, Guy J., Habtemariam, Abraha, Wills, Martin, Sadler, Peter J.
• Format: Article
• Language: English
• Subjects: 639/638/263/49; 639/638/92/603; Analytical Chemistry; Anticancer properties; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biochemistry; Catalysis; Catalysis - drug effects; Catalysts; Cell culture; Chemistry; Chemistry/Food Science; Crystallography, X-Ray; Deformation mechanisms; Diamines; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Enantiomers; Female; Fibroblasts; Fibroblasts - drug effects; Humans; Hydrogenation; Hydrogenation - drug effects; Inorganic Chemistry; Metabolic pathways; Models, Molecular; Molecular Structure; Organic Chemistry; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Osmium - chemistry; Osmium - pharmacology; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Physical Chemistry; Prostate cancer; Pyruvic acid; Reduction; Selectivity; Side effects; Sodium; Sodium formate; Structure-Activity Relationship
• ISSN: 1755-4330; 1755-4349
• DOI: 10.1038/nchem.2918

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. Intracellular asymmetric transfer hydrogenation catalysis using Os( II ) complexes has now been demonstrated and offers a new approach for selectively killing cancer cells. Enantiomers of Os( II ) arene catalysts can penetrate cell membranes enabling the reduction of pyruvate to D - or L -lactate using formate as a hydride source, with high enantioselectivity.