As of 2015, the main theories were inhibition of the process of angiogenesis, its inhibition of cereblon, a ubiquitin ligase, and its ability to generate reactive oxygen species which in turn kills cells. In 2018, results were first published which suggested that thalidomides teratogenic effects are mediated through degradation of the transcription factor, SALL4, an as yet unverified finding.Thalidomide also binds to and acts as an antagonist of the androgen receptor (AR) and hence is a nonsteroidal antiandrogen (NSAA) of some capacity. In accordance, it can produce gynecomastia and sexual dysfunction as side effects in men. Chirality and biological activity
Thalidomide is provided as a racemic mixture of two enantiomers; while there are reports that only one of the enantiomers may cause birth defects, the body converts each enantiomer into the other through mechanisms that are not well understood. The (R)-enantiomer has the desired sedative effect while the (S)-enantiomer harbors embryo-toxic and teratogenic effect. The hypothesis that the tragedy could be avoided in this case by using a single enantiomer is misleading and pointless, because it was later demonstrated that the “safe” R-thalidomide undergoes an in vivo chiral inversion to the “teratogenic” S-thalidomide. Under biological conditions, the enantiomers interconvert [bidirectional chiral inversion - (R)- to (S)- and vice versa]. Chemistry
Thalidomide is racemic; while S-thalidomide is the bioactive form of the molecule, the individual enantiomers can racemize to each other due to the acidic hydrogen at the chiral centre, which is the carbon of the glutarimide ring bonded to the phthalimide substituent.
However, thalidomide is a teratogenic substance, and a proportion of children born during the 1960s had thalidomide embryopathy (TE). Of these babies born with TE, "about 40% of them died before their first birthday". The surviving individuals are now middle-aged and they report experiencing challenges (physical, psychological, and socioeconomic) related to TE. Individuals born with TE frequently experience a wide variety of health problems secondary to their TE. These health conditions include both physical and psychological conditions. When compared to individuals of similar demographic profiles, those born with TE report less satisfaction with their quality of life and their overall health. Access to health care services can also be a challenge for these people, and women in particular have experienced difficulty in locating healthcare professionals who can understand and embrace their needs. Brand names
Brand names include Contergan, Thalomid, Talidex, Talizer, Neurosedyn, Distaval and many others. Research
Research efforts have been focused on determining how thalidomide causes birth defects and its other activities in the human body, efforts to develop safer analogs, and efforts to find further uses for thalidomide. Thalidomide analogs
The exploration of the antiangiogenic and immunomodulatory activities of thalidomide has led to the study and creation of thalidomide analogs. Celgene has sponsored numerous clinical trials with analogues to thalidomide, such as lenalidomide, that are substantially more powerful and have fewer side effects — except for greater myelosuppression. In 2005, Celgene received FDA approval for lenalidomide (Revlimid) as the first commercially useful derivative.