Science Concentrates DRUG DISCOVERY
Pinning a bull’s-eye on cancer cells Bioorthogonal technique tags cancer cell surfaces for selective drug targeting A new small-molecule strategy could help cancer drugs selectively target tumors with the help of click chemistry (Nat. Chem. Biol. 2017, DOI: 10.1038/nchembio.2297).
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University of Illinois, Urbana-Champaign (UIUC), Lichen Yin of Soochow University, and Xuesi Chen of Changchun Institute of Applied Chemistry has now come up with
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Protected azido sugar O N3 AcO HN O AcO O AcO P
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N N N
N Drug
Drug N
Two enzymes overexpressed in cancer cells Cancer
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Dibenzocyclooctynedrug conjugate Azide-modified cancer
Drug-targeted cancer
P = Enzyme-removable protecting group Ac = acetyl
Bioorthogonal technique marks cancer cells for selective ATTACK. Many cancer drugs attack healthy tissue in addition to tumors, leading to harmful side effects. So scientists want therapeutics to target cancer cells more selectively. One such approach that has reached the clinic is antibody-drug conjugates. Antibodies recognize antigens, such as HER2 on some breast cancer cells, allowing antibody-attached drugs to kill those cancer cells selectively. But disease-specific antigens aren’t always available, and antibody-drug conjugates are costly and must be administered intravenously. A group led by Jianjun Cheng of the
a strategy called active tissue targeting via anchored click chemistry (ATTACK) that may have advantages over antibody-drug conjugates. In the two-step ATTACK process, the researchers first give tumor-bearing mice an ether-protected sugar that carries an azide group. Cells can deprotect and metabolize the sugar, which then gets attached to glycoproteins in the cell membrane. Because cancer cells proliferate quickly, they overexpress some enzymes, two of which catalyze deprotection of the azido sugar. This makes cancer cells more likely than normal cells to
be tagged by the bioorthogonal azide groups. In the second step, researchers give the mice an anticancer drug conjugated to dibenzocyclooctyne (DBCO). DBCO’s alkyne group undergoes a selective click-chemistry reaction with azides, thus recruiting the conjugated drug selectively to azide-decorated cancer cells. In the mice, ATTACK improved drug-targeting selectivity 50% for treated tumors over untreated ones. And compared with doxorubicin alone, a DBCO-doxorubicin conjugate was much less toxic and significantly more effective at treating colon cancer and two forms of breast cancer in mice. ATTACK has potential advantages over antibody-drug conjugates: It doesn’t require that a given cancer have a cell-surface antigen because the method creates its own targets, and ATTACK’s small-molecule agents could be orally available and less expensive to make. The strategy “is very elegant” for achieving selective action because the ether is deprotected primarily in cancer cells, comments drug delivery expert Liangfang Zhang of the University of California, San Diego. “The approach is clever in that it translates an intracellular molecular signature, cancer-related enzyme expression, to a cell-surface signature, azide groups that allow for targeting,” says bioorthogonal chemistry specialist Carolyn R. Bertozzi of Stanford University, adding that she is interested to see if the approach can be developed commercially.—STU BORMAN
SPECTROSCOPY
The power of nuclear magnetic resonance spectroscopy lies in its high resolution, while the technique’s weakness is its low sensitivity. One way to boost NMR signals is through dynamic nuclear polarization (DNP), in which microwave irradiation transfers spin polarization from electrons of a stable radical to the nuclear spins of interest. A research team has now demonstrated signal enhancement of two to three orders of magnitude for room-temperature carbon-13 NMR experiments (Nat. Chem. 2017, DOI: 10.1038/ nchem.2723).
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C&EN | CEN.ACS.ORG | FEBRUARY 20, 2017
DNP has historically worked well in solid-state NMR experiments but struggled in liquids. Spectroscopists believed that molecular motions in liquids impeded the transfer of spin polarization at high magnetic fields. One work-around is to polarize the radical at low temperatures and then warm up the sample, but that approach limits the number of scans that can be taken for signal averaging. The new work was conducted by a team at the Max Planck Institute for Biophysical Chemistry, led by Marina Bennati and Guoquan Liu, who is now at Peking University.
The researchers found that one key to improving DNP-enhanced carbon-13 NMR of liquids at high magnetic fields was using a nitroxide radical as a polarizer. After optimizing several parameters in their DNP-NMR protocol, including efficiently saturating the radical electron spin polarization, the team obtained significantly improved signals for molecules such as CCl4 and CHCl3, as well as for biologically relevant compounds such as pyruvate and ethyl acetoacetate. The experiments can be repeated within seconds for signal averaging.—JYLLIAN KEMSLEY
CREDIT: ADAPTED FROM NAT. CHEM. BIOL.
Enhancing carbon-13 NMR signals in liquids
