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

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.

Chiral Plasmonics and Their Potential for Point-of-Care Biosensing Applications

“…The therapeutic effects of a chiral drug are often associated with a single enantiomer whereas the other is inactive and/or contributes to undesirable effects [1][2][3][4][5][6]. Thalidomide is one of the most notorious examples, as its L enantiomer produced the teratogenic side effects responsible for limb malformations in the late 1950s [7][8][9]. Furthermore, toxicity due to proteins with wrong chirality is believed to be one of the underlying causes of diseases such as Alzheimer's, Parkinson's, Huntington's, and type II diabetes [10].…”

Synthesis, in Vivo and in Silico Studies of N-Aryl-4-(1,3-Dioxoisoindolin-2-Yl)Benzamides as an Anticonvulsant Agent

“…However, studies show that only the (S)-enantiomer leads to teratogenic side, whereas no teratogenicity was observed for (R)-enantiomer. 3 In recent years, thalidomide have been one of the most notable topics in studies due to its numerous effects on neurological pathways. [3][4][5] Anti-epileptic drugs such as phenytoin, valproic acid, carbamazepine and thalidomide has multiple side effects, including diplopia, anemia and teratogenicity.…”

“…3 In recent years, thalidomide have been one of the most notable topics in studies due to its numerous effects on neurological pathways. [3][4][5] Anti-epileptic drugs such as phenytoin, valproic acid, carbamazepine and thalidomide has multiple side effects, including diplopia, anemia and teratogenicity. 6,7 The word of teratogen is given to any peripheral or congenital factor that causes fetal harm and disorder in its development during prenatal period.…”

Enantiomers of Chloroquine and Hydroxychloroquine Exhibit Different Activities Against SARS-CoV-2in vitro, EvidencingS-Hydroxychloroquine as a Potentially Superior Drug for COVID-19

“…It was later determined that the two enantiomers caused distinctly different effects from one another, and the S-isomer was attributed to being the culprit for the teratogenic properties. 53 Since the enantiomers of thalidomide interconverts in vivo, efforts to develop a stable, single-enantiomer thalidomide was thwarted. Eventually, the racemic form was repurposed and launched for oncology applications under the brand Thalomid, strictly contraindicated for pregnancy.…”