Enantiomer thalidomide

H. Y. Aboul-Enein and M. R. Islam, Direct HPLC separation of thalidomide enantiomers using cellulose tris-4-methylphenyl benzoate chiral stationary phase, J. Liquid Chromatogr., 14 667... 

P. Hdglund, T. Eriksson, S. Bjdrkman, A double-blind study of the sedative effects of the thalidomide enantiomers in humans, J. Pharma-cokin. Biopharm. 26 (1998) 363-383. 

Murphy-Poulton SF, Boyle F, Gu XQ, Mater LE, Thalidomide enantiomers Determination in biological samples by HPLC and vancomycin-CSP, J. Chromatogr. B 2006 831 48-56. 

Where is the punch line of our story Well, if you look at Figure 7.10, you will see that thalidomide has a chiral carbon. It turns out that only one of the enantiomers causes the birth defects. Chirality of biological systems strikes again However, in this case, the two enantiomers transform to one another quite rapidly, and hence administering the right thalidomide enantiomer will give rise to formation of the wrong one... However, as in every Shakespearean story, the thalidomide story is full of twists and turns, as recently, it was found to be efficient in cancer therapy. If we needed another proof of the Janusian character of molecules, then here it is. 

It has now been well established that the (R)-( + )-thalidomide enantiomer is responsible for the sedative effects of this drug, and that the (S)-(—)-enantiomer is responsible for causing the birth defects [9]. It might initially seem possible to still use this compound as a sedative if the enantiomers are separated, and to prescribe the active R-enantiomer alone (i.e., ensuring that the patient does not ingest the S-enantiomer). Well, it turns out that in the body there is a fairly rapid racemization (interconversion of the two enantiomers) of this compound, so that the harmful enantiomer cannot be eliminated [10]. 

Figure 5.5. Molecular structures of adrenaline enantiomers Figure 5.6. Molecular structures of thalidomide enantiomers Figure 5.7. Molecular structures of ibuprofen enantiomers Figure 5.8. Molecular structures of fluoxetine enantiomers...

One enantiomer of penicillamine (D-) exhibits antiarthritic properties but foe other is highly toxic (Figure 8.3). The teratogenic effects of thalidomide were induced by one enantiomer, foe other exhibited foe beneficial effects against morning sickness. 

The ideal solubility equation has significant value in chiral systems, where a single enantiomer is desired as the product [20]. The behaviour of chiral compounds is very important in biological systems and in drug development, where it is typical for just one enantiomer of an API to be biologically active. The undesired enantiomer may be inert, or possess more serious toxicity effects, as in the case of Thalidomide. Many enantiomeric systems form three discrete solid phases, depending on the solution concentration. Pure crystals of each enantiomer will form at high concentrations of their respective enantiomer. At... 

One should not conclude from the above that the glutarimide ring is always resistant to hydrolysis. Indeed, its hydrolysis is a major metabolic pathway for the thalidomide analogue EM12 (4.198). After administration of EM 12 to marmoset monkeys, two products of hydrolysis, 4.199 and 4.200, were found in urine. The concentrations of the two metabolites were similar after administration of the racemate. In contrast, regioselectivity (i.e.. different ratios of the two metabolites) was seen after separate administration of the enantiomers [125],... 

H. J. Schmahl, W. Heger, H. Nau, The Enantiomers of the Teratogenic Thalidomide Analogue EM 12. 2. Chemical Stability, Stereoselectivity of Metabolism and Renal Excretion in the Marmoset Monkey , Toxicol. Lett. 1989, 45, 23-33. 

A four-compartment model consisting of a two-compartment model for each enantiomer, with elimination from both compartments, connected by rate constants for chiral inversion was fitted to the concentration data, whereas the sedative effects were correlated with the blood concentrations of R- and S-thalidomide by means of logistic regression. PK modeling predicted that varying the infusion time of a fixed dose of S-thalidomide between 10 min and 6 h would have little influence on the maximal blood concentration of formed R-thaKdomide. These effects may chiefly be exerted by S-thalidomide, but the enantiomers are interconverted in vim... 

Eriksson, T., Bjorkman, S., Roth, B., and Hoglund, P., Intravenous formulations of the enantiomers of thalidomide pharmacokinetic and initial pharmacodynamic characterization in man, /. Pharm. Pharmacol., 52, 807-817, 2000. 

Thalidomide The (i )-enantiomer is a sedative and the (5)-enantiomer is teratogenic (i.e., causes fetal deformity). 

A well known example of tragic consequences is provided by "Thalidomide" (or "Contergan") which was commercialised in the 60 s whereas the (/ )-enantiomer shows a weak sedative activity, the enantiomer of (5)-configuration, administered together in the racemate, caused in the expectant mothers a teratogenic effect (malformations) on the foetus. 

Like fluorochlorobromomethane, thalidomide exists in right-handed and left-handed forms. Thalidomide as marketed contained equal amounts of both forms. As was learned later, the beneficial effect for pregnant women is mostly due to one of these forms. The potential to cause birth defects is largely due to the other. However, thalidomide would have been a hopeless case for morning sickness even if the marketed drug contained only the good molecule. The two enantiomers of thalidomide are interconverted in vivo. Any threat to the ferns is unacceptable. 

Enantiomers are characterized as nonsuperimposable mirror images. Enantiomers are said to be chiral (note that some diastereomers may be chiral as well). In the context of the same bonding pattern or connectivity, which atoms are bonded to which, enantiomers have handedness and are related to each other as the right hand is related to the left hand. In the specific example we saw earlier, the carbon atom is linked to four different atoms. Such molecules have non-superimposable mirror images. Stereoisomerism occurs in some molecules that do not have such a carbon atom but these cases are more exotic than we need to worry about here. Stereoisomers frequently have different, and sometimes strikingly different, biological properties, exemplified by the thalidomide case. 

Thalidomide was in 2006 approved by the FDA for the treatment, in combination with dexametha-sone, of newly diagnosed multiple myeloma patients. Thalidomide was sold in the late fifties as an hypnotic, with the infamous epidemic of birth defects as a result. Thalidomide is racemic and the S enantiomer is teratogenic. However the enantiomers interconvert in vivo, so giving only the R enantiomer cannot be a solution. After oral administration peak levels are reached in 2-A hours. It is eliminated mainly by biotransformation with a halfiife of about 6 hours. The most common side effects observed with use of thalidomide in myeloma include drowsiness or fatigue, constipation, dizziness, dry skin or rash, low white blood cell counts, and peripheral neuropathy. 

---