Understanding the Thalidomide Chirality in Biological Processes by the Self-disproportionation of Enantiomers.

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Tokunaga E, Yamamoto T, Ito E, Shibata N

Understanding the Thalidomide Chirality in Biological Processes by the Self-disproportionation of Enantiomers.

Sci Rep. 2018 Nov 20;8(1):17131. doi: 10.1038/s41598-018-35457-6.

PubMed ID
30459439 [ View in PubMed
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Abstract

Twenty years after the thalidomide disaster in the late 1950s, Blaschke et al. reported that only the (S)-enantiomer of thalidomide is teratogenic. However, other work has shown that the enantiomers of thalidomide interconvert in vivo, which begs the question: why is teratogen activity not observed in animal experiments that use (R)-thalidomide given the ready in vivo racemization ("thalidomide paradox")? Herein, we disclose a hypothesis to explain this "thalidomide paradox" through the in-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 epimerizes in 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.

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