Hydrogenation Of Pyruvate Research Articles

Targeting cancer lactate metabolism with synergistic combinations of synthetic catalysts and monocarboxylate transporter inhibitors

Synthetic anticancer catalysts offer potential for low-dose therapy and the targeting of biochemical pathways in novel ways. Chiral organo-osmium complexes, for example, can catalyse the asymmetric transfer hydrogenation of pyruvate, a key substrate for energy generation, in cells. However, small-molecule synthetic catalysts are readily poisoned and there is a need to optimise their activity before this occurs, or to avoid this occurring. We show that the activity of the synthetic organometallic redox catalyst [Os(p-cymene)(TsDPEN)] (1), which can reduce pyruvate to un-natural d-lactate in MCF7 breast cancer cells using formate as a hydride source, is significantly increased in combination with the monocarboxylate transporter (MCT) inhibitor AZD3965. AZD3965, a drug currently in clinical trials, also significantly lowers the intracellular level of glutathione and increases mitochondrial metabolism. These synergistic mechanisms of reductive stress induced by 1, blockade of lactate efflux, and oxidative stress induced by AZD3965 provide a strategy for low-dose combination therapy with novel mechanisms of action.Graphical abstract

Cover Feature: On the Origin of the Rate Enhancement by a R‐(+)‐1‐(1‐Naphthyl)‐Ethylamine‐Modified Pd(111) Model Catalyst for Methyl Pyruvate Hydrogenation (ChemCatChem 1/2023)

Cover Feature: On the Origin of the Rate Enhancement by a R‐(+)‐1‐(1‐Naphthyl)‐Ethylamine‐Modified Pd(111) Model Catalyst for Methyl Pyruvate Hydrogenation (ChemCatChem 1/2023)

On the Origin of the Rate Enhancement by a R‐(+)‐1‐(1‐Naphthyl)‐Ethylamine‐Modified Pd(111) Model Catalyst for Methyl Pyruvate Hydrogenation

AbstractChiral modifiers of heterogeneous catalysts can function as activity promotors to minimize the influence of unmodified sites on the enantiomeric excess to obtain highly enantioselective catalysts. However, the origin on this effect is not well understood. It is investigated using a model catalyst of R‐(+)‐1‐(1‐naphthyl)‐ethylamine (R‐1‐NEA)/Pd(111) for the hydrogenation of methyl pyruvate (MP) to methyl lactate (ML). The activity of the model catalyst remains constant for multiple turnovers. No rate enhancement is found for R‐1‐NEA coverages below ∼0.5 monolayer (ML), but a significant increase is found at R‐1‐NEA coverages of ∼0.75 ML, with a rate approximately twice that of the unmodified catalyst. This is investigated using infrared spectroscopy to distinguish between MP monomers and dimers. MP titration experiments with hydrogen show a half‐order hydrogen pressure dependence, with the monomer reacting at twice the rate as the dimer. It is found that the dimer is the most abundant species on clean Pd(111), but the ratio of monomers to dimers increases as the R‐1‐NEA coverage increases due to surface crowding. The monomeric species is also found to be more stable on the crowded surface than on clean Pd(111); the chiral modifier also serves to stabilize the reactant. Finally, this model nicely explains the unusual 1‐NEA‐covergae dependence of the reactivity.

New Triazolyl N^N Bidentate Rh(III), Ir(III), Ru(II) and Os(II) Complexes: Synthesis and Characterization, Probing Possible Relations between Cytotoxicity with Transfer Hydrogenation Efficacy and Interaction with Model Biomolecules.

