Y.fluorobutyric acid

From a study of the fluoroacetates so far mentioned, it appears that any compound which can give rise to fluoroacetic acid (or the fluoroacetate ion), either by hydrolysis or by oxidation (or both), is toxic. The toxic grouping is thus F-CH2-CO, and any substitution in this radical destroys the toxicity as far as relatively simple compounds are concerned. We had reached this conclusion by May 1943.1 We subsequently showed that esters of / -fluoropropionic acid were non-toxic, whereas esters of y-fluorobutyric acid were shown by American workers to be toxic. In 19442 we reported the synthesis of ethyl 5-fluoro-pentanecarboxylate, F,[CH2]g C02Et (I). This is a stable, colourless liquid and we showed that it possessed very potent toxic properties of the fluoroacetate type. By subcutaneous injection of the propylene glycol solution into mice the l.d. 50 was 4 mg./kg. Methyl fluoroacetate (II) may be taken as a convenient standard (p. 115) and has a l.d. 50 of about 6 mg./kg. for saline solutions, and 15 mg./kg. for propylene glycol solution.3 Therefore ethyl 5-fluoropentanecarboxylate was about 7 times as toxic as methyl fluoroacetate (molecule for molecule).4... 

The very high toxicity of ethyl 5-fluoropentanecarboxylate and its derivatives and the fluoroacetate-like symptoms produced seemed to us to be of particular interest, since by a process of /9-oxidation in the animal body 5-fluoropentanecarboxylic acid would readily give rise to the toxic fluoroacetic acid. Similar remarks apply to y-fluorobutyric acid and its derivatives prepared independently by American workers. The non-toxicity of /9-fluoropropionic acid and its derivatives may, on the other hand, be due to the inability of this acid to give the toxic fluoroacetic acid by a process of /9-oxidation. 

Although our results support the / -oxidation theory, one point must not be overlooked, namely, that fluoroacetic acid is not the actual toxic agent and has to be converted into fluoro-citrate before exerting its activity (see p. 142). It should also be noted that American workers1 showed that both methyl y-fluorobutyrate and methyl -fluorocrotonate,... 

Emara et al. [1392] extracted the antineoplastic anthracycline compounds adriamycin (and its metabolites adriamycinol, adriamycinone) and daunomycin from urine and plasma and resolved them on a C,g column (/. = 460nm, ex 555 nm, em) using a 35/65 acetonitrile/water (0.1 M phosphate and 0.3% hepta-fluorobutyric acid to pH 3) mobile phase. The authors noted that the chemical stability of these materials was significantly enhanced when lOmM y-cyclodextrin was added b> the samples. The analysis was conq>lete in 10 min but the adriamycinol eluted with co-extracted compounds. The reported working concentration range was 2.5-25 nmol/mL. Sodium heptanesufonate at the 0.5% level was found to be an accq)table rqilacement for the butyric acid material. Useful plots of retention time vs. ion-pair identity and concentration are presented. Detection limits of 0.02 nmol/mL were reported. 

In Chapter vm (p. 149) we discuss our suggestion that fS oxidation of w-fluorocarboxylic acids takes place in the animal body. Nevertheless, there is some indication that y-fluoro-butyrate (but not y-fluorocrotonate), even if it does undergo oxidation, also acts per se. For example, progressive cardiac failure without ventricular fibrillation is noted in Rhesus monkeys poisoned with fluorobutyrate. Rabbits poisoned with fluorobutyrate do indeed show ventricular fibrillations and weak convulsions, but in addition appear to manifest a para-... 

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