化学
转移加氢
甲酸钠
组合化学
对映选择合成
催化作用
癌细胞
格式化
氢化物
有机化学
癌症
钌
生物化学
医学
内科学
氢
作者
James P. C. Coverdale,Isolda Romero‐Canelón,Carlos Sanchez‐Cano,Guy J. Clarkson,Abraha Habtemariam,Martin Wills,Peter J. Sadler
出处
期刊:Nature Chemistry
[Springer Nature]
日期:2018-01-08
卷期号:10 (3): 347-354
被引量:170
摘要
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.
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