Epoxidation of the Stilbene Double Bond, a Major Pathway in Aminostilbene Metabolism

Abstract

1. The vicinal diol 1-(4-acetylamino)-phenyl-2-phenyl-1,2-ethanediol is shown to be a major metabolite of cis- and trans-4-dimethylaminostilbene in the rat. 2. The threo-diastereomeric diols were identified in urine with both the cis- and trans-aminostilbene. This is consistent with enzymic trans-opening of an epoxide intermediate only for the cis-stilbene. For the hydrolysis of the trans-stilbene epoxide alternative mechanisms are discussed. 3. A mercapturic acid isolated from urine is identical with the reaction product of 4-acetylaminostilbene epoxide and N-acetylcysteine. This provides additional evidence for an epoxide intermediate. 4. Oxidation of the intercyclic linkage occurs also in 4-dimethylaminobibenzyl, leading to 1-phenyl-2-(4-acetylamino)-phenyl-1-ethanol as a major urinary metabolite. 5. The syntheses of several reference compounds, including the epoxides and dihydrodiols of cis- and trans-4-acetylaminostilbene are described.

Design and synthesis of cis-restricted benzimidazole and benzothiazole mimics of combretastatin A-4 as antimitotic agents with apoptosis inducing ability

“…This mostly included either modification of the olefinic bond by the introduction of saturation, substituents and other functionalities or its replacement with a three to six membered ring system, which resulted in cis restricted analogues of CA4. 16,[19][20][21][22] Similar to CA4, a number of colchicine site binding ligands are known to inhibit tubulin polymerization and are considered as potential lead like molecules. One of them, E7010 is the first orally active antimitotic sulphonamide derivative that has received much interest in recent years and currently it is in clinical trials.…”

Metabolism of [14C]diethylstilboestrol epoxide by rat liver in vitro

“…Covalent binding was inhibited by CO and compound SKF 525-A, but was increased by prior treatment of the rats with phenobarbital, which further supports the participation of a monooxygenase in the reaction. These findings, together with the known epoxidation of the stilbene double bond during the metabolism in vivo of aminostilbene derivatives (Metzler & Newmann, 1977) and the nature of the urinary products of rats treated with diethylstilboestrol (Metzler, 1975), some of which could be formed via diethylstilboestrol epoxide, all provide indirect evidence for the possible conversion of diethylstilboestrol into an epoxide. It was therefore decided to synthesize '4C-labelled as well as unlabelled diethylstilboestrol epoxide to study its chemical and biological properties and its metabolism by rat liver Abbreviation used: GSH, glutathione, reduced.…”

In vitro antileishmanial activity of trans-stilbene and terphenyl compounds

“…Additionally, in an attempt to increase the chemical diversity of the compounds we studied a series of terphenyl derivatives (6e12, Fig. 1, Table 1) that notably do not bear the ethylene double bond that is the main reason for the chemical and metabolic instability of the stilbene derivatives (Metzler and Neumann, 1977;Metzler, 1975).…”