The Thalidomide Disaster teaches us an important lesson about optical isomerism in Pharmacology

When first released in the 1950s, pharmaceutical drug thalidomide was promoted for a number of issues, including anxiety, trouble sleeping, and morning sickness. The over-the-counter medicine was initially declared “completely safe, even during pregnancy,” as its developers “could not find a dose high enough to kill a rat”. Tragically, thalidomide was found to have serious side-effects - issues such as birth defects arose in large numbers when pregnant women took the drug. The drug was quickly removed from the market in 1961, but an estimated 10,000 mothers who had already taken it experienced extreme issues in their pregnancy, and about 40% of children born died around the time of birth. Those who survived had limb, eye, urinary tract, and heart problems. This was labelled the 'Thalidomide Disaster' of the late 50s, and was a key case study used to promote stronger drug testing and regulations in the pharmaceutical industry.

The story of the Thalidomide disaster is heartbreaking, but it illustrates why a drug's stereochemistry is so crucial to investigate in pharmacology.

An obvious question which arises in relation to this disaster is how the drug could have possibly passed clinical trials when it was clearly unsafe for use in a large demographic of the population. Alongside the central factor of insufficient testing, there lies another, more intricate reason for the drug's adverse effects.

Twenty years after the disaster, Blaschke et al. reported that one of the two enantiomers of thalidomide was in fact teratogenic (causing birth defects). An enantiomer of a molecule is its optical isomer of a molecule - a non-superimposable mirror reflection. In essence, enantiomers are the "same" molecule, and can be converted into each other under certain conditions (see image below).

Thalidomide possesses a chiral carbon center, meaning it can form S- and R-enantiomers.  Because the thalidomide receptor proteins are also chiral, they have different effects upon binding with the two enantiomers, hence the enantiomer which binds to the receptor makes a big difference. When the R-thalidomide enantiomer binds to the receptor, the drug's intended effects occur, whilst when the S-thalidomide enantiomer binds to the receptor, its effects are teratogenic, inhibiting new blood vessel growth in the foetus and hence causing birth defects.

A seemingly obvious answer to the problem would be would be to sell only the R-enantiomer of thalidomide on the market, thereby bypassing the teratogenic effects of its S-enantiomer. However, in vivo, the problem becomes complicated: the human liver contains an enzyme that can convert R-thalidomide to S-thalidomide, and hence even the administration of enantiomerically pure R-thalidomide results in a racemic (50/50) mixture of each enantiomer. This means that the S-enantiomer will be present in the body whether or not it was originally taken, and hence can still cause its adverse effects.

Therefore, the enantiomeric composition of pharmaceutical drugs (especially in vivo) is a critical factor to consider in drug development. Currently, regulatory guidelines do not prohibit the development of racemic mixtures of chiral drugs. Whilst appears unproblematic if neither enantiomer is hazardous, drug companies should make sure to investigate the properties of each enantiomer of a new chiral drug before they introduce it to the market. In most cases, only one of the two enantiomers is effective, and the ineffective enantiomer is quickly excreted from the body. However, bearing in mind anomalies to the trend such as s-thalidomide, it is important to never assume this harmlessness, and instead thoroughly investigate the properties of each enantiomer.

sources:
​ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3614593/ 
https://www.avericadiscovery.com/blog/why-thalidomide-is-important-to-chiral-separation/