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Thalidomide Chirality

Thalidomide Chirality

Why Thalidomide Is Important to Chiral Separation

The tragic history of the drug Thalidomide is familiar to many scientists in drug development – some of the more senior among us remember the disaster all too well. The problem with Thalidomide is one of the reasons chiral separation has become so important in drug development chemistry.

Contergen (thalidomide) was launched by the German pharmaceutical company Chemie Grünenthal in 1957. It was prescribed as a sedative and hypnotic, but was used for nausea and gastritis as well. When it was approved for over the counter sale in late 1957 it became popular for relief of morning sickness in pregnant women. Between 1957 and 1961, 10,000 infants exposed to the drug in utero were born with catastrophic limb malformation called phocomelia. Only half of the infants survived.

During this time, drugs were not tested for teratogenicity – the potential to harm or cause abnormalities in a developing fetus. The thalidomide disaster led to the development of more structured drug regulations and control over drug use and development.

Thalidomide is chiral, and the Contergen was a racemic mixture: equal amounts of the (R)- and (S)-enantiomers. The two enantiomers cause distinctly different effects from one another, and it is thought that only one is the teratogen. Efforts to develop a stable, single-enantiomer thalidomide – with no teratogenic activity – focused great attention on chiral drugs at the time.

Paving the way for new drugs

Professor Werner Hofer, from Newcastle University, UK, and one of the authors on the paper, says this new research furthers our understanding how chiral molecules behave and could pave the way for the development of new drugs and other synthetic materials.

"In the biological world, we see inorganic minerals being shaped with remarkable control but until now we haven't understood how it was happening at the level of the atoms," explains Professor Hofer.

"Now we see that the organic molecules are acting as a scaffold, dictating where the atoms of the minerals are placed and how they are linked together -- a bit like building blocks. And as they do this, the biomolecules transfer their left or right-handed nature, or chirality, to the crystal structure.

Thalidomide has just one chiral atom and so exists as two enantiomers. The diagram to the right shows the molecule without hydrogens. Notice that two of the groups attached to the chiral centre are part of the same ring structure. They are classified as two different groups. since moving around from the chiral centre the order of atoms is different each way. It is said the chiral atom has two different views around the ring.

Chirality In Natural And Synthetic Materials

Much of the function of biologically active molecules depends on fit, on an exquisite lock-and-key connection between molecules that allows some biochemical activity to turn on or off. In the evolutionary process, chirality—handedness—came to be a critical part of the lock-and-key fit. The principle behind this notion is simple. A left-hand glove does not fit a right hand, and, in the same way, one member of an enantiomeric pair of molecules might fit another molecule whereas the other member would not. The specificity of biological reactions and their dependence on fit have both benefits and penalties.

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