The antitrypanosomal agent K777•HCl was labeled with carbon-14 to support absorption, distribution, metabolism, and excretion studies of this potential new drug for the treatment of Chagas disease. The radiolabeled compound was prepared in eight steps from [(14) C(U)]-(l)-phenylalanine with a specific activity of 54.4 mCi/mmol and an overall radiochemical yield of 4.1%.
2RS,3S,4S)-[2-14C,4-3H,]Isoleucine has been prepared by stereospecific synthesis, using LiAl[3H4] reduction of optically pure 2-butene oxide to introduce tritium stereospecifically at the prochiral methylene group of 2-butanol. The tritiated alcohol was carried forward in a malonic ester synthesis with I4C-labeled dimethyl malonate, followed by Schmidt reaction of the sec-butyl malonic acid, to afford doubly labeled isoleucine. Feeding this substrate to Datura innoxia plants led to isolation of 3a,6~-ditigloyloxytropane, from which tiglic acid was obtained by hydrolysis and degraded to locate the labels. More than 95% of the tritium was retained in the tiglic acid, allowing the conclusion that the enzymatic dehydrogenation involves antiperiplanar elimination of the hydrogen at C-2 and the pro-R hydrogen at C-3 of (2S)-2-methylbutanoic acid.Metabolism of isoleucine,* like that of other branched-chain amino acids, begins with transamination to the a-ketoacid followed by oxidative decarboxylation, yielding 2-methylbutanoyl coenzyme A (scheme I). The next metabolic step is enzymatic dehydrogenation to tigloyl coenzyme A. This dehydrogenation occurs in plants and microorganisms as well as in animals. It has been shown in the laboratories of Leete3 and Wooley4 that the tiglic (1) acid component of the tropane ester alkaloids is derived specifically from isoleucine and 2-methylbutanoic acid in Datura meteloides, and Crout has shown5 that isoleucine is the precursor of the geometric isomer angelic acid in Cynoglossum officinale. Neither the 2-hydroxy nor the 3-hydroxy derivatives of 2-methylbutanoic acid serve as precursors to tiglate,"-6 and angelate is not converted (3) Leete, E.
Tetrabenazine (TBZ) (1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolin-2-one), a vesicular monamine transporter 2 inhibitor, was prepared as a tritium-labeled compound with high specific activity and radiochemical purity. Catalytic hydrogenation of a precursor with the terminal double bond was used to introduce the tritium. This method provides tritium-labeled TBZ with high specific activity and radiochemical purity, which allow the further investigation of a TBZ in the neurological field.
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