REAGENTS
COURTESY OF SHATRUK GROUP (FLASKS); BETHANY HALFORD/C&EN (DRAWING)
▸ Red phosphorus gets a green light When it comes to making phosphorus compounds, chemists have traditionally relied on white phosphorus, P4, a tetrahedral-shaped allotrope of the element. The downside with white phosphorus is that it’s toxic and flammable. Red phosphorus, an air-stable amorphous oligomeric allotrope, is a safer alternative. But chemists have had difficulty processing the relatively inert material in large quantities without resorting to high temperature and strong reducing agents. Florida State University chemists have now solved that problem by discovering an easy way to convert red phosphorus to soluble polyphosphides (Angew. Chem. Int. Ed. 2016, DOI: 10.1002/ anie.201511186). Alina Dragulescu-Andrasi, a postdoctoral researcher in Michael Shatruk’s group, explained in San Diego how the team simply passes a solution of inexpensive potassium ethoxide in an organic solvent through red phosphorus under mild heating to produce P5–, P162–, and P213–. These variously sized clusters, which the researchers isolate as potassium or tetrabutylammonium salts, could be used to synthesize phosphorus compounds or to make two-dimensional semiconductors and lithium-ion battery anodes. Taking the process a step further, the researchers adapted it to run as a continuous-flow reaction by passing potassium ethoxide through a stainless steel column packed with red phosphorus, generating multigram amounts of the soluble polyphosphides. “This appears to be a relatively safe and convenient methodology for generating soluble salts of polyphosphide anions,”
By passing potassium ethoxide solution (flask at left) through a column packed with red phosphorus (top), chemists created a continuous process for making polyphosphide salts (flask at right).
DRUG DEVELOPMENT
Candidates get their moment in the spotlight The Division of Medicinal Chemistry’s “First-time Disclosures” symposium, where pharmaceutical companies unveil the structures of their clinical drug candidates for the first time, is sort of like the television singing competition “American Idol.” The companies’ star molecules vie for the audience’s attention on a public stage. Last week in San Diego, symposium attendees got a peek into the development of eight drug candidates from seven different companies, with aims at treating conditions such as asthma, diabetes, and thrombosis. C&EN’s own Bethany Halford was on the ground live-tweeting the candidates. To see her hand-drawn structures, go to cenm.ag/firsttime.
commented MIT’s Christopher C. Cummins, who builds new compounds from elemental phosphorus. “It should open the door to more widespread study and application of these interesting little bits of reduced phosphorus.”—STEVE RITTER
NH2 O
O
O
HN P
N O
▸ Small-molecule treatment for Ebola When an Ebola outbreak began ravaging West Africa in 2013, doctors and scientists had few medicines to treat the thousands of people who would become infected with the deadly virus in the years to follow. In fact, no antiviral therapeutics have received regulatory approval or demonstrated clinical efficacy against Ebola to date. There might be new hope, though, thanks to researchers at Gilead Sciences, the U.S. Army Medical Research Institute of Infectious Diseases, the Centers for
O
O HO GS-5734
DRUG DEVELOPMENT
N
N N
OH
Disease Control & Prevention, and Boston University. Those scientists, who presented in San Diego, have developed a small molecule called GS-5734 that’s effective at treating monkeys infected with the Ebola virus (Nature 2016, DOI: 10.1038/nature17180). GS-5734 is a monophosphoramidate prodrug of an adenosine analog. Once the small molecule is administered, enzymes in the body cleave GS-5734’s monophosphoramidate and eventually replace it with a triphosphate. This metabolite, the researchers suspect, inhibits the virus’s RNA-dependent RNA polymerase, effectively preventing the virus from replicating by blocking the synthesis of its RNA. Because GS-5734 is also active against other pathogenic RNA viruses in cells, it might find wider medical use, the researchers note. Safety and pharmacokinetic studies are currently ongoing.—
BETHANY HALFORD MARCH 21, 2016 | CEN.ACS.ORG | C&EN
