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.

• Authors: James P C Coverdale, Isolda Romero-Canelón, Carlos Sanchez-Cano, Guy J Clarkson, Abraha Habtemariam, Martin Wills, Peter J Sadler
• Journal: Nature chemistry (Nat Chem) Vol. 10 Issue 3 Pg. 347-354 (03 2018) ISSN: 1755-4349 [Electronic] England
• PMID: 29461524 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Organometallic Compounds
• Osmium

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Catalysis (drug effects)
• Crystallography, X-Ray
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Female
• Fibroblasts (drug effects)
• Humans
• Hydrogenation (drug effects)
• Models, Molecular
• Molecular Structure
• Organometallic Compounds (chemical synthesis, chemistry, pharmacology)
• Osmium (chemistry, pharmacology)
• Ovarian Neoplasms (drug therapy, metabolism, pathology)
• Structure-Activity Relationship