Cisplatin and other metallodrugs have realised great success in clinical chemotherapeutic applications as anticancer drugs. However, severe toxicity to healthy cells and non-selectivity to cancer cells remains a challenge, warranting the further search for alternative agents. Herein, we report the anticancer potential of a series of complexes of the general formula [MCl(p-cym)(k2-N^N-L)]+ X− and [MCl(Cp*)(k2-N^N-L)]+ X−, where M is the metal centre (Ru(II), Os(II), Rh(III) or Ir(III)), L = 1-benzyl-4-pyridinyl-1-H-1,2,3-triazole for L1 and 1-picolyl-4-pyridinyl-1-H-1,2,3-triazole for L2 and X− = Cl−, BF4−, BPh4−. When evaluated for activity against some cancerous and non-cancerous cell lines (namely, HeLa, HEK293, A549 and MT4 cancer cells and the normal healthy kidney cells (BHK21)), most of the compounds displayed poor cytotoxicities against cancer cells except for complexes C2 ([RuCl(p-cym)(k2-N^N-L1)]+ BPh4−, EC50 = 9–16 µM and SI = 14), C7 ([RuCl(p-cym)(k2-N^N-L2)]+ BPh4−, EC50 = 17–53 µM and SI = 4) and C11 ([IrCl(Cp*)(k2-N^N-L2)]+ BF4−, EC50 < 5 µM and SI > 10). Selected complexes C1 ([RuCl(p-cym)(k2-N^N-L1)]+ BF4−), C5 ([IrCl(Cp*)(k2-N^N-L1)]+ BF4−) and C11 showed significant interactions with model biomolecules such as guanosine-5′-monophosphate (5′-GMP), bovine serum albumin (BSA) and amino acids under physiological conditions, possibly through carbenylation and N-coordination with 5′-GMP, N-coordination with L-Histidine and L-proline. While the compounds showed good activities in reducing pyruvate to lactate, there was no direct correlation between catalytic transfer hydrogenation of pyruvate and the observed cytotoxic activities. As observed in this work, the marked influence of single atom replacement in ligand may provide a pivotal approach to improving the cytotoxicity and fine-tuning the selectivity to cancer cells.

Restructuring Effects in the Platinum-Catalysed Enantioselective Hydrogenation of Ethyl Pyruvate

Restructuring Effects in the Platinum-Catalysed Enantioselective Hydrogenation of Ethyl Pyruvate

High-performance Pt catalysts supported on amine-functionalized silica for enantioselective hydrogenation of α-keto ester

Heterogeneous enantioselective catalysis is an attractive approach to produce enantiopure chemicals, which are key intermediates for pharmaceutical products. Herein, mesocellular silica foams (MCFs) functionalized by primary, secondary, and tertiary amine groups were used as supports for Pt nanoparticles. The catalytic performances of the Pt/amine-functionalized MCFs were evaluated for the enantioselective hydrogenation of methyl pyruvate in the presence of cinchonidine. Compared to Pt/MCF, the Pt/amine-functionalized MCFs exhibited enhanced activity and enantioselectivity. Particularly, 0.5 wt% Pt/NH2-MCF showed a superior performance than 5 wt% Pt/Al2O3, a highly efficient catalyst in the enantioselective hydrogenation of α-keto esters, despite a 10 times lower Pt loading. Furthermore, the Pt/NH2-MCF yielded 100% conversion and 96% ee at 0.1 MPa H2 pressure during nine successive cycles, thus showing high reusability. The excellent performance of the Pt/amine-functionalized MCFs is attributed to the formation of electron-deficient Pt species through strong interactions between the Pt nanoparticles and amine groups.

Osmium(ii) tethered half-sandwich complexes: pH-dependent aqueous speciation and transfer hydrogenation in cells.

