Easy to synthesize, robust organo-osmium asymmetric transfer hydrogenation catalysts

Asymmetric transfer hydrogenation (ATH) is an important process in organic synthesis for which the Noyori-type RuII catalysts [(arene)Ru(Tsdiamine)] are now well established and widely used. We now demonstrate for the first time the catalytic activity of the osmium analogues. X-ray crystal structures of the 16-electron OsII catalysts are almost identical to those of RuII. Intriguingly the precursor complex was isolated as a dichlorido complex with a monodentate amine ligand. The OsII catalysts are readily synthesised (within 1 h) and exhibit excellent enantioselectivity in ATH reactions of ketones

In‐cell Catalysis by Tethered Organo−Osmium Complexes Generates Selectivity for Breast Cancer Cells

Anticancer agents that exhibit catalytic mechanisms of action offer a unique multi‐targeting strategy to overcome drug resistance. Nonetheless, many in‐cell catalysts in development are hindered by deactivation by endogenous nucleophiles. We have synthesised a highly potent, stable Os‐based 16‐electron half‐sandwich (‘piano stool’) catalyst by introducing a permanent covalent tether between the arene and chelated diamine ligand. This catalyst exhibits antiproliferative activity comparable to the clinical drug cisplatin towards triple‐negative breast cancer cells and can overcome tamoxifen resistance. Speciation experiments revealed Os to be almost exclusively albumin‐bound in the extracellular medium, while cellular accumulation studies identified an energy‐dependent, protein‐mediated Os accumulation pathway, consistent with albumin‐mediated uptake. Importantly, the tethered Os complex was active for in‐cell transfer hydrogenation catalysis, initiated by co‐administration of a non‐toxic dose of sodium formate as a source of hydride, indicating that the Os catalyst is delivered to the cytosol of cancer cells intact. The mechanism of action involves the generation of reactive oxygen species (ROS), thus exploiting the inherent redox vulnerability of cancer cells, accompanied by selectivity for cancerous cells over non‐tumorigenic cells

Asymmetric transfer hydrogenation by synthetic catalysts in cancer cells

Catalytic anticancer metallodrugs active at low doses could minimise side-effects, introduce novel mechanisms of action which combat resistance, and widen the spectrum of anticancer drug activity. We have used new highly-stable chiral half-sandwich organometallic Os(II) arene sulfonyl diamine complexes, [Os(arene)(TsDPEN)] to achieve highly enantioselective reduction of pyruvate, a key intermediate in metabolic pathways, both in aqueous model systems and in human cancer cells, using non-toxic concentrations of sodium formate as a hydride source. Importantly 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 over-express a deformylase enzyme. Transfer hydrogenation catalysts generating reductive stress in cancer cells offer a ground-breaking new approach to cancer therapy

Albumin-mediated extracellular zinc speciation drives cellular zinc uptake

This work was financially supported by the Leverhulme Trust (RPG-2017-214) and BBSRC (BB/J006467/1 and BB/V014684/1). We thank Prof. Andrew Riches (University of St. Andrews) for provision of materials, and Dr. Elizabeth Bolitho (University of Warwick) for assistance with cell culture experiments.The role of the extracellular medium in influencing metal uptake into cells has not been described quantitatively. In a chemically defined model system containing albumin, zinc influx into endothelial cells correlates with the extracellular free zinc concentration. Allosteric inhibition of zinc-binding to albumin by free fatty acids increased zinc flux.Publisher PDFPeer reviewe

Transfer hydrogenation and antiproliferative activity of tethered half-sandwich organoruthenium catalysts

We report the synthesis and characterization of four neutral organometallic tethered complexes, [Ru(η6-Ph(CH2)3-ethylenediamine-N-R)Cl], where R = methanesulfonyl (Ms, 1), toluenesulfonyl (Ts, 2), 4-trifluoromethylbenzenesulfonyl (Tf, 3), and 4-nitrobenzenesulfonyl (Nb, 4), including their X-ray crystal structures. These complexes exhibit moderate antiproliferative activity toward human ovarian, lung, hepatocellular, and breast cancer cell lines. Complex 2 in particular exhibits a low cross-resistance with cisplatin. The complexes show potent catalytic activity in the transfer hydrogenation of NAD+ to NADH with formate as hydride donor in aqueous solution (310 K, pH 7). Substituents on the chelated ligand decreased the turnover frequency in the order Nb > Tf > Ts > Ms. An enhancement of antiproliferative activity (up to 22%) was observed on coadministration with nontoxic concentrations of sodium formate (0.5–2 mM). Complex 2 binds to nucleobase guanine (9-EtG), but DNA appears not to be the target, as little binding to calf thymus DNA or bacterial plasmid DNA was observed. In addition, complex 2 reacts rapidly with glutathione (GSH), which might hamper transfer hydrogenation reactions in cells. Complex 2 induced a dose-dependent G1 cell cycle arrest after 24 h exposure in A2780 human ovarian cancer cells while promoting an increase in reactive oxygen species (ROS), which is likely to contribute to its antiproliferative activity

Osmium–arene complexes with high potency towards Mycobacterium tuberculosis

The treatment of tuberculosis (TB) poses a major challenge as frontline therapeutic agents become increasingly ineffective with the emergence and spread of drug-resistant strains of Mycobacterium tuberculosis (Mtb). To combat this global health problem, new antitubercular agents with novel modes of action are needed. We have screened a close family of 17 organometallic half-sandwich Os(II) complexes [(arene)Os(phenyl-azo/imino-pyridine)(Cl/I)]+Y– containing various arenes (p-cymene, biphenyl, or terphenyl), and NMe2, F, Cl, or Br phenyl or pyridyl substituents, for activity towards Mtb in comparison with normal human lung cells (MRC5). In general, complexes with a monodentate iodido ligand were more potent than chlorido complexes, and the five most potent iodido complexes (MIC 1.25–2.5 µM) have an electron-donating Me2N or OH substituent on the phenyl ring. As expected, the counter anion Y (PF6–, Cl–, I–) had little effect on the activity. The pattern of potency of the complexes towards Mtb is similar to that towards human cells, perhaps because in both cases intracellular thiols are likely to be involved in their activation and their redox mechanism of action. The most active complex against Mtb is the p-cymene Os(II) NMe2-phenyl-azopyridine iodido complex (2), a relatively inert complex that also exhibits potent activity towards cancer cells. The uptake of Os from complex 2 by Mtb is rapid and peaks after 6 h, with temperature-dependence studies suggesting a major role for active transport. Significance to Metallomics Antimicrobial resistance is a global health problem. New advances are urgently needed in the discovery of new antibiotics with novel mechanisms of action. Half-sandwich organometallic complexes offer a versatile platform for drug design. We show that with an appropriate choice of the arene, an N,N-chelated ligand, and monodentate ligand, half-sandwich organo–osmium(II) complexes can exhibit potent activity towards Mycobacterium tuberculosis (Mtb), the leading cause of death from a single infectious agent. The patterns of activity of the 17 azo- and imino-pyridine complexes studied here towards Mtb and normal lung cells suggest a common redox mechanism of action involving intracellular thiols

Analysis of radially resolved spectra and potential for lasing in Mo wire array Z pinches

Measurements of radially resolved L-shell Mo spectra from wire array pinches on Sandia's Z generator are presented and analyzed using a collisional-radiative model. The spectra indicate large radial gradients in density over the {approx}8-mm-diameter plasma column, but only the emission from the {approx}2 mm central region of the pinch appears to be influenced by opacity. Population inversions and significant gain factors for 100-200 {angstrom} transitions in Ne-like Mo are predicted to exist at the diagnosed plasma conditions