Thalidomide, a History

Written by The American Chemical Society with comments by Dr Jerry L Krause on April 4, 2019. Posted in Current News

Preface:  Historical facts are important but too many tend to forget historical facts or do not do a literature search to be sure that one knows everything about the topic before they expound upon it.

My major professor in graduate school suggested a possible thesis research project.  But when I did a literature search I found that what he proposed had already been done and its results reported.

Thus, by this good scientific practice, I saved myself a lot of wasted effort.

“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.”  (https://www.acs.org/content/acs/en/molecule-of-the-week/archive/t/thalidomide.html)

I knew that the compound—Thalidomide—had two structures (forms) which were mirror images of each other which were not superimposable on each other.  This latter condition was not mentioned in the ACS (American Chemical Society) brief comment.  And in chemistry, molecules which meet both conditions are commonly referred to as ‘optical’ isomers (molecules which have the same elemental composition but different physical structures.)

Other isomers than optical isomers have different chemical properties and physical properties like melting and boiling points.  But until this case of thalidomide chemists had only observed that optical isomers had the same chemical and physical properties except for the ability to ‘rotate’ polarized light in opposite directions (clockwise or counter clockwise).

After the tragic problem of this compound was discovered, I was aware that one isomer had one biological effect and the other a different biological effect.  But, until John O’Sullivan invited me to write one of my essays about these details, I did know that “Under biological conditions, the isomers interconvert, so separating the isomers before use is ineffective.”

For not written in this ACS comment is that, I expect but do not know, that chemists learned how to synthesize the pure (R)-enantiomer and therefore concluded that this solved the problem.  Maybe they tested if on pregnant rats and found that this was not the solution that it seemed to be.  I can only hope this was the case which led to the discovery that “Under biological conditions, the isomers interconvert, so separating the isomers before use is ineffective.”

So, the bottom-line of this essay, do not expect a good scientist to know everything immediately.

“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.”

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