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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Catalysis / drug effects
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Crystallography, X-Ray
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Dose-Response Relationship, Drug
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Drug Screening Assays, Antitumor
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Female
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Fibroblasts / drug effects
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Humans
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Hydrogenation / drug effects
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Models, Molecular
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Molecular Structure
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Organometallic Compounds / chemical synthesis
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Organometallic Compounds / chemistry
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Organometallic Compounds / pharmacology*
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Osmium / chemistry
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Osmium / pharmacology*
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Ovarian Neoplasms / drug therapy*
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Ovarian Neoplasms / metabolism*
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Ovarian Neoplasms / pathology
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Organometallic Compounds
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Osmium
Associated data
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PubChem-Substance/348400921
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PubChem-Substance/348400922
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PubChem-Substance/348400929
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PubChem-Substance/348400931
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PubChem-Substance/348400923
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PubChem-Substance/348400924
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PubChem-Substance/348400925
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PubChem-Substance/348400926
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PubChem-Substance/348400927
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PubChem-Substance/348400930
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PubChem-Substance/348400932
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PubChem-Substance/348400928