formation of 3,5-dihydroxyphenylacetic acid, the former was incubated under similar conditions with intestinal micro-organisms, when the formation of 3,5-dihydroxyphenylacetic acid was shown. Administration of 3,4,5-trihydroxyphenylacetic acid to rats resulted in the excretion of 3,5-dihydroxyphenylacetic acid.To determine whether myricetin breakdown is dependent on the activity of the intestinal microflora in vivo, the antibiotic neomycin (100mg) was fed daily to rats before and during the period of myricetin administration, when the formation of 3,5-dihydroxyphenylacetic acid was suppressed.Incubation of the glycoside myricitrin (myricetin 3-rhamnoside) with intestinal micro-organisms gave rise to free myricetin, 3,4,5-trihydroxyphenylacetic acid and 3,5-dihydroxyphenylacetic acid, indicating that rat intestinal micro-organisms are capable of effecting the cleavage of the glycosidic linkage as well as the heterocyclic ring system of myricitrin. This report describes preliminary results from an investigation into the metabolism of the selective herbicide, MCPA,* in plants.Radioactive MCPA, 36C1-or carboxy-14C-labelled, was applied to the leaves of 21-day-old pea plants (Pisum sativum var. Progress no. 9). After 24h the plants were extracted with boiling ethanol. Extracts were concentrated and fractionated by partition into ether. Fractions were examined by t.l.c. for labelled metabolites. Two of the breakdown products (MX, and MX2) were found to be ether-soluble, whereas a third was not. In each case both the chlorine atom and the carboxyl carbon remained on the molecule.This application technique did not permit the use of enough herbicide to isolate sufficient of any metabolite for its chemical identification. Thus incubation experiments with excised plant tissue were set up. Light-grown pea shoot sections were * Abbreviation: MCPA, 4-chloro-2-methylphenoxyacetic acid.incubated for 48h in a medium containing 0.5mM-MCPA. Examination of tissue extracts showed the presence ofall three previously observed metabolites. Repeated t.l.c. of ether-soluble fractions led to the isolation of products MX, and MX2 as crystalline compounds.Both substances are non-phenolic acids with u.v. spectra identical with that of MCPA. Compound MX1 has an i.r. spectrum characteristic ofa hydroxylated compound. It was shown to be 4-chloro-2-hydroxymethylphenoxyacetic acid, after synthesis of this compound. Compound MX2 has an i.r. spectrum characteristic of an amido acid. Acid and alkaline hydrolysis yielded MCPA and a ninhydrin-positive ether-insoluble component. Though still impure, the chemical, chromatographic and spectroscopic properties of compound MX2 are similar to those of synthetic N-(4-chloro-2-methylphenoxyacetyl)-L-aspartic acid.The ether-insoluble metabolite is also acidic and unstable to hydrolysis. Its purification and chemical characterization are currently under investigation.

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A series of substituted omega-[2-(1H-imidazol-1-yl)ethoxy]alkanoic acid derivatives were synthesized and evaluated for their ability to inhibit thromboxane synthase both in vitro and in vivo. Compound 13 was identified as a potent and selective competitive inhibitor of human platelet thromboxane synthase having a Ki value of 9.6 X 10(-8) M. In collagen-treated human whole blood, 13 potentiated levels of 6-keto PGF1 alpha. Enantiospecific syntheses afforded the R and S enantiomers of 13, of which the S enantiomer 13b was the more potent. Compounds 13 and 13b were potent in vivo inhibitors of thromboxane synthase with good oral activity and duration of action.

Analogues of 4-[[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl] ethoxy]methyl]benzoic acid (5m) were prepared and evaluated as thromboxane synthase inhibitors. A series of esters of 5m showed a parabolic relationship between lipophilicity and inhibition of TxB2 generation in intact platelets, with activities up to 50 times greater than that of dazoxiben. However, on administration to rabbits the ethyl ester 5d had a short duration of action, due to rapid metabolism and excretion via deesterification and beta-glucuronidation. Attempts at replacing the carboxylate group with other potential pharmacophores were unsuccessful.