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.

Figure 1

(S)- and (R)-enantiomers of thalidomide (1).

Figure 2

Self-disproportionation of non-racemic 1 (for Table 1).

Figure 3

Self-disproportionation of non-racemic 1 in water and phosphate buffer (pH = 7) (for Table 2).

Figure 4

Self-disproportionation of non-racemic thalidomide at practical scale; ^aDMSO (0.25 mL) was used.

Figure 5

Structures of the (S/S)-homodimer and the (R/S)-heterodimer of 1 based on X-ray crystallographic analyses.

Figure 6

(a) Mechanism of the SDE for (R)-1. (b) An SDE-based hypothesis that feasibly explains why (R)-1 does not show any teratogenic effect in vivo.

Figure 7

Self-disproportionation of non-racemic 2 in water. (S)-2 (23% ee, 5 mg) was dissolved in DMSO, and the SDE experiment was carried out upon addition of water. The final ee was determined from the supernatant after 1 h of stirring by HPLC using a CHIRALCEL OJ-H column with ethanol as the eluent. A substantial amount of precipitate was also observed.