Thalidomide chirality paradox explained
Molecule chirality (“left-handedness” and “right-handedness”) has been in the news again recently.
What is little known is the relevance of chirality to the thalidomide disaster. Thalidomide, the drug which was prescribed widely to pregnant women in the 1950s for the treatment of morning sickness, was later discovered to be a chiral molecule, and while the left-handed molecule was effective, the right-handed one was extremely toxic, causing thousands of children around the world to be born with severe birth defects. The mystery is, why didn’t this toxicity emerge during animal experiments? Here’s a paper with a potential explanation:
Twenty years after the thalidomide disaster in the late 1950s, Blaschke et al. reported that only the (S)-enantiomer of thalidomide is teratogenic [jm: causing birth defects]. However, other work has shown that the enantiomers [“mirror” molecules] 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 [equally mixed between R/S forms] 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.
Tags: chirality thalidomide molecules drugs medicine papers chemistry