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Версия для печати | Главная > Институт > Научные советы > Научный совет по катализу > ... > 2017 год > № 83

№ 83

 

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  • Владимир Александрович Лихолобов
    К 70-летнему юбилею
  • Премия имени В.А. Коптюга
  • III Российский конгресс по катализу РОСКАТАЛИЗ-2017
  • За рубежом
  • Приглашения на конференции



Владимир Александрович Лихолобов
К 70-летнему юбилею

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Премия имени В.А. Коптюга

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III Российский конгресс по катализу РОСКАТАЛИЗ-2017

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Metallopeptide catalyst eases synthesis of antibody-drug conjugates

A promising drug-targeting approach is made easier thanks to a new rhodium-based catalyst

Antibody-drug conjugates are promising next-generation cancer therapies that can target and selectively kill malignant cells while sparing healthy ones. These conjugates—in which a drug is bound to an antibody through a small chemical linker—harness the antibody’s ability to recognize markers specific to cancer cells and bring the potent drugs to their intended site of action. But one conundrum that has plagued drug developers and scientists is how to consistently tether a drug onto a predictable site on an antibody.

A rhodium-peptide catalyst binds to an antibody (left) and facilitates the addition of an alkyne-functionalized diazo group (center). The group serves as a chemical linker for attaching drugs, such as the cancer drug doxorubicin. The drug is modified with an azide group for the attachment reaction and desthiobiotin (purple circle) to make purification with chromatography easier.

Now, chemists have reported a new metallopeptide catalyst that can reliably link drug molecules to a variety of antibodies, at the same location on the antibody every time (J. Am. Chem. Soc.2017,  DOI: 10.1021/jacs.7b06428 ). Inconsistent linkage can make it difficult for researchers to study the biological effects of these new compounds, or interfere with the antibody’s ability to bind to its target.

Previously, scientists used genetic engineering to create antibodies with chemical groups to which drugs could be attached. But this new approach bypasses the need for genetic engineering, a time-intensive process. The catalyst consistently binds to a particular location on an antibody’s so-called “constant chain,” an amino acid sequence that is found in all human antibodies and is conserved among many species. The catalyst produces reproducible results on human, pig, rabbit, and dog antibodies, the researchers found.

“Antibodies are pretty complicated molecules,” says Dennis G. Gillingham, a chemical biologist at the University of Basel not involved in this study. “This new technique is truly unique because it doesn’t require any engineering of any amino acids; the catalyst controls the reaction.”

Zachary T. Ball of Rice University and colleagues made the catalyst by taking a segment of a protein isolated from the bacterium Staphylococcus aureus that binds to the asparagine-79 residue on an antibody’s constant chain and then coordinated the peptide with three rhodium (II) ions. The rhodium complexes catalyze the addition of a linker group to the antibody—an alkyne-functionalized diazo that can react with many other small molecules, including drugs or fluorescent dyes, in a simple click-chemistry reaction.

To prove that antibody-drug conjugates made with the catalyst can target cells, the authors attached fluorescent dyes and the chemotherapy drug doxorubicin to Herceptin, an antibody drug that recognizes the HER2 protein on the surface of mammalian breast cancer cells, and then visualized the localization using confocal microscopy. The dye appeared at the cell surface, confirming that the antibody still recognized the cell surface markers.

“We’re building next-generation drug conjugates using this method and testing those in cell and tumor model studies,” Ball says. He adds that it would be relatively easy to produce the catalyst in bulk for future drug development applications.

 

Copper nanoparticles could help recycle CO2 into fuel

New catalyst converts carbon dioxide to two- and three-carbon compounds

Copper nanoparticles on carbon paper fuse to form cubes, which provide an interface for catalyzing carbon dioxide reduction.

Through photosynthesis, plants and some bacteria use energy from sunlight to turn carbon dioxide and water into useful organic chemicals. Chemists have serious enzyme envy because designing inorganic catalysts that can do the same is difficult. Now researchers have developed a catalyst that can turn CO2 into ethanol and propanol when operating at voltages that solar cells could provide (Proc. Natl. Acad. Sci. USA 2017, DOI: 10.1073/pnas.1711493114).