Aquation is often acknowledged as a necessary step for metallodrug activity inside the cell. Hemilabile ligands can be used for reversible metallodrug activation. We report a new family of osmium(ii) arene complexes of formula [Os(η6-C6H5(CH2)3OH)(XY)Cl]+/0 (1–13) bearing the hemilabile η6-bound arene 3-phenylpropanol, where XY is a neutral N,N or an anionic N,O− bidentate chelating ligand. Os–Cl bond cleavage in water leads to the formation of the hydroxido/aqua adduct, Os–OH(H). In spite of being considered inert, the hydroxido adduct unexpectedly triggers rapid tether ring formation by attachment of the pendant alcohol–oxygen to the osmium centre, resulting in the alkoxy tethered complex [Os(η6-arene-O-κ1)(XY)]n+. Complexes 1C–13C of formula [Os(η6:κ1-C6H5(CH2)3OH/O)(XY)]+ are fully characterised, including the X-ray structure of cation 3C. Tether-ring formation is reversible and pH dependent. Osmium complexes bearing picolinate N,O-chelates (9–12) catalyse the hydrogenation of pyruvate to lactate. Intracellular lactate production upon co-incubation of complex 11 (XY = 4-Me-picolinate) with formate has been quantified inside MDA-MB-231 and MCF7 breast cancer cells. The tether Os–arene complexes presented here can be exploited for the intracellular conversion of metabolites that are essential in the intricate metabolism of the cancer cell.

Asymmetric hydrogenation of ethyl pyruvate over aqueous dispersed Pt nanoparticles stabilized by a cinchonidine-functionalized β-cyclodextrin

Cinchonidine-functionalized β-cyclodextrin was used as stabilizing agent for platinum nanoparticles dispersed in water, but also as chiral modifier for the asymmetric hydrogenation of ethyl pyruvate at 30 °C under 40 bar of hydrogen. This functionalized cyclodextrin allowed getting more stable, more catalytically active and also more enantioselective Pt nanoparticles compared to control catalytic systems. NMR and MALDI-MS analyses clearly showed the reduction of the vinyl group of the cinchonidine graft during the nanoparticles preparation. Under hydrogen pressure, the hydrogenation of the quinolinic moiety was also proven and can be responsible for the difficulties encountered during the recycling study.

Mesoporous silica-supported Pt catalysts in enantioselective hydrogenation of ethyl pyruvate

Catalytic properties of Pt catalysts supported on mesoporous silica (Pt/m-SiO2) have been studied in enantioselective hydrogenation of ethyl pyruvate. The influences of pore structure of mesoporous silica (m-SiO2), type of chiral modifier, and H2 pressure on the catalytic performance have been investigated by using various m-SiO2 supports and cinchona alkaloids and by varying H2 pressure. The use of MCM-41, SBA-15, KIT-6, and MCF reveals that characteristic pore structure and size of m-SiO2 supports significantly affect both activity and enantioselectivity. A facile diffusion of chiral modifier through large mesopores of MCF support enables Pt/MCF to exhibit excellent performance. A comparison of the efficiency of cinchona alkaloids-modified Pt catalysts shows that QN and QD lead to higher performance than CD and CN at ambient H2 pressure. The influence of cinchona alkaloids on enantioselectivity noticeably depends on H2 pressure. Cinchona alkaloid-modified Pt/m-SiO2 exhibit superior enantioselectivity to the corresponding Pt/Al2O3 under various H2 pressures. These results imply that m-SiO2 is a promising support and that fine control of pore structure can further improve catalytic performance of Pt/m-SiO2 in heterogeneous enantioselective hydrogenation.

Platinum nanoparticles supported on mesocellular silica foams as highly efficient catalysts for enantioselective hydrogenation

