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Thalidomide and stereochemistry — a lie from undergraduate organic chemistry

Photo credit to Niko von Glasow

The image above is a photo of German filmmaker Niko von Glasow. He submitted it to wikipedia in 2009 to illustrate the effects of thalidomide. The image is licensed under the creative commons license .

Goals of the article

I wrote this into the cannabis article as I was trying to find references to show the thalidomide diaster as an important example of stereochemistry. This was a myth I had been taught in undergraduate organic chemistry. This article is here so I can find the references when I need them.

Thalidomide and stereochemistry

Stereoisomers are commonly overlooked in chemistry unless they have profound implications. For example, thalidomide is a drug which maimed tens of thousands of children across Europe in the mid 1900s when their mothers took it during pregnancy for morning sickness. The drug was never prescribed for morning sickness in the US because a skeptical FDA official, Frances Oldham Kelsey PhD [1], heeded early reports of the impending harms [2]. Thalidomide is now an approved drug in the US but it is never used in pregnant women.

Thalidomide has one chiral center. Some modern organic chemistry courses use thalidomide as an example of the importance of stereochemistry claiming that the drug was toxic because both stereoisomers were packaged together and one treated morning sickness while the other caused birth defects [3,4]. This is not true but it is a widespread misconception. Both enantiomers of thalidomide are teratogenic (causes birth defects) because, once in the body, the enantiomers interconvert [5,6,7]. There is some evidence that one enantiomer is doing most of the harm [8,9] but as a practical matter, if the stereoisomers interconvert once in the body, this has no bearing on the results. However, there are undergrad courses which are happy to repeat the thalidomide-stereochemistry myth to illustrate the importance of stereochemistry while citing papers that debunk that story [10]. Khan academy briefly relays their version of the story without mentioning the interconversion. This story persists in the chemical community today because if it were true, it would be the most consequential example of the importance of stereochemistry. The thalidomide-stereochemistry tale appears in a wonderfully titled 2010 Nature paper "Urban legends of chemistry" [11].

Stereochemistry undoubtedly has important effects on the nature of biological interactions. Most stereoisomers do not interconvert in the body. It is therefore important that, regardless of whether a drug interconverts or not, we understand what stereoisomers exist, use our language precisely to describe the molecules we are discussing, learn how they interact with the body, and determine whether or not they interconvert under physiological conditions.

References

[1] M. Rouhi, "Thalidomide," Chemical & Engineering News, vol. 83, 2005.

[2] S. Fabro, R. L. Smith, and R. Williams, "Toxicity and teratogenicity of optical isomers of thalidomide," Nature, vol. 215, pp. 296—296, 1967.

[3] P. Y. Bruice, "Isomers and Stereochemistry," in Essential Organic Chemistry 2nd International Ed, pp. 169, 2014.

[4] G. Piizi, and S. Hardinger, "Stereochemistry: an introduction," UCLA Chemistry 30A Presentation, Fall, 2002.

[5] M. E. Franks, G. R. Macpherson, and W. D. Figg, "Thalidomide," The Lancet, vol. 363, pp. 1802—1811, 2004.

[6] B. A. Chabner, J. Barnes, J. Neal, E. Olson, H. Mujagic, L. Sequist, W. Wilson, D. L. Longo, C. Mitsiades, and P. Richardson, "Target therapies: tyrosine kinase inhibitors, monoclonal antibodies, and cytokines," in The Pharmacological Basis of Theraputics, pp. 1731—1754, 2011.

[7] M. Reist, P. Carrupt, E. Francotte, and B. Testa, "Chiral inversion and hydrolysis of thalidomide: mechanisms and catalysis by bases and serum albumin, and chiral stability of teratogenic metabolites," Chemical Research in Toxicology, vol. 11, pp. 1521—1528, 1998.

[8] G. Blaschke, H. P. Kraft, K. Fickentscher, and F. Köohler, "Chromatographischeracemattrennung von thalidomid und teratogene wirkung der enantiomere," ArzneimittelForschung, vol. 29, pp. 1640—1642, 1979.

[9] T. D. Stephens, C. J. Bunde, and B. J. Fillmore, "Mechanism of action in thalidomide teratogenesis," Biochemical Pharmacology, vol. 59, pp. 1489—1499, 2000.

[10] L. A. Nguyen, H. He, and C. Pham-huy, "Chiral drugs: an overview," International Journal of Biomedical Science, vol. 2, pp. 85, 2006.

[11] M. Francl, "Urban legends of chemistry," Nature Chemistry, vol. 2, pp. 600—601, 2010.

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