Thalidomide has a tragic history: It was introduced in Germany in 1957 as a sedative and hypnotic and was marketed over the counter largely as a drug for treating morning sickness in pregnant women. In the following few years, about 10,000 infants worldwide were born with phocomelia, or limb malformation. Only half of the infants survived, and some of those who did had other defects in addition to limb deficiencies. The thalidomide disaster caused many countries to tighten drug approval regulations.
Thalidomide exists in two mirror-image forms: it is a racemic mixture of (R)- and (S)-enantiomers. The (R)-enantiomer, shown in the figure, has sedative effects, whereas the (S)-isomer is teratogenic. Under biological conditions, the isomers interconvert, so separating the isomers before use is ineffective.
More recently, thalidomide has proven useful for treating cancer and leprosy and is approved for these uses. But although more than 2000 papers have been written about its mechanism of teratogenic action, it was not until the past few years that this mechanism was established. In 2010, H. Handa and colleagues at the Tokyo Institute of Technology showed that its biological target is cereblon, a component of an E3 ubiquitin ligase complex. Earlier this year, N. H. Thomä and co-workers at the Friedrich Miescher Institute for Biomedical Research (Basel, Switzerland) determined the crystal structure of thalidomide bound to cereblon, which allowed them to characterize the mechanism.
Thalidomide was also the Molecule of the Week for May 17, 2010.
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