Wednesday, May 23, 2012

#ToxicCarnival: Fluoroacetate

Credit: Wikipedia
I don't really have a favorite element, but if I had to choose one, I'd choose fluorine. It's such an interesting atom, especially combined with carbon. Its small size and strong electronegativity provide polymer chemists with interesting physical properties; the strong bond with carbon allows medicinal chemists the ability to block metabolic oxidation and keep their drug compounds in circulation just a little longer.

When Matt Hartings asked for bloggers to write about their favorite toxic compounds, I couldn't help but think of one of the first things I learned about fluorine and fluoroacetic acid. What happens when fluoroacetic acid (oh-so-similar to acetic acid in size) enters the citric acid cycle in place of acetic acid and is converted to fluorocitric acid? 
It is quite interesting to note that citrate synthase stereospecifically constructs (2R, 3R)-4 (fluorocitric acid) out of four possible diastereomers and, in spite of the extremely poisonous nature of this isomer, causing convulsions and ventricular fibrillation, the three other stereoisomers are not toxic. Thus, this is expressed as the "lethal synthesis" by citrate synthase.
Lethal synthesis! As you can imagine, this really struck me -- what a phrase! It was just a remarkable thing to learn, reading page 2 of a book on fluorine chemistry (the source of the above quote.)

Fluoroacetic acid (or its sodium salt, sodium fluoroacetate), one notes, is quite the poison. It's naturally occuring in a number of rather toxic plants in Africa, Asia and Australia. It's apparently toxic to just about everything (probably because just about everything has the citric acid cycle.) It's used to kill coyotes and (perhaps unsurprisingly) rodents.

Credit: Cox et al. J. Med. Chem. 2008, 51, 4239–4252
The ability of fluoroacetate to kill rodents brings us to our last story. The last thing that I really enjoy about fluoroacetic acid is how it popped up as an interesting little side note in a 2008 J. Med. Chem. paper where some Merck medicinal chemists were concerned about the acute toxicity of an anti-cancer compound with a fluoroethylpiperidine moiety. The authors explain their findings:
As part of our preclinical evaluation of 14, we studied dose proportionality in the rat with iv bolus doses of 1, 4, and 12 mg/kg. As desired, a linear increase in exposure with dose was observed, with 14 achieving AUC levels of 0.5, 2.5, and 9.5 μM h-1, respectively; however, we were surprised to find mortality within 12 h postdose in 2 of 3 rats in the 12 mg/kg group. 
Acute toxicity is not an expected mechanism-based effect for inhibition of KSP and has not been observed in our preclinical program with any compound other than 14. The dose-limiting, mechanism-based toxicity observed for KSP inhibitors both preclinically and in humans is neutropenia (depletion of white blood cells) and typically manifests in 4-10 days following compound adminstration. 
In our search for a compound-specific source of toxicity, we identified the fluoroethylamine of 14 as a potential liability. If N-dealkylation of the piperidine ring were to occur in vivo, a likely byproduct would be fluoroacetate, a known toxin with acute pharmacology. In fact, we discovered that N-dealkylated analogue 12 is the major metabolite generated in rat liver microsome and hepatocyte incubations, suggesting that formation of fluoroacetate is indeed the source of toxicity in vivo.
One imagines that Cox et al always viewed that fluoroethyl moiety with some level of apprehension and their fears were confirmed by their metabolic studies. The ability of the liver (even the rat liver!) to chew apart molecules is remarkable -- oxidizing a fluoroethyl to fluoroacetate is just another fascinating (and not entirely unexpected) example.

So for fluoroacetate's ability to reveal the inner workings of biochemistry, it's one of my favorite toxic compounds. 


  1. CJ: I suppose the fluoro acetic acid is suicide in TCA/Krebs’s cycle. So as a medicinal chemist I am always mindful of those scenarios. Simple attachment of mono-fluoro methyl next to oxygen or nitrogen atom is OK, but mono fluoro ethyl is another story.

  2. And to think, as a first year grad student I went through a ton of 2-fluoroethanol. Wish I knew this back then!

  3. Not neccessarily tis group has to be toxic:

  4. @3
    The exception that proves the rule? No, in that paper mice dosed at 100mpk were pre-dosed with 100mpk ABT, thus blocking oxidative metabolism and sparing them from an untimely end.


looks like Blogger doesn't work with anonymous comments from Chrome browsers at the moment - works in Microsoft Edge, or from Chrome with a Blogger account - sorry! CJ 3/21/20