Enantiomers

Up until the 1950’s pharmaceutical drugs were produced by either the use or modification of natural products. This changed with the introduction of synthetic “designer” drugs into the industry, bringing with it a range of unforeseen issues.

Thalidomide first became available as an over the counter morning sickness remedy in Germany in 1957.  The drug was marketed as having no side effects, making it extremely popular around the world. Over the course of the next few years a number of children were born with severe deformities, and it was eventually discovered that all of the mothers of these children had taken Thalidomide at some point during the pregnancy. Official estimates put the number of victims of the thalidomide incident at 12,000. This event is widely recognized as one of the key incidents involved in the birth of regulatory affairs.

During inquiries, it was discovered that Thalidomide was administered incorrectly.  Thalidomide was the first designer drug of its kind, and during the manufacture of the drug, two naturally occurring forms were produced; each mirror images of one another, exhibiting different reactions in the body. This information was initially overlooked, either through lack of understand or lack of interest.

Molecular properties are generally determined by the spatial arrangement of its substituents. Enantiomers are organic compounds sharing the same physical and chemical properties, differing only in how they interact.  Enantiomers are mirror images of each other, but are non-superimposable. The most universally accepted examples of enantiomers are the Human hands. Your hands have the same arrangement of four fingers and a thumb, but a left handed glove can’t be worn on the right hand. Limonene is an example of an enantiomer. The point of asymmetry in a molecule is defined as a chiral center, and the geometry annotated by the prefixes R– or S-. The two different Limonene compounds have identical chemical properties, but have different aromas. R-limonene smells of oranges, whilst S-limonene smells like lemons.

Thalidomide was administered as a racemic mixture; one that has equal amounts of the left handed and right handed enantiomers. Whilst the R- isomer of Thalidomide is considered to be an effective sedative, the mirrored S- isomer was found to cause deformities in developing fetuses. As drugs up until this point were of natural origin, each compound was effectively stereochemically pure. The presence of the S- enantiomer in Thalidomide was essentially an impurity.

In the wake of this disaster, measures were put in place to ensure the safety, efficacy and quality of manufactured pharmaceuticals. Five years after Thalidomide hit the market in the USA, the FDA introduced strict approval requirements on advertising and GMP audits. A year later, the British government set up the Commission on Human Medicines (CHM), formerly Committee on Safety of Medicines (CSM), independently monitoring quality, efficacy and safety of medicinal products on sale in the UK. In 1968, eleven years after Thalidomide was first retailed, parliament passed the UK Medicines Act governing the control, manufacture and supply of medicinal substances.

The pharmaceutical company Grünenthal who produced Thalidomide, did not carry out any animal testing for effects on reproduction at the point of production. Manufactured drugs are now rigorously tested for the effects of enantiomeric mixtures in a range of scenarios, meaning such a disaster will never happen again.

Despite the tragedy, Thalidomide is once again on the market, this time in cancer and leprosy treatments. Scientists have studied the drug, learned how and why it worked as it did, and in the process have ensured a safer medicinal future in the process. Authorities now weigh up the risks versus the benefits of each medicinal compound before being released for sale; medical advancements cannot be limited by ignorances of the past.