Mesocellular silica foams (MCFs) with different pore size were synthesized and used as supports for Pt catalysts for enantioselective hydrogenation of ethyl pyruvate. The influences of the pore size of MCFs, the amount of Pt loading and H2 pressure on catalytic performance of cinchonidine-modified Pt/MCFs were investigated. Both activity and enantioselectivity of the Pt/MCF catalyst increased with the increase in the pore size. These results were attributed to the fact that the larger mesopores facilitate intraparticle diffusion of bulky chiral modifier molecules and generate more chirally modified Pt sites. The performances of Pt/MCFs were compared to those of Pt supported on non-porous silica (Pt/SiO2) and commercial Pt/Al2O3 catalysts. The 1 wt% Pt/MCFs showed superior performance than the 1 wt% Pt/SiO2 and the commercial 1 wt% Pt/Al2O3 catalysts. Furthermore, the 0.6 wt% Pt/MCF exhibited higher activity and enantioselectivity than the commercial 5 wt% Pt/Al2O3, one of the most efficient heterogeneous catalysts for this reaction, in spite of a considerably less Pt loading. At optimized reaction conditions, the Pt/MCF catalyst gave enantiomeric excess of 96% at 100% conversion. They also maintained high enantioselectivity during 10 successive reaction cycles, exhibiting high reusability.

New Strategies in Enantioselective Hydrogenation on Supported Transition Metal Catalyst: Effects of Metal Sintering and Support Swelling

The effect of noble metal catalysts supported on an ionic exchange resin for the enantioselective hydrogenation of ethyl pyruvate to ethyl lactate was studied. High activity and moderate enantioselectivity levels were obtained. Pt was the best enantioselective metallic phase, followed by Pd and Au; Rh was the less enantioselective metallic phase. The effect of the active site was evaluated for the most enantioselective catalyst: 2Pt-WA30 (prefix indicates the metal loading). A novel method for sintering the Pt metal particles by nitriles reduction was used, and a controlled migration of the metal particles to the surface layers was observed. There existed an optimal particle size with maximization of the enantiomeric excess, corresponding to 24 h sintering. The hydrogenation of ethyl pyruvate to ethyl lactate was found to be structure-sensitive and the importance of the metal particle size for the adsorption of the chiral modifier was proved. Two different chirality induction methods were tried for the 2Pt-WA30 catalyst: (i) the addition of the chiral modifier (CM) to the reaction media, or (ii) the modification of the catalyst in a swelling medium prior to the reaction in order to encapsulate CM. Lower activity but higher enantioselectivity levels were obtained with method (ii). Finally, the reuse of the catalysts was also assessed by means of consecutive reaction tests.

Reversible pH-Responsive Behavior of Ruthenium(II) Arene Complexes with Tethered Carboxylate.

Five complexes of formula [Ru(η6-C6H5CH2COOH)(XY)Cl]Cl/Na (XY = ethylenediamine (1), o-phenylenediamine (2), phenanthroline (3), and oxalato (4)) and [Ru(η6:κ1-C6H5CH2COO)(tmen)]Cl (tmen = N, N, N', N'-tetramethylethylenediamine, 5C) have been synthesized and fully characterized. Five new X-ray crystal structures ([Ru(η6-C6H5CH2COOH)(μ-Cl)Cl]2, 1, 3, 4, and 5C·PF6) have been determined, which are the first examples of ruthenium(II) structures with phenylacetic acid as arene ligand. Furthermore, 5C·PF6 is the first example of a five-membered tether ring with a Ru(η6:κ1-arene:O) bond. The tether ring in these complexes opens in acidic pH (<5) and closes reversibly in aqueous solution. The chlorido open-form undergoes aquation, and the aqua adduct can be observed (prior to ring closure) by NMR. The speciation has an attractive complexity in the pH range 0-12, showing interconversion of the three species (chlorido, aqua, and closed tether), dependent on the proton concentration and the nature of the XY chelating ligand. The closed tether version of 3, complex 3C, with σ-donor/π-acceptor phenanthroline as chelating ligand, opens up more readily (pH 4), while the tether ring in complex 5C hardly opens even at pH as low as 1. We have determined the p Ka of the pendant carboxylic group and that of the aqua adduct (ca. 3 and ca. 7, respectively), which can be finely tuned by the appropriate choice of XY. Complexes 1 and 2, which predominate in their inactive (closed-tether) form in intracellular conditions, show some cytotoxic activity (IC50 130 and 117 μM, respectively) in A2780 ovarian cancer cells. Complex 1 catalyzes the reduction through transfer hydrogenation of pyruvate to lactate and NAD+ to NADH in the presence of formate as H-source. Co-incubation with sodium formate decreases the IC50 value of 1 in A2780 cancer cells significantly.

