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

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...

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Autores principales: Tokunaga, Etsuko, Yamamoto, Takeshi, Ito, Emi, Shibata, Norio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244226/
https://www.ncbi.nlm.nih.gov/pubmed/30459439
http://dx.doi.org/10.1038/s41598-018-35457-6
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author Tokunaga, Etsuko
Yamamoto, Takeshi
Ito, Emi
Shibata, Norio
author_facet Tokunaga, Etsuko
Yamamoto, Takeshi
Ito, Emi
Shibata, Norio
author_sort Tokunaga, Etsuko
collection PubMed
description 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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spelling pubmed-62442262018-11-28 Understanding the Thalidomide Chirality in Biological Processes by the Self-disproportionation of Enantiomers Tokunaga, Etsuko Yamamoto, Takeshi Ito, Emi Shibata, Norio Sci Rep Article 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. Nature Publishing Group UK 2018-11-20 /pmc/articles/PMC6244226/ /pubmed/30459439 http://dx.doi.org/10.1038/s41598-018-35457-6 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Tokunaga, Etsuko
Yamamoto, Takeshi
Ito, Emi
Shibata, Norio
Understanding the Thalidomide Chirality in Biological Processes by the Self-disproportionation of Enantiomers
title Understanding the Thalidomide Chirality in Biological Processes by the Self-disproportionation of Enantiomers
title_full Understanding the Thalidomide Chirality in Biological Processes by the Self-disproportionation of Enantiomers
title_fullStr Understanding the Thalidomide Chirality in Biological Processes by the Self-disproportionation of Enantiomers
title_full_unstemmed Understanding the Thalidomide Chirality in Biological Processes by the Self-disproportionation of Enantiomers
title_short Understanding the Thalidomide Chirality in Biological Processes by the Self-disproportionation of Enantiomers
title_sort understanding the thalidomide chirality in biological processes by the self-disproportionation of enantiomers
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244226/
https://www.ncbi.nlm.nih.gov/pubmed/30459439
http://dx.doi.org/10.1038/s41598-018-35457-6
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