Masato Tanabe

Metabolic studies of tolbutamide in the rat

Abstract Hydroxymethyltolbutamide was found to be the major oxidation product in the urine of rat and rabbit given tolbutamide. The metabolite was identified by its infrared spectrum and by paper and thin-layer chromatography. The enzyme system responsible for the oxidation of tolbutamide is a typical microsomal drug-metabolizing system subject to induction by 3,4-benzpyrene, phenobarbital, and tolbutamide itself. The only product observed after incubating tolbutamide with either the fortified microsomes or with liver homogenate was hydroxymethyltolbutamide. Only a small isotope effect was seen in the oxidation of trideuterated tolbutamide. Hydroxymethyltolbutamide was approximately half as active as tolbutamide in its hypoglycemic activity in mice.

Biosynthetic studies with 13C : The antifungal antibiotic ilicicolin H

Abstract The results of feeding experiments conducted with 13C-labeled acetates, 15N-labeled phenyl-alanine, and 14C-labeled phenylalanine in fermentations of Cylindrocladium ilicicola MFC 870 are consistent with the polyketide pathway to ilicicolin H, the principal metabolite. The origin of the 5-(4-hydroxyphenyl-α-pyridone) unit in ilicicolin H is via an intermediate tetramic acid derivative, analogous to the biosynthesis of the same unit in tenellin. The two reduced carbocyclic rings of ilicicolin H are derived through cyclization of a linear polyketide precursor.

Effects of various chemical agents on drug metabolism and cholesterol biosynthesis

Abstract The effects of representative inhibitors of drug metabolism, hypocholesterolemic agents and insecticide synergists on microsome-catalyzed drug metabolism and cholesterol biosynthesis were examined in the rat. In the experiments in vitro , both biochemical reactions were inhibited to varying degrees by all of the test compounds. Cholesterol biosynthesis appeared to be more sensitive to these compounds than was the drug metabolism system. However, in an experiment in vivo , only microsome inhibitors prolonged the sleeping time of mice induced by hexobarbital. The administration of AY-9944 and Compound A at doses sufficient to lower the plasma cholesterol level had no effect on the microsomal enzyme activity. Two effects on cholesterol metabolism were observed with microsome inducers. Administration of 3,4-benzpyrene resulted in an elevated plasma cholesterol level in the rat. However, the incorporation of 14 C-labeled acetate or mevalonic acid into cholesterol by the liver of benzpyrene-treated rats was not higher than that by the liver of the control rats. Phenobarbital did not elevate the plasma cholesterol level, but the liver from phenobarbital-treated rats showed increased 14 C-acetate incorporation into cholesterol.

Utilization of 13C–13C coupling in structural and biosynthetic studies; the Fourier transform 13C nuclear magnetic resonance spectrum of mollisin

The biosynthetic pathway to mollisin has been clarified by the use of [1,2-13C]acetate and FT 13C-n.m.r.

In vitro metabolic studies on propyl p-nitrophenyl ether☆

1. 1. This study was conducted to examine how the metabolic rates at the three sites on propyl p-nitrophenyl ether (PNPE) varied with respect to each other under various experimental conditions. The hepatic microsomal system of the rat and guinea pig showed differences in some respects. 2. 2. The rates of metabolism at the three sites varied independently of each other after pretreatment of the rat or the guinea pig with phenobarbital or 3-methyl-cholanthrene. Moreover, the major metabolite in these two species was different after enzyme induction, although (ω-2)-alcohol was the major metabolite in both species before induction. 3. 3. Substitution of hydrogen atoms with deuterium atoms at each of the metabolic sites resulted in selective inhibition of metabolism at the particular site. A general trend for a slightly increased formation of other metabolites was observed to compensate for the decreased formation of the major metabolite in both animal systems. Implications of these findings with regard to the number of enzymes involved in the metabolism of PNPE is discussed.

Synthesis and testing of 17aβ-hydroxy-7α-methyl-d-homoestra-4, 16-dien-3-one: a highly potent orally active androgen

Abstract The title compound, 17aβ-hydroxy-7α-methyl- d -homoestra-4, 16-dien-3-one (3), was synthesized in five steps (17% overall yield) from 7α-methylestrone methyl ether (5) and was found to possess oral androgenic activity, in excess of other known androgens, without using 17α-alkyl substitution. (Steroids 55 :59–64, 1990)

Total synthesis of cortisol: application to selective deuteriation at C-1 and C-19

An 11-step total synthesis of cortisol and its application to selective deuteriation at the 19-methyl and the C-1 positions is described. The dihydroxy acetone group at C-17 of prednisone (3) was protected as the bismethylenedioxy derivative (4) and degraded to the ring C/D fragment, oxoindanylpropionic acid (2), by Birch reduction followed by ozonolysis. The reaction of deuterioisopropenyl anion with compound (2), followed by dehydration, cyclisation, and ozonolysis produced [1,1,2,2,4,4,4,19,19,19-2H10]-4,5-seco-17α,20;20,21-bismethylenedioxypregnane-3,5,11-trione [the 2H-labelled trione (16a)]. Cyclisation of (16a) in KOH–MeOH afforded the bismethylenedioxy cortisone (17), which upon reduction with KBH4 gave the desired [2H5]cortisol (19).

Synthesis of pentacyclic lα,11-(2-oxethano) steroids

Abstract Treatment of a 1α,2α-methyleneandrostan analog (4) with hydrobromic acid/acetic acid gives an apparent intramolecular homoconjugate ring-opening, which serves as the key step in the synthesis of a new type of pentacyclic steroid analogs (2).

Generation and reaction of 2,4-dienolate ions from Δ4-3-keto-steroids with lithium hexamethyldisilazane

Reaction of Δ4-3-keto-steroids with lithium hexamethyldisilazane yields 2,4-dienolate ions which can be methylated at C-2 or trapped as 2,4-dienolsilyl ethers.

Detection of C–C bond fission during the biosynthesis of the fungal triprenylphenol ascochlorin using [1,2-13C]-acetate

Studies on ascochlorin biosynthesis with 1,2-13C-acetate and Fourier transform 13C-n.m.r. reveal that the C-14 methyl group migrates in the process.