Revealing Catalytically Relevant Surface Species by Kinetic Isotope Effect Spectroscopy: H-Bonding to Ester Carbonyl of trans-Ethyl Pyruvate Controls Enantioselectivity on a Cinchona-Modified Pt Catalyst.

Monitoring active surface species on an operating technical catalyst is a challenging task due to the presence of multiple different adsorption sites and the abundance of bulk species. In this work, kinetic isotope effect (KIE) spectroscopy is introduced to capture the signals of catalytically relevant hydrogenation species from the IR spectroscopic detection in attenuated total reflection mode. The catalytic interface formed between a cinchona-modified Pt/Al2O3 catalyst and the solvent toluene is sensitively probed directly at the rate limiting step(s) during the asymmetric hydrogenation of ethyl pyruvate by measuring the effects of substituting H2 by D2 kinetically and spectroscopically in the same operando experiment. The application of KIE spectroscopy provides unprecedented molecular level insight into the structure of the diastereomeric intermediate surface complex and the phenomenon rate enhancement, which revolutionizes our understanding of chirally modified metal catalysts.

Effective and durable Pt nanocatalyst supported on three-dimensionally ordered macroporous carbon for asymmetric hydrogenation

Pt nanoparticles supported on three-dimensionally ordered macroporous carbon (Pt/3DC) were prepared and applied as catalyst after chirally modified with cinchonidine for the enantioselective hydrogenation of ethyl pyruvate. The catalyst was characterized by SEM, TEM, powder XRD, N2 sorption, and CO chemisorption, which confirmed the well-defined periodic macroporous structure of Pt/3DC and the high dispersion of Pt nanoparticles on the support. High catalytic performance was achieved over chirally modified Pt/3DC catalyst in the asymmetric hydrogenation of ethyl pyruvate. A high turnover frequency of 11,800h−1 with an enantiomeric excess of 79.5% was acquired in acetic acid. In particular, this catalyst exhibited high durability in the asymmetric hydrogenation system and could be easily reused at least 13 times with well-maintained catalytic activity and slightly decreased enantioselectivity. Moreover, the comparison of catalytic performance between Pt/3DC and commercial Pt/C as well as Pt/Al2O3 was carried out.

3 D Ordered Macroporous Alumina–Carbon Nanocomposite Supported Platinum Nanoparticles as Effective and Reusable Catalysts for Asymmetric Hydrogenation

AbstractThe three‐dimensionally ordered macroporous alumina‐carbon composite materials were firstly prepared through a surfactant‐assisted colloidal crystal template method and applied to support Pt nanoparticles. The results of SEM, XRD, TEM, and N2 sorption analyses revealed that these composite materials possessed highly ordered macroporous structures with meso‐ and micropores within the skeletons of macropores and that the Pt nanoparticles were well dispersed on these materials with a very narrow size distribution. These prepared Pt nanocatalysts were evaluated in the asymmetric hydrogenation of ethyl pyruvate after chiral modification with cinchonidine. Excellent catalytic activity and enantioselectivity were achieved. More importantly, these catalysts exhibited extraordinary stability and reusability during the reaction and could be reused at least 26 times without significant loss in catalytic activity and enantioselectivity.

Enhanced hydrogenation activity and diastereomeric interactions of methyl pyruvate co-adsorbed with R-1-(1-naphthyl)ethylamine on Pd(111).

