Which enantiomer of thalidomide is teratogenic

Figure 3. Figure 4. Cell death and ROS induction hypothesis Another attractive hypothesis suggests Thalidomide can induce formation of ROS, which causes oxidative stress to cells, which has been proposed to cause limb defects Parman et al.

Cereblon Cereblon is a candidate gene linked to human mental retardation Higgins et al. Summary Many gene expression changes result from thalidomide exposure, and seem linked to the vasculature and the cytoskeleton. Conclusions and Challenges Thalidomide caused a disaster that still shocks the world today and sadly is happening again in Brazil. Figure 5. Thalidomide is not a human mutagen. Br Med J Thalidomide: lack of mutagenic activity across phyla and genetic endpoints.

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Clin Perinatol 13 — Clin Rehabil 13 — Cancer Res 63 — Am J Hum Genet 74 — The sensitive phase in thalidomide embryopathy. 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. Thalidomide is one of the most notorious drugs, responsible for a tragic global medical disaster of limb malformations in the late s 1 , 2 , 3 , 4 , 5 , 6 , 7.

However, the increased number of limb malformations was later confirmed to be caused by thalidomide. Although thalidomide was banned in in Germany, and later worldwide, it has once again attracted clinical interest due to the discovery of its unique pharmacological action against a number of intractable diseases, such as leprosy, human immunodeficiency virus replication in acquired immune deficiency syndrome, and cancer 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , Thalidomide 1 possesses a single stereogenic carbon center and thus S - and R -enantiomers Fig.

Commercially, it was marketed as a racemate. In , Blaschke et al. This paper suggested that the thalidomide disaster could have been avoided if only R - 1 had been marketed instead of racemic 1. Thus, how can these results be rationalized in the light of the findings by Blaschke et al.

Although several enantioselective biological studies on the metabolism of thalidomide have been reported 21 , the confirmation of the different biological activity of the pure thalidomide enantiomers has ultimately remained problematic. In , Handa and co-workers carried out a landmark biological study on thalidomide by identifying cereblon CRBN as a thalidomide-binding protein 22 , They found that thalidomide induces its teratogenic effects by binding to CRBN in zebrafish and chicks.

This report opened a new era for thalidomide in science and completely redirected the research on this drug 24 , 25 , 26 , In , Hakoshima, Handa, and co-workers, including two of the authors of the present study, finally put an end to the debate on the teratogenicity of S -thalidomide via structural and biochemical studies of the S - and R -enantiomers of thalidomide coordinated to CRBN The biochemical studies were carried out on deuterium-substituted enantiomers of thalidomide 29 to suppress any enantiomeric interconversion.

The results revealed that the S -enantiomer of 1 displayed a fold stronger binding to CRBN and inhibition of self-ubiquitylation compared to the R -isomer. The crystal structure of the thalidomide-binding domain of CRBN bound to each of the enantiomers revealed that both bind to the CRBN pocket, although the bound form of the S -enantiomer exhibits a more natural ring conformation of the six-membered glutarimide moiety.

Thus, the report by Blaschke is absolutely correct, i. However, one question remains regarding the clear biological differences between the thalidomide enantiomers reported in , despite the observed racemization of thalidomide. Why do animal experiments that use R - 1 not display teratogenicity if R - 1 readily racemizes in vivo?

During our continuous studies on 1 and its derivatives 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , we noticed that the physicochemical properties of racemic 1 and its pure enantiomers are very different The term self-disproportionation of enantiomers SDE was introduced by Soloshonok in to describe the transformation of an enantiomerically enriched system through the formation of fractions with a different proportion of enantiomers relative to the original ratio 40 , 41 , 42 , 43 , 44 , 45 , Our investigation began by examining whether SDE would occur in a solution of 1.

In these solutions, the progressive formation of a precipitate was observed. The use of 0. Further details for the applied conditions are shown in the Supplementary Information Table S1. Self-disproportionation of non-racemic 1 for Table 1. Next, experiments under conditions simulating biological media were carried out, i.

Other ratios of R - and S - 1 were also examined in water and similar behavior was observed entries 9— In all cases, a substantial amount of precipitate was observed in the final solution, and the precipitate showed a low ee of 1 vide infra.

Further details for the different conditions applied are shown in the Supplementary Information Table S2. Subsequently, we attempted to carry out the SDE of non-racemic thalidomide at a practical scale Fig. The filtrate and precipitate were dried separately by freeze drying. The filtrate afforded R - 1 3. This experiment was repeated three times and similar results were obtained. Self-disproportionation of non-racemic thalidomide at practical scale; a DMSO 0.