This process of powering chemical synthesis via solar power, called artificial photosynthesis, could enable carbon-neutral fuels. In such a system, every molecule of CO2 emitted when a fuel is burned could be captured to make another fuel molecule. But developing catalysts that can recycle CO2 is challenging, says Peidong Yang, a chemist at the University of California, Berkeley.

Using catalysts based on iron, copper, indium, and other metals, researchers have successfully transformed CO2 into single-carbon compounds, including carbon monoxide, formate, and methanol. Making multicarbon compounds directly has proved more difficult.

Because biology’s metabolic capabilities are hard to beat, Yang’s group and others have built systems that pair catalysts and microorganisms to build molecules with more than one carbon. Other labs have made two- and three-carbon molecules using nanostructured copper and copper oxides, but these catalysts work only at voltages too high to be supplied by solar cells. And these high voltages waste electricity—only a small fraction of the energy gets stored in chemical bonds.

Yang’s group found that the right amount of copper nanoparticles loaded on carbon paper can catalyze the reduction of CO2 to two- and three-carbon compounds, including ethylene, ethanol, and n-propanol, with 60% selectivity at 600 millivolts, a voltage Yang believes is low enough to be supplied by solar cells. Previous catalysts performed similar reactions but required 900 millivolts, Yang says.

The team discovered this better catalyst by systematically studying the performance of different densities of copper nanoparticles on support structures made of various materials. Graduate student Dohyung Kim found the best catalytic performance when he covered carbon paper with about 45 µg of the copper particles per square centimeter of the paper.

Despite these fastidious efforts, Yang says the researchers are not yet sure why the catalyst works so well. The researchers observed that after seven minutes under reaction conditions, the spherical nanoparticles fuse into larger cubic ones, with an interface between copper, copper oxide, and carbon from the paper. The group is still investigating the mechanism, but they believe this interface is key to the structure’s catalytic activity. “We’ve finally identified a key active interface to produce two- and three-carbon compounds,” Yang says.

The new work “helps move the bar in investigating the applications of copper-based catalysts for electrochemical transformation of CO2 to useful products,” says Ellen Williams, a nanoscale physicist at the University of Maryland, College Park, who serves on the board of the Global CO2 Initiative. However, she notes, it remains to be proven whether this catalyst works on large, industrial scales.

Yang says that in addition to exploring the catalyst’s mechanism, his group is now testing the catalyst in a full system that’s coupled to photovoltaics.

 

Reaction plays favorites in polyols

Chemists would like to be able to modify compounds containing multiple hydroxyl groups, such as the toxin ouabain and the antiparasitic drug ivermectin, to generate new molecules with diverse uses in medicine, molecular biology, and agroscience. One way to do this would be to selectively oxidize individual hydroxyls to ketones, which are synthetically versatile groups in that they can be readily converted to nitrogen-based groups, such as oximes and amines, or can be leveraged to add adjacent groups in a molecule’s carbon framework.

A team of researchers at the University of California, Berkeley, has now designed a catalyst capable of such a feat.

Dehydrogenating selected hydroxyls to ketones in multi-hydroxylated compounds known as polyols has been difficult. A common strategy is to add protecting groups to the hydroxyls you don’t want to react and then deprotect them later. But this is laborious, requiring multiple reactions instead of just one. Although a few synthetic procedures can oxidize specific hydroxyls in polyols to ketones, they generally cause undesirable side reactions or are poorly selective for specific hydroxyls, producing complex mixtures instead of relatively pure ketone products.

In this example of the new reaction, the secondary hydroxyl in the antibiotic natural product fusidic acid (left) is selectively oxidized to a ketone. The resulting ketone can then be converted readily to an amine (bottom right) or the ketone’s ring can be expanded by insertion of a nitrogen group (top right).