Unmodified racemic sites on heterogeneous chiral catalysts reduce their overall enantioselectivity, but this effect is mitigated in the Orito reaction (methyl pyruvate (MP) hydrogenation to methyl lactate) by an increased hydrogenation reactivity. Here, this effect is explored on a R-1-(1-naphthyl)ethylamine (NEA)-modified Pd(111) model catalyst where temperature-programmed desorption experiments reveal that NEA accelerates the rates of both MP hydrogenation and H/D exchange. NEA+MP docking complexes are imaged using scanning tunnelling microscopy supplemented by density functional theory calculations to allow the most stable docking complexes to be identified. The results show that diastereomeric interactions between NEA and MP occur predominantly by binding of the C=C of the enol tautomer of MP to the surface, while simultaneously optimizing C=O····H2N hydrogen-bonding interactions. The combination of chiral-NEA driven diastereomeric docking with a tautomeric preference enhances the hydrogenation activity since C=C bonds hydrogenate more easily than C=O bonds thus providing a rationale for the catalytic observations.

Experimental and theoretical investigation of the enantioselective hydrogenation of ethyl pyruvate with a Pt catalyst with new non-cinchona chiral modifiers

The enantioselective hydrogenation of ethyl pyruvate using a Pt/SiO2 catalyst modified with six different chiral modifiers was studied. The chiral modifiers chosen were: (S)-(+)-1-aminoindan, (R)-(−)-1-aminoindan, (1R,2S)-(+)-cis-1- amino-2-indanol, (1S,2R)-(−)-cis-1-amino-2-indanol, (S)-(+)-1-indanol and (R)-(−)-1-indanol.An excess of the (R) enantiomer of the product of 63% and 45% with (S)-(+)-1-aminoindan and (R)-(−)-1-aminoindan modifiers, respectively was obtained. When using (1S,2R)-(−)-cis-1-amino-2-indanol and (1R,2S)-(+)-cis-1-amino-2-indanol, the enantiomeric excess (ee%) obtained was 30% and 5%, respectively, while with both indanols ee% did not exceed 8%. Molecular modeling of the complex formed between the chiral modifier and ethyl pyruvate performed by DFT calculations allowed predicting the values of ee% obtained experimentally. The low ee% value obtained both aminoindanol chiral modifiers were used, could be explained by the analysis of non-covalent interactions (NCI) method. These calculations demonstrated the presence of an intramolecular hydrogen bond in the structure of these modifiers.

Pt nanoparticles stabilized by thermosensitive polymer as effective and recyclable catalysts for the asymmetric hydrogenation of ethyl pyruvate

Thermosensitive polymer stabilized Pt nanocatalysts were firstly applied in asymmetric hydrogenation and exhibited excellent catalytic activity and durability.

Platinum functionalized multiwall carbon nanotube composites as recyclable catalyst for highly efficient asymmetric hydrogenation of methyl pyruvate

A highly efficient platinum nanoparticle functionalized carbon nanocomposite is demonstrated to be a recyclable heterogeneous catalyst for asymmetric hydrogenation of methyl pyruvate.

NanoSelect Precious Metal Catalysts and their Use in Asymmetric Heterogeneous Catalysis

AbstractWe studied the surface modification of supported colloidal precious metal catalysts. Chiral compounds derived from cinchona alkaloids and prolinol were synthesized and used as stabilizers/reductants to yield Pd and Pt colloidal nanoparticles. The new Pd catalysts were found to be highly active and selective catalysts for the semihydrogenation of 3‐hexyn‐1‐ol to cis‐3‐hexen‐1‐ol. The stabilizers affected the activity of the catalyst but not the selectivity. The catalysts were also evaluated in the asymmetric hydrogenation of methyl pyruvate and isophorone. No enantioselectivity was observed, which indicated that surface modification by the stabilizer did not induce chirality in the substrate. Achiral supported Pd and Pt colloidal catalysts were modified with cinchonidine. The modified Pt catalysts demonstrated a high activity for the hydrogenation of methyl pyruvate and a modest enantioselectivity of 47 %, which indicated that the chiral induction of supported colloidal catalysts is possible by modifying the catalyst surface with a chiral reagent.