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|
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.