Mirror image molecules were separated using backbone chemistry

Mirror image molecules were separated using backbone chemistry

Two forms of thalidomide.  Molecular models of the S-(left) and R-(right) forms of thalidomide.

The optical isomers of thalidomide have different effects within the body.Photography: Alfred Paseka/SPL

Chemists have shown that it is possible to use mass spectrometry – a technique commonly used to identify molecules by mass – to separate chiral molecules, those that exist as different shapes with identical atoms but mirror-image structures that cannot be superimposed on each other.

The technique described today in Sciences1It could one day have applications in drug discovery. Different versions of chiral molecules — called photoenantiomers — often have very different properties. This drug, thalidomide, has shown a dramatic effect: one enantiomer is an analgesic, but the other causes birth defects when taken during pregnancy. As a result, separation of optical isomers is an important, but often laborious, part of drug discovery. Current methods require specialized equipment and different protocols for each pair of optical isomers.

The ions are far apart

A team of researchers led by Cheng Ouyang at Tsinghua University in Beijing was able to use mass spectrometry to separate the optical enantiomers of a class of chiral molecules called penaphthyl triterpenes.

The researchers placed pairs of these fan-shaped molecules into a mass spectrometer, where they were vaporized, ionized, and transferred to a component called an ion trap mass analyzer. The team then applied alternating currents to the ions, causing each isomer to spin along a slightly different path, based on its chirality.

“When they collide with background gas molecules, the different symmetrical shapes experience different effects due to the collisions,” says Ouyang, who separates them. Then, when they are taken out the other end of the spectrometer, the ions come out one by one and can be detected separately. The machine can also determine the proportion of each antidote in the mixture – known as the antidote excess (ee) and expressed as a percentage.

“Chemists can take a dip of the crude reaction product as a sample, send it to a mass spectrometer, and obtain both photocrystallization as well as confirm molecular structures within a minute,” says Ouyang. He adds that once the mass spectrometry system is scaled up, it can also be used to prepare pure samples of optical isomers in larger quantities.

“I love this work,” says Perdita Baran, director of the Michael Barber Center for Collaborative Mass Spectrometry at the University of Manchester, UK. Being able to simply separate optical isomers has been a “huge endeavor,” she says. “The method used to separate optical isomers is important in drug discovery and design,” she says.

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