Gene W. Holbert

Enantiospecific synthesis of (s)-4-amino-4,5-dihydro-2-furancarboxylic acid, a new suicide inhibitor of gaba-transaminase.

Abstract The title compound has been prepared in optically pure form from (S)-glutamic acid.

Arene oxides in biosynthesis. On the origin of crotepoxide, senepoxide, and pipoxide

Abstract In light of new experimental evidence a theory is proposed for the biogenesis of the plant metabolites crotepoxide 1, senepoxide 2, and pipoxide 3 based on the intramolecular cyclization of isochorismic acid to its corresponding epoxide 7, possibly the first non-K-region arene oxide to originate in this manner. An analog of 7, 9, has been synthesized and found to be an unusually stable arene oxide. It undergoes stereospecific photooxygenation and rearrangement in accord with the postulated biogenetic scheme.

Synthesis of 11β-hydroxy-18-ethynylprogesterone: an inhibitor of aldosterone biosynthesis

Abstract The title compound was prepared by thermolysis of a C20 cyanohydrin peracetate to yield a C18 nitrile which was subsequently converted to an acetylene.

Enzyme inactivation by potential metabolites of an aromatase-activated inhibitor (MDL 18,962).

MDL 18,962, 19-acetylenic androstenedione, is an enzyme-activated inhibitor of estrogen biosynthesis which is in Phase I clinical evaluations as a potential therapeutic agent for estrogen-dependent cancers. 19-Acetylenic analogs corresponding to the major metabolites of androstenedione were synthesized as potential metabolites of MDL 18,962. These compounds were 19-acetylenic testosterone, the product of 17 beta-hydroxy steroid oxidoreductase, 6 beta-hydroxy- and 6-oxo-19-acetylenic androstenedione, products of P450 steroid 6 beta-hydroxylase and alcohol dehydrogenase, respectively. All of these analogs showed time-dependent inactivation of human placental aromatase activity. The time-dependent Ki and t1/2 at infinite inhibitor concentration (tau 50) were 4.3 nM, 12.0 min for MDL 18,962; 28 nM, 7.8 min for 17-hydroxy analog; 13 nM, 37 min for 6 beta-hydroxy analog; and 167 nM, 6.1 min for the 6-oxo analog. The 19-acetylenic testosterone, a confirmed metabolite from primate studies, was 25% as efficient as MDL 18,962 for aromatase inactivation, while 6 beta-hydroxy- and 6-oxo analogs were 11% and 5%, respectively as efficient as their parent compound. These data indicate that first-pass metabolism of MDL 18,962 does not cause an obligatory loss of time-dependent inhibition of human aromatase activity.

α-Trifluoromethylhistamine: A mechanism-based inhibitor of mammalian histidine decarboxylase

Abstract α-Trifluoromethylhistamine (1), proposed as a suicide inhibitor of histidine decarboxylase, has been prepared from β-trifluoromethyl-β-alanine. Histidine decarboxylase from hamster placenta is inhibited in a time-dependent manner by 1; however, the adduct formed between inhibitor and enzyme is labile. 1 inhibits stomach histidine decarboxylase activity in vivo in rats, but has no antisecretory effect in the pyloric-ligated stomach of the mouse.