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Science Concentrates: ACS meeting news ▸ Nanoparticles to diagnose and treat atherosclerosis Researchers have developed nanoparticles that localize to arterial plaques and provide a possible new means to diagnose and treat atherosclerosis. Early detection of atherosclerosis is difficult and effective therapies are not available, making the condition a common cause of death worldwide. Plaques that are the hallmark of the disease form when white blood cells called macrophages attract cholesterol and agglomerate in arteries. These buildups can cause heart attacks, and when macrophages die, they can cause plaques to rupture and block blood flow, potentially causing strokes. High-density lipoprotein (HDL, or “good cholesterol”) deters This nanoparticle plaque formation by was designed promoting transport for diagnosis of cholesterol from and treatment of plaques to the liver atherosclerotic for excretion. In 2013, plaques; some Shanta Dhar’s group components are at the University of not labeled. Georgia reported the
OUTREACH
A scene from San Diego This budding chemist tried his hand at pencil electrolysis during the ACS national meeting’s presidential outreach event, held in conjunction with the San Diego Festival of Science & Engineering. In this demo, two pencils, serving as electrodes, are hooked up to a battery and dunked into water. The current that runs through the pencils’ graphite breaks down the water, forming bubbles of oxygen at one pencil tip and bubbles of hydrogen at the other. C&EN reporters were in San Diego last week, sharing news stories and photos like this one online. To see more of their coverage, go to acssandiego2016.cenmag.org.
plaques. After zeroing in on atherosclerotic lesions with their targeting ligands, the nanoparticles transport macrophages and cholesterol to the liver for disposal. Dhar hopes to begin clinical trials of the nanoparticles in a few years.—STU BORMAN
HO O
+N
N
NH2
N
▸ A new twist for ribozyme catalysis
Macrophage-targeting ligand Apolipoprotein-like peptide Magnetic agent
development of synthetic nanoparticles that mimic HDL functionally. In San Diego last week, Dhar and coworkers reported a modified version. The nanoparticles include a sugar-based macrophage-targeting ligand; an apolipoprotein-like peptide to bind cholesterol; and a magnetic agent that allows magnetic resonance imaging of
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C&EN | CEN.ACS.ORG | MARCH 21, 2016
RNAs called ribozymes can catalyze chemical reactions and often play a role in regulating gene expression. Twister ribozymes, which get their name because their overall structure resembles an ancient Egyptian hieroglyph representing twisted flax, are widespread in bacteria and eukaryotes and cut their own phosphodiester backbone. They may accomplish that cleavage through a novel acid catalysis mechanism, according to computational simulations presented at the meeting by Darrin M. York of Rutgers University. Twister ribozymes crystallize in an inactive conformation, which has made it difficult to determine how they selfcleave between adjacent uracil and adenine residues. York and graduate student Colin S. Gaines simulated both the crystalline and solution forms of a twister ribozyme (J. Am. Chem. Soc. 2016, DOI: 10.1021/jacs.5b12061). The chemists found that in solution the uracil can adopt an active conformation in
O–
O–
N
H O
P
N
BIOCHEMISTRY
Adenine N NH2 N
H
N
O
O Guanine
O O
O
N Uracil
HN O
In the proposed mechanism for twister ribozyme self-cleavage (red), a guanine N1 hydrogen-bonds (blue) to the uracil 2’-OH, promoting it as a nucleophile. The protonated adenine N3 hydrogen-bonds to its own 5’-O (green), promoting it as a leaving group. which it stacks with a nearby guanine. The guanine N1 may then hydrogen-bond to the uracil 2’-OH, promoting it as a nucleophile to attack a neighboring phosphate. Meanwhile, the adenine N3 is protonated and can hydrogen-bond to its own 5’-O, promoting it as a leaving group. Although the N1 of adenine residues has been implicated in catalysis by other ribozymes, such a role has not previously been suggested for N3.—
JYLLIAN KEMSLEY
COURTESY OF SHANTA DHAR (NANOPARTICLE); LINDA WANG/C&EN (BOY)
NANOMEDICINES
