Understanding the Thalidomide Chirality in Biological Processes by the Self-disproportionation of Enantiomers. Issue 1 (December 2018)

• Record Type: Journal Article
• Authors: Tokunaga, Etsuko; Yamamoto, Takeshi; Ito, Emi; Shibata, Norio
• Is Part Of: Scientific reports. Volume 8:Issue 1(2018)
• Page Start: 1
• Page End: 7
• Publication Date: 2018-12
• Subjects: Natural history -- Research -- Periodicals; Biology -- Research -- Periodicals; Physical sciences -- Research -- Periodicals; Earth sciences -- Research -- Periodicals; Environmental sciences -- Research -- Periodicals; 502.85
• DOI: 10.1038/s41598-018-35457-6
• Languages: English
• ISSNs: 2045-2322

Abstract

Abstract Twenty years after the thalidomide disaster in the late 1950s, Blaschkeet al . reported that only the (S )-enantiomer of thalidomide is teratogenic. However, other work has shown that the enantiomers of thalidomide interconvertin vivo, which begs the question: why is teratogen activity not observed in animal experiments that use (R )-thalidomide given the readyin vivo racemization ("thalidomide paradox")? Herein, we disclose a hypothesis to explain this "thalidomide paradox" through thein-vivo self-disproportionation of enantiomers. Upon stirring a 20% ee solution of thalidomide in a given solvent, significant enantiomeric enrichment of up to 98% ee was observed reproducibly in solution. We hypothesize that a fraction of thalidomide enantiomers epimerizesin vivo, followed by precipitation of racemic thalidomide in (R /S )-heterodimeric form. Thus, racemic thalidomide is most likely removed from biological processes upon racemic precipitation in (R /S )-heterodimeric form. On the other hand, enantiomerically pure thalidomide remains in solution, affording the observed biological experimental results: the (S )-enantiomer is teratogenic, while the (R )-enantiomer is not.