#thalidomide

Thalidomide was originally introduced as a non-barbiturate sedative in 1957 and later marketed for the treatment of nausea in pregnant women by the German company Chemie Grünenthal, as antiemetic properties were discovered. In the 1960s however it became apparent that thalidomide treatment resulted in severe teratogenic birth defects and from November 1961 it began to be withdrawn worldwide. It has since been reintroduced into a number of studies and treatments due to its immunosuppresive and anti-angiogenic activity.

Chemical structure of thalidomide. Thalidomide is a stereo-isomer and can exist, depending on the state of the chiral carbon, in two enantiomeric states. Both R and S can interconvert in body fluids and tissues.  Thalidomide was distributed as a racemic mix of both enantiomers.

• Thalidomide is a piperidinyl isoindole and synthetic derivative of glutamic acid, consisting of two linked glutarimide and pthalimide rings. 
• The unstable chiral carbon allows two enantiomers to coexist - the S-enantiomer being teratogenic (Franks, 2004.) 
• The mechanism of action that resulted in these teratogenic effects is still not fully understood. 
• Leading theories focus on thalidomide’s antiangiogenic properties; ability to induce cell death and generate reactive oxygen species; and Cereblon, a thalidomide-binding protein and primary source of teratogenic action (Takumi, 2010). 
• Thalidomide is hydrolyzed in bodily fluids and metabolized in the liver by cytochrome p450.

When first developed thalidomide was deemed so non-toxic that an LD50 could not be established, but tragically an estimated 25,000 babies were born severely impaired and a further 123,000 miscarried or stillborn (Johnson, 2016).

Antiangiogenic properties 

Thalidomide has the ability to inhibit angiogenic vascularization in embryos, thus carrying out teratogenic damage. 

• The bulk of its damage occurs in days 20-36 of fertilization. 
• During this time, the primitive vessels formed by vasculoneogensis mature and begin to proliferate and migrate in response to signals and growth factors such as FGF. 
• It is thought that analogues of thalidomide could block a number of these signals, thus preventing embryonic vascular development outwards towards the limbs and resulting in limb deformities such as phocemelia. 

Molecular targets of thalidomide

Cereblon 

• Forms part of a ubiquitination complex with DNA Binding Protein 1, which in turn selects molecules for destruction. 
• Thalidomide binds, preventing formation of the complex and proper regulation of developmental signaling molecules, thus initiating teratogenis by inhibiting angiogenesis (Takumi, 2010). 
• Could also degrade some proteins and prevent breakdown of others.

Tubulin 

• part of the cytoskeleton and  required for cell proliferation and formation of  new vessels in the embryo. 
• When bound by the 5HPP-33 thalidomide analogue, cytoskeletal dynamics are altered preventing cell division. 
• This could prevent cell proliferation and migration and consequently tissue morphogenesis, the severity of which would be dependent on vascular and tissue maturation at the point of contact with thalidomide (Vergesson, 2015).