Then, we examined the solubility of enantiomeric and racemic 1. The solubility of 1 in water was determined by absorption spectroscopy. After filtering off all insoluble solids, the saturated water solution of 1 1. The water solubility of 1 was calculated using a calibration curve.

The water solubility of S - 1 Such differences in the solubility of the individual enantiomers and the racemate of thalidomide 1 are in good agreement with the differences in their X-ray crystal structures that have previously been reported by us 39 , The crystal structure of S - 1 shows two types of arrangements: a solvated monomer and a non-solvated homodimer of two S - 1 molecules with hydrogen-bonding at the glutarimide rings.

On the other hand, a non-solvated heterodimer of R - and S -thalidomide molecules was obtained for racemic- 1. Obviously, the solvated monomer of S - 1 is more soluble than the other structures.

Moreover, the homodimer of S - 1 should be more soluble than the heterodimer of racemic 1 , as the latter is more closely packed on account of two intermolecular hydrogen bonds. The SDE of S - 1 can be explained in the same way. The results by Blaschke et al. First, the acidic hydrogen atom at the asymmetric center of enantiomerically pure R - 1 epimerizes under physiological conditions, resulting in the formation of enantiomerically poor R - 1 e.

Such enantiomer mixtures of thalidomide with low ee spontaneously undergo a SDE to provide enantiopure R - 1 and racemic 1. This hypothesis is also supported by the fact that the oral absorption of racemic thalidomide is slower than that of the individual thalidomide enantiomers 50 , Since the report by Blaschke et al. Finally, we carried out similar experiments using non-racemic fluoro-thalidomide 2 30 , 37 , which is a non-racemized bioisostere of thalidomide 1.

Compound 2 exhibits potent anti-tumor activity against the human multiple myeloma cell line H 38 , while it is non-teratogenic We thus briefly optimized the conditions for SDE of non-racemic 2 in water cf.

Table S3 and similar results were observed, i. Self-disproportionation of non-racemic 2 in water. A substantial amount of precipitate was also observed. In summary, we have disclosed the SDE of non-racemic thalidomide 1 in water and phosphate buffer solution.

The SDE of non-racemic 1 induces a spontaneous separation into dissolved and precipitating components based on the differences in solubility of the different structures of 1 , i. Since the SDE of non-racemic fluoro-thalidomide 2 was also observed, this phenomenon may also occur in other chiral drugs 52 , Thus, chiral drugs with low enantiomeric purity should be used only with extreme care due to potential SDE processes in biological systems.

R - 1 , S - 1 , and S - 2 were prepared according to previously reported methods 31 , Only half of the infants survived, and some of those who did had other defects in addition to limb deficiencies.

The thalidomide disaster caused many countries to tighten drug approval regulations. Thalidomide exists in two mirror-image forms: it is a racemic mixture of R - and S -enantiomers. The R -enantiomer, shown in the figure, has sedative effects, whereas the S -isomer is teratogenic. Under biological conditions, the isomers interconvert, so separating the isomers before use is ineffective.

More recently, thalidomide has proven useful for treating cancer and leprosy and is approved for these uses. But although more than papers have been written about its mechanism of teratogenic action, it was not until the past few years that this mechanism was established.

In , H. Of course, most people know that getting FDA approval for a drug requires several stringent guidelines to be met, and that meeting these guidelines is no easy task. However, this was not always the case. Before the s, the FDA existed in name, but its regulatory functions were lax at best, and negligent at worst. The turning point occurred in the early s after the thalidomide tragedy, a disaster which demonstrates the importance of regulating the pharmaceutical industry.

The thalidomide tragedy occurred in the s, a time when the standards of regulation in the pharmaceutical industry were not nearly as rigorous as they are today. Thalidomide was first marketed in Germany during the mids as a drug to aid with sleeping problems and insomnia. Not long after thalidomide started being used for this purpose, scientists began to observe birth defects in children born to mothers who had taken thalidomide during their pregnancy; studies showed that exposure was particularly dangerous for infants born to mothers that had used the drug approximately 20—34 days post-fertilization.

Common birth defects seen in these children included deletion of the ears, deafness, severe underdevelopment or absence of the arms, defects in the femur and tibia bones of the legs , and many more. More than 10, children around the world were born with thalidomide-related birth defects, and tragically, many of these children, now adults, still suffer from the effects of thalidomide.

What exactly is the chemistry behind this tragedy? This is where the concept of enantiomers comes in. The thalidomide molecule occurs naturally in two forms, R - thalidomide and S - thalidomide, which are enantiomers, or mirror image molecules, of each other.

The R - form has remedial properties, while the S - form is a teratogen, an agent that can cause birth defects.