Easy To Synthesize, Robust Organo‐osmium Asymmetric Transfer Hydrogenation Catalysts

Coverdale, James P. C.; Sanchez‐Cano, Carlos; Clarkson, Guy J.; Soni, Rina; Wills, Martin; Sadler, Peter J.

doi:10.1002/chem.201500534

Cited by 42 publications

(55 citation statements)

References 68 publications

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“…We recently reported chiral 16-electron osmium(II) complexes ( Figure 1), analogous to the Noyori ruthenium(II) complexes, which are highly stable even in the catalytically-active 16-electron state, and have comparable efficiency to Ru(II) compounds. 23 As well as stability upon isolation and storage, we now find that these osmium complexes are particularly stable in aqueous media (phosphate-buffered saline) and also in DMSO, as studied by UV-visible and 1 H-NMR spectroscopy (Figure 2b and Supplementary Figure 4). This high stability suggested that it may be possible to deliver intact active organo-osmium catalysts inside cells and for them to remain functional in order to carry out catalytic reactions.…”

Section: Resultsmentioning

confidence: 70%

“…These confirmed the 16-electron nature of the catalysts, and are similar to those of 2. 23 The antiproliferative activities of complexes 2-8 against A2780 cancer cells ranged from moderate to high (IC50 = 4-30 µM) and were not statistically different between enantiomers (Table 1). The antiproliferative activity of 2 was re-determined after 24 h incubation in RPMI-1640 medium and did not differ significantly from the activity determined with freshlyprepared solutions, suggesting that p-cymene complex 2 remains highly stable in the cell culture medium.…”

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confidence: 95%

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Asymmetric transfer hydrogenation by synthetic catalysts in cancer cells

et al. 2018

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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.

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Section: Resultsmentioning

confidence: 70%

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confidence: 95%

Asymmetric transfer hydrogenation by synthetic catalysts in cancer cells

et al. 2018

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“…There is growing interest in the chemistry of organometallic osmium complexes, with potential applications in a range of areas, including catalysis 1 − 4 and anticancer activity. 5 − 9 For example, osmium(II) arene complexes containing N,N -chelating phenylazopyridine (AZPY) ligands exhibit promising anticancer properties and novel mechanisms of action.…”

Section: Introductionmentioning

confidence: 99%

Halide Control of N,N-Coordination versus N,C-Cyclometalation and Stereospecific Phenyl Ring Deuteration of Osmium(II) p-Cymene Phenylazobenzothiazole Complexes

et al. 2017

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We report the synthesis of halido Os(II) p-cymene complexes bearing bidentate chelating phenylazobenzothiazole (AZBTZ) ligands. Unlike the analogous phenylazopyridine (AZPY) complexes, AZBTZ-NMe2 is capable of both N,N-coordination to Os(II) and cyclometalation to form N,C-coordinated species. N,C-Coordination occurs via an azo nitrogen and an ortho carbon on the aniline ring, as identified by 1H NMR and X-ray crystallography of [Os(p-cym)(N,N-AZBTZ-NMe2)Cl]PF6 (1a), [Os(p-cym)(N,N-AZBTZ-NMe2)Br]PF6 (2a), [Os(p-cym)(N,C-AZBTZ-NMe2)Br] (2b), and [Os(p-cym)(N,C-AZBTZ-NMe2)I] (3b). The N,C-coordinated species is more stable and is not readily converted to the N,N-coordinated complex. Analysis of the crystal structures suggests that their formation is influenced by steric interactions between the p-cym and AZBTZ-NMe2 ligands: in particular, larger monodentate halide ligands favor N,C-coordination. The complexes [Os(p-cym)(N,N-Me2-AZBTZ-NH2)Cl]PF6 (4) and [Os(p-cym)(N,N-Me2-AZBTZ-NH2)I]PF6 (5) were synthesized with methyl groups blocking the ortho positions on the aniline ring, forcing an N,N-coordination geometry. 1H NMR NOE experiments confirmed hindered rotation of the arene ligand and steric crowding around the metal center. Complex 2b exhibited unexpected behavior under acidic conditions, involving regiospecific deuteration of the aniline ring at the meta position, as observed by 1H NMR and high-resolution ESI-MS. Deuterium exchange occurs only under acidic conditions, suggesting an associative mechanism. The calculated partial charges on 2b show that the meta carbon is significantly more negatively charged, which may account for the regiospecificity of deuterium exchange.

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“…[Ru(µ-Cl)(η 6 -pcym)Cl] 2 and [Os(µ-Cl)(η 6 -pcym)Cl] 2 were prepared in a microwave reactor Monowave 300 (Anton PaarGmbH, Graz, Austria), according to the reported protocols [ 46 , 47 ]. Silver(I) dichloroacetate, Ag(dca), was prepared as white solid from Hdca, which was neutralized by stoichiometric amount of 1 M NaOH (in methanol) providing Na(dca), which subsequently interacted in situ (15 min of stirring at ambient temperature in the dark) with 1 molar equiv.…”

Section: Methodsmentioning

confidence: 99%

Half-Sandwich Ru(II) and Os(II) Bathophenanthroline Complexes Containing a Releasable Dichloroacetato Ligand

et al. 2018

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We report on the preparation and thorough characterization of cytotoxic half-sandwich complexes [Ru(η6-pcym)(bphen)(dca)]PF6 (Ru-dca) and [Os(η6-pcym)(bphen)(dca)]PF6 (Os-dca) containing dichloroacetate(1–) (dca) as the releasable O-donor ligand bearing its own cytotoxicity; pcym = 1-methyl-4-(propan-2-yl)benzene (p-cymene), bphen = 4,7-diphenyl-1,10-phenanthroline (bathophenanthroline). Complexes Ru-dca and Os-dca hydrolyzed in the water-containing media, which led to the dca ligand release (supported by 1H NMR and electrospray ionization mass spectra). Mass spectrometry studies revealed that complexes Ru-dca and Os-dca do not interact covalently with the model proteins cytochrome c and lysozyme. Both complexes exhibited slightly higher in vitro cytotoxicity (IC50 = 3.5 μM for Ru-dca, and 2.6 μM for Os-dca) against the A2780 human ovarian carcinoma cells than cisplatin (IC50 = 5.9 μM), while their toxicity on the healthy human hepatocytes was found to be IC50 = 19.1 μM for Ru-dca and IC50 = 19.7 μM for Os-dca. Despite comparable cytotoxicity of complexes Ru-dca and Os-dca, both the complexes modified the cell cycle, mitochondrial membrane potential, and mitochondrial cytochrome c release by a different way, as revealed by flow cytometry experiments. The obtained results point out the different mechanisms of action between the complexes.

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Easy To Synthesize, Robust Organo‐osmium Asymmetric Transfer Hydrogenation Catalysts

Cited by 42 publications

References 68 publications

Asymmetric transfer hydrogenation by synthetic catalysts in cancer cells

Asymmetric transfer hydrogenation by synthetic catalysts in cancer cells

Halide Control of N,N-Coordination versus N,C-Cyclometalation and Stereospecific Phenyl Ring Deuteration of Osmium(II) p-Cymene Phenylazobenzothiazole Complexes

Half-Sandwich Ru(II) and Os(II) Bathophenanthroline Complexes Containing a Releasable Dichloroacetato Ligand

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