Science Concentrates METAL-ORGANIC FRAMEWORKS
Lowest density MOF to date Simple building blocks produce surprisingly complex structure With a density of just 0.124 g/cm3, NU-1301 now holds the record for lowest density metal-organic framework, or MOF. Although NU-1301 is made up of just uranium oxide and tricarboxylate organic linker units, the MOF’s structure is incredibly complex: Its unit cell measures 173 Å across and is composed of 816 uranium nodes and 816 organic linkers (Science 2017, DOI: 10.1126/science.aam7851). Omar K. Farha, a chemistry professor at Northwestern University who led the MOF-making effort, says his team didn’t predict they would get such an elaborate structure based on first principles. “This is the first MOF that has this kind of complexity,” he says. Farha says his group knew the uranium oxide nodes and tricarboxylate bridging ligands would take the shape of a basic cuboctahedron building block, and that these could assemble into pentagons and hexagons. But from there, they weren’t certain what form the larger structure of the MOF would take. They determined NU-1301’s structure using X-ray analysis and modeling—no easy feat because the uranium diffracts so strongly, it makes it impossible to observe the organic linkers using X-ray diffraction techniques. They found that the cubocta-
hedrons assemble into five types of larger cage structures that form the unit cell. “A few people have been making MOFs with actinides, but it’s an area that has been not well understood,” Farha notes. “We were able to show that with an actinide building block, we could make a material that is comUranium oxide nodes plex, that is unusual, and tricarboxylate and that at the same bridging ligands form a time has the lowest cuboctahedron building esting properties too: It’s stadensity of any MOF block (top lef), which forms ble in water and can capture that has been made so five cage structures (shown cations, which could make for far.” He points out that in green and other colors) some interesting applications most scientists don’t that make up the unit cell of in separation science, Farha equate actinides, which NU-1301 (top right). notes. are heavy elements Omar Yaghi, a MOF expert that reside at the bottom of the periodic at the University of California, Berkeley, table, with low-density materials. He hoped says the work from Farha’s group shows that the size of the metal wouldn’t matter “how control of the angles between buildif the MOF’s structure was very porous and ing units can have profound impact on the empty. assembly of complex extended MOFs.” He Not only is NU-1301 low density, he adds, “It is clear the design of MOFs is taknotes, it’s also high in surface area and high ing another stride forward in its sophisticain pore volume. The MOF has other intertion.”—BETHANY HALFORD
Simple to complex
DRUG DISCOVERY
The ability of covalent drugs to form strong bonds to protein targets tends to give them the advantage of long-lasting action. So far, covalent drug discovery has almost exclusively involved electrophilic small molecules that react with cysteine thiol groups (–SH) on proteins. The approved anticancer drug afatinib, for instance, is an electrophile that bonds covalently to a cysteine in epidermal growth factor receptor. A new study could help expand the reach of covalent drugs to nucleophiles. Cells often regulate proteins by using reactive oxygen species to oxidize cysteine thiols to cysteine sulfenic acids (–SOH).
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C&EN | CEN.ACS.ORG | APRIL 24, 2017
Cysteine oxidation makes thiol’s sulfur less reactive with electrophiles. About 15% of cellular cysteines are oxidized. To extend covalent drug discovery to cysteine-oxidized proteins, Kate Carroll of Scripps Research Institute Florida and coworkers recently developed a library of nucleophilic drug candidates. Compared with electrophiles, which react readily with nontarget biomolecules, nucleophiles are less promiscuous, potentially reducing side effects when used as drugs. Carroll and coworkers have now found that five of the library nucleophiles react covalently with 1,280 unique S-sulfenylated cysteines in 761 cancer-cell proteins
(J. Am. Chem. Soc. 2017, DOI: 10.1021/ jacs.7b01791). One of the compounds, a pyrrolidinedione nucleophile, reacts with four protein tyrosine phosphatases, signaling proteins involved in diabetes, obesity, cancer, and rheumatoid arthritis. The researchers think this nucleophile could be a starting point for designing covalent inhibitors that target that family of enzymes. “The work advances strategies to hit targets like phosphatases, which have historically been very difficult to drug,” comments protein-inhibitor expert Nathanael Gray of Harvard Medical School.—STU BORMAN
CREDIT: SCIENCE
Extending the reach of covalent drugs