John F. Hartwig and Christopher K. Hill of UC Berkeley speculated that one way to improve selectivity would be to develop a catalyst that oxidizes polyol secondary alcohol groups—hydroxyls on carbon atoms that are bonded to two other carbon centers—much more readily than primary alcohol groups—hydroxyls on carbons connected to only a single carbon center.

The catalyst they designed has strongly electron-donating phosphine ligands that make its ruthenium center electron-rich, weakening its oxidizing powers. That makes the catalyst selective for secondary hydroxyls, which are more electron-rich than primary hydroxyls and thus better substrates for a weakly oxidizing catalyst.

Hartwig and Hill demonstrated the catalyst’s power and versatility by using it to selectively oxidize a single hydroxyl group in over a dozen polyol natural products and using subsequent catalytic reactions to convert the resulting ketones into nitrogen-modified products. They recently reported the work in Nature Chemistry (2017, DOI: 10.1038/nchem.2835) and presented it during the ACS national meeting in Washington, D.C., during a session sponsored by the Catalysis Science & Technology Division.

The researchers developed a set of rules that predict which hydroxyls in a polyol the catalyst will oxidize selectively. In general, the catalyst is selective for electron-rich, sterically hindered secondary hydroxyls. The reaction does not produce dione products by oxidizing multiple hydroxyls in the same compound, owing to the catalyst’s high sensitivity for electronic and steric differences in the properties of different hydroxyls.

The new selective alcohol dehydrogenation reaction “has many advantages over traditional methods, including lower catalyst loading, milder conditions, higher yields, and improved selectivity,” says transition-metal catalysis specialist Guangbin Dong of the University of Chicago. “I am most impressed by the reaction’s unusual chemoselectivity in the dehydrogenation of secondary hydroxyls. Without doubt, this technology is going to be highly useful for medicinal chemistry.”

The technique represents “a very important step forward in the ability to do catalytic, site-selective alterations of complex molecules,” says Scott Miller of Yale University, an expert on site-selective catalysts. It will be useful for achieving selectivity in the conversion of complex starting materials to bioactive analogs, he says.

 

Copper pairs up to reduce nitrogen oxides in diesel exhaust

Single copper ions in a zeolite catalyst (white geometric shapes) bind two ammonia molecules, migrate through the zeolite, and form oxygen-bridged dimer complexes, which catalyze exhaust cleanup.

High schoolers aren’t the only ones who pair-up and break-up frequently. Catalytic species in the systems that clean up engine exhaust do it too, according to a study presented at the American Chemical Society national meeting in Washington, D.C., on Tuesday.

The investigation uncovers an unusual mechanism in the catalytic process that rids diesel engine exhaust of smog-causing nitrogen oxides (NOx). The findings may eventually lead to more effective catalysts.

Diesel-powered engines score high marks for fuel efficiency, which is why nearly all long-haul trucks use them. But they emit various pollutants including hydrocarbons, CO, and NOx.

Selective catalytic reduction (SCR) systems—part of the overall exhaust cleanup equipment on diesel vehicles—reduce NOx to nitrogen and water through a reaction with ammonia. The ammonia comes from an aqueous urea solution, which is carried on-board like windshield cleaner. SCR systems catalyze NOx reduction with the help of chabazite zeolite that has been treated to incorporate copper in its lattice.

These systems come standard on many diesel vehicles, yet details of how they work remain a subject of debate.

A team led by Rajamani Gounder of Purdue University and William F. Schneider of the University of Notre Dame studied some of the details in copper-chabazite SCRs. Using X-ray spectroscopy, kinetics measurements, and quantum calculations, the researchers tracked unusual behavior of the zeolite’s copper ions.

