Why does thalidomide racemize in the body?

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After doing some research on thalidomide for my A2 chemistry course I've learned some facts regarding the 2 optical isomers of thalidomide and their differences.

I've found that even if pure one optical isomer of thalidomide is injected into the body racemizing occurs and equal amounts of each isomer are produced.

I'm interested in why this occurs, as I've found little information on this on google.

Thanks for any help.
 

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KnowledgeIsPower said:
After doing some research on thalidomide for my A2 chemistry course I've learned some facts regarding the 2 optical isomers of thalidomide and their differences.

I've found that even if pure one optical isomer of thalidomide is injected into the body racemizing occurs and equal amounts of each isomer are produced.

I'm interested in why this occurs, as I've found little information on this on google.

Thanks for any help.

I'm interested in where you found this out. I was under the impression that thalidomide did NOT racemize in vivo.

Anywho, look at the structure of thalidomide. Are you familiar with what an enol or enolate is? Well, the chiral carbon is enolizable. I'm not sure of your O-chem background, but it loses its stereochemical information when it hybridizes to an sp2 carbon. This wouldn't happen rapidly at physiological pH, so I'm guessing it occurs enzymatically.
 
Yes, just trying to help.

Just google keto-enol tautomerization, or tautomers.
Or index it in your O-chem book.
:)
 
Thanks for the advice people, I'm just starting to realize really that not everything is known in the world of science so maybe my source was wrong, who knows.
I'll check out the 'keto-enol tautomerization', thanks.
 
I found that quite interesting too,
if this drug would already racemize
why only optical impure drug would result in disease ??

if it racemize, even optically pure thalidomide can be dangerous...

so could u mind telling us how this occur ??

Thx :smile:
 
Hello Folks,

In regards to the racemization of Thalidomide, most undergraduate textbooks will show how this is bad because it is way easier for people to learn something by example of a real life consequence.

However, if you need a reference article:

Testa, B.; Carrupt, P. A.; Gal, J. Chirality 5: 105-111 (1993)

The main explanation for how this occurs is enolization/tautomerization as was mentioned by Chemicalsuperfreak above. One can isolate either isomer, but upon addition to either an acidic or basic environment such as the human body one pure form will slowly convert to the other to give approximately the same amount of either isomer.

Since blood is widely reported to be slightly basic, a hydroxide ion would remove the hydrogen at the chiral center making water. The electrons from the bond would form a double bond with the carbon that has the oxygen attached to it. One of the bonds from the oyxgen carbon bond would kick up to the oxygen. At this point, there is water present because it is the main solvent in the body, so the negatively charged oxygen would remove one of the hydrogens from the water molecule regenerating the hydroxide ion used in the first step.

To get the other enantiomer of Thalidomide, just reverse the steps but place the chiral carbon's hydrogen in the other configuration.

As for Thalidomide's inability to racemize at body pH, I am unsure as to the kinetics of the reaction. It may be a slow reaction, but I remember reading or hearing about it in a lecture that one can detect Thalidomide in the body up to a week later.

As to why someone would give the drug, one has to look into the history of identifying isomers of molecules. At the time Thalidomide was being marketed, there was no sure way to identify one isomer from the other conclusively. People thought that they were giving a pure drug to people, and they didn't know about the teratogenic abilities of the one isomer because this was probably tested on people who were not pregnant.

As to how one isomer is good and one is bad, DNA is the culprit. Newer research suggests that the bad isomer binds to DNA and prevents proper cell replication. This would in turn inhibit proper skeletal formation. The good isomer can not properly attach to the DNA and therefore can not cause any of the effects seen with the bad isomer.

That is about all I can think of right now. If someone wants more info, just go to a Chemistry building and talk with an organic professor. Almost all would happily chat with you on this topic.
 
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The problem with the racemization explanation is that physiological pH, there isn't a strong enough base to remove the hydrogen at the chiral center to an appreciable extent. The enzymatic explanation makes sense though.
 
A post-script to my last post:

I was just looking through a textbook to answer another question on the board here and stumbled upon a section that says that Thalidomide does indeed racemize in the body. Very interesting. It says that they do believe that only on of the enantiomers is teratogenic (causes birth defects). However, it also says that the effect on cell growth is being investigated for the drugs use as an anti-tumor agent. Obviously it can't be administered to pregnant women, but it may make a comeback as a pharmaceutical.


Info is from Organic Chemistry, Loudon, 4th ed. pp 214-215.
 
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That's very interesting. Thanks all, the articles and information proved very useful.
I'll have to have a go at drawing out a mechanism for this racemizing.
If thalidomide was to be administered as an anti-tumour agent how exactly would it be administered? Injection?
 
Well, when it was given to treat morning sickness it was administered as a pill, right? So I would assume that it would be administered the same way. It might be injected directly at the site of the tumor though as well. It's really hard to say until the thing is out on the market as I am sure that they test all of the possible methods.

It might not matter though, as it seems that it only affects cells that are actively growing, therefore bad for a fetus, good against a tumor.
 
I wasn't aware it had shown any cytotoxic activity. I do know it is being used to treat leprosy. And it is being synthesized in its enantiopure form, so I'm assuming the rate of racemization under physiological conditions is much too slow to cause the deleterious side effects.
 
I think that they are using the toxic enantiomer for both applications, although the section in the textbook doesn't go into a lot of detail. It says that both enantiomers have been shown to racemize in the bloodstream though. I would be surprisized if they were going to administer the racemic drug though. As I would have to agree that racemization would be rather slow.