Understanding the Thalidomide Chirality in Biological Processes by the Self-disproportionation of Enantiomers
Understanding the Thalidomide Chirality in Biological Processes by the Self-disproportionation of Enantiomers
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DOI：
10.1038/s41598-018-35457-6
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发表时间：
2018-11-20
影响因子：
4.6
通讯作者：
Shibata, Norio
中科院分区：
文献类型：
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作者：
Tokunaga, Etsuko;Yamamoto, Takeshi;Shibata, Norio
在20世纪50年代末沙利度胺灾难发生20年后，Blaschke等人报道，只有沙利度胺的（S）-对映体是致畸的。然而，其他研究表明，沙利度胺的对映体在体内相互转化，这就引出了一个问题：为什么在使用（R）-沙利度胺的动物实验中没有观察到致畸活性，考虑到体内外消旋化（“沙利度胺悖论”）？在此，我们揭示了一个假说来解释这种“沙利度胺悖论”通过在体内自我-反映异构体。在搅拌沙利度胺在给定溶剂中的20%ee溶液后，在溶液中可重复地观察到高达98%ee的显著对映体富集。我们推测，沙利度胺对映异构体的一部分在体内差向异构化，然后沉淀外消旋沙利度胺（R/S）-异二聚体形式。因此，外消旋沙利度胺很可能在以（R/S）-异二聚体形式外消旋沉淀后从生物过程中除去。另一方面，对映体纯的沙利度胺保留在溶液中，提供观察到的生物实验结果：（S）-对映体是致畸的，而（R）-对映体不是。
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.