Speaking at a symposium sponsored by the Division of Catalysis Science & Technology, Gounder reported that in the presence of ammonia, copper ions form Cu(NH3)2 complexes. The NH3 moities make the species mobile, allowing them to migrate through openings that interconnect hollow cages in the porous zeolite framework. As the coppers species move about, they briefly and reversibly form dimers that are bridged by a pair of oxygen atoms. The dimers facilitate an O2-mediated Cu(I) to Cu(II) redox step that’s central to reducing NOx to nitrogen and water (Science 2017, DOI: 10.1126/science.aan5630).

Gounder explained that, in effect, individual copper ions come together and work in tandem to carry out the difficult step of breaking apart oxygen molecules. The copper ions then go back to being isolated after the reaction is complete. He noted that this step might be accelerated by fine-tuning the spatial distribution of copper ions in the zeolite, leading to lower NOx emissions at cooler operating temperatures than is possible with current SCR systems.

“Exquisite” is how Robert J. Davis described the team’s techniques for exploring this SCR system. Davis, a catalysis specialist at the University of Virginia, remarked that this exciting finding regarding the mobility of copper ions and the dynamic formation of paired copper species may also be relevant to the high selectivity of Cu-treated zeolites used for oxidizing methane to methanol.

 

Liquid metals catalyze industrial reactions

Gallium-palladium droplets drive alkane dehydrogenation with high selectivity

A Ga-Pd alloy forms microscopic droplets on glass (left) and serves as an active dehydrogenation catalyst, remaining liquid even after 20 hours of reaction (right).

Gallium’s quirky liquid-state properties have pushed that element into the scientific spotlight recently, as researchers have tapped the liquid metal for applications in stretchable electronics and three-dimensional printing. Now gallium is back in the news, this time as a catalyst.

Researchers in Germany report that liquid droplets of Ga-Pd alloys function as active and durable catalysts for alkane dehydrogenation. That industrial-scale reaction converts low-value alkanes to higher-value olefins, compounds with C=C bonds that are used to make polymers and chemicals (NatChem. 2017, DOI: 10.1038/nchem.2822).

Gallium and some of its alloys exhibit a handful of unique properties, such as a tendency to remain liquid over an enormous temperature range—about 2,000 °C. The metal also has a knack for spontaneously forming an ultrathin oxide skin that stabilizes liquid droplets but easily breaks, allowing the metal to flow momentarily until the skin re-forms around the liquid.

A team including Nicola Taccardi and Peter Wasserscheid of Friedrich-Alexander University, Erlangen-Nьrnberg, took advantage of those properties of gallium and its ability to dissolve numerous metals, generating alloys with various concentrations of palladium, a catalytically active metal. Then they deposited the liquid metals onto porous glass, forming supported liquid metal catalysts, and used them in a test reaction: butane dehydrogenation.

Homogeneous, solution-phase catalysts have the advantage of possessing clearly defined active sites and mechanisms. The aim of the new work was to create a hybrid catalyst with these advantages that can also be easily separated from reaction products and reused, a task that’s currently difficult to carry out with homogeneous versions. Various researchers have attempted this feat previously. But the stability of their liquid-phase catalysts typically limited reactions to roughly 200 °C and below, far lower than temperatures required in many industrial catalytic processes.

The Friedrich-Alexander team ran test reactions at roughly 450 °C and found that gallium-rich catalysts, for example, ones with a Ga-to-Pd ratio of 10:1, had high activity for butane dehydrogenation, produced butene with high selectivity (85%), and remained in the liquid state even after 20 hours of reaction. In addition, they did not accumulate the layer of carbon (coke) that gunks up and deactivates commercial Pt-Al2O3 and Cr2O3-Al2O3 dehydrogenation catalysts.

“Supported liquid metal catalysis is an interesting concept,” says Arizona State University’s Jingyue (Jimmy) Liu, a catalysis specialist. He is particularly intrigued by the researchers’ atomic-level description of their catalyst as individual isolated Pd atoms supported on the surface of a Ga-Pd liquid metal. He adds, “Systematic investigations are needed to better understand reaction processes in such a system and to provide deeper insights into the nature of the newly synthesized liquid metal.”


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