Stilbene estrogens

Zeranol and stilbene estrogens are the two major types of compounds included in this class of anabolics (Fig. 7.3). Major members of group of stilbene estrogens are diethylstilbestrol, hexestrol, and dienestrol. 

Diethylstilbestrol, hexestrol, and dienestrol are all stilbene estrogens currently banned worldwide for use in food-producing animals. They are genotoxic, not easily metabolized compounds, which are considered capable of irreversibly initiating the carcinogenic process even at small residue concentrations. 

Diethylstilbestrol and hexestrol have been legally permitted for use as anabolics for quite some time in many countries, while the use of dienestrol, which is a metabolite of diethylstilbestrol, was restricted to illegal practice. Since all stilbene estrogens have high oral activity, both oral and parenteral formulations have been in use in catde and, to a lesser extent, in sheep and swine. 

In cattle feces, 64% of the total residues was identified as diethylstilbestrol, 23% as 3-(p-hydroxyphenyl)-2-hexene-4-one, and less than 1% as 4 -hydroxypro-piophenone (43). The identification of 4 -hydroxypropiophenone as a metabolite of diethylstilbestrol implies that dienestrol is formed through an epoxide-diol pathway and that these metabolites show electrophilic reactivity (45). These observations have to be seen in connection with the mutagenic and carcinogenic activity of diethylstilbestrol and possibly also the other stilbene estrogens. 

Roy D, Bernhardt A, Strobel H, et al. Catalysis of the oxidation of steroid and stilbene estrogens to estrogen quinone metabolites by the 3-naphthotlavone-inducible cytochrome P450 1A family. Arch Biochem Biophys 1992 296 450-456. 

Stilbene estrogens (either diethylstilbestrol [DES] or hexoestrol) have been banned in most countries as anabolic agents because of residue and food safety concerns. 

Many stilbenelike thiophene compounds have been prepared for a study of estrogenic activity, especially by Buu-Hoi et al. Thiophene derivatives of nonhydroxylated stilbene types showed no significant activitywhereas weak estrogenic activity was found in 5-acetyl-, 5-propionyl-, and 5-benzoyl-2-(-stilbenyl)thiophene. 1-Bromo-l,2-diphenyl-2-(5-bromo-2-thienyl)ethylene (258) was found to inhibit body growth and to produce extensive testicular atropy in male rats. A thiophene analog of estrogenic isoflavones (259)... 

Diethylstilbestrol is a derivative of stilbene, and it differs from sin-estrol by the presence of a double bond with trans-configuration of the two phenyl groups. In terms of estrogenic activity, this drug surpasses both estrone and hexestrol. Synonyms of this drug are distil-ben, menopax, stilphostrol, tilosteron, antigestil, and many others. 

Of these various nonsteroidal compounds, the first were fran.y-diethylstilbestrol (DES) (5.31) and its reduced derivative hexestrol (5.33). The way in which these nonsteroidal stilbene (diphenylethylene) derivatives are usually drawn suggests a resemblance to the steroid skeleton. However, this resemblance is purely incidental, since the two ethyl groups are not indispensable for estrogenic activity. For example, four methyl groups will give comparable pharmacological activity. It seems, however, that the... 

In liquid chromatography, reversed-phase materials such as Cig and Cg are the most commonly used sorbents (429, 430, 434, 438, 446, 447, 453, 454). Examples of baseline separations with reversed-phase columns of several groups of anabolics including stilbenes, resorcyclic acid lactones, and other, frequently used anabolics have been reported (463-466). In addition to reversed-phase separations normal-phase separations of anabolics using either Hypersil (467) and Brownlee (456) silica or diol-modified silica have been reported. Although not all analytes were completely separated, the latter column could be efficiently used to differentiate between estrogenic and androgenic compounds within a mixture of 15 anabolics and their metabolites (468). 

One concern raised about isoflavones, coumestanes, and stilbenes is that they have estrogenic activities. Indeed, some of the health benefit claims for these compounds... 

Chemical/Pharmaceutical/Other Class A nonsteroidal, synthetic stilbene derivative with estrogenic activity. It is an odorless, white crystalline powder, with a molecular weight of 268.36. Its ds-isomer tends to revert to the trans-ioim Chemical Formula C18H20O2 Chemical Structure ... 

CAS 56-53-1. A nonsteroid, synthetic estrogen, always in the trans form. It is the most active of the commonly used stilbene compounds. 

The steroid nucleus is not required for estrogenic action. Several derivatives of stilbene (diphenylethylene) that were used therapeutically demonstrate potent estrogenic activity. Diethylstilbestrol (DES), prepared in 1939, was one of these stilbenes (Fig. 46.8). A trans stilbene, DES has 10-fold the estrogenic potency of its cis isomer, largely because the trans isomer more closely resembles estradiol (20). Unfortunately, when DES was administered to relieve pregnancy-related symptoms, it was correlated with abnormal growth in the offspring. 

The triphenylethylene antiestrogens (Fig. 46.9) are structurally related to the stilbene family of estrogens and exhibit high affinity for the ER. They prevent translocation of the estrogen-receptor complex into the nucleus of target cells and interfere with the binding of the receptor-hormone complex to the acceptor site of the chromatin (29,30). 

Tarbin, J.A. Sharman, M. Development of molecularly imprinted phase for the selective retention of stilbene-type estrogenic compounds. Anal. Chim. Acta. 2001,... 

The active stilbene agents, reported in this chapter, derived from either marine or terrestrial sources tested in clinics have a unique chemistry that offers valuable information for their use as compounds for further chemical synthesis of more potent chemotherapeutic drugs against a variety of cancers. The stilbenes also possess the antioxidative, anti-inflammatory, and estrogenic effects and chemo-preventive activities. A challenging goal is the search for more active natural products as therapeutic agents in cancer and other diseases. This search should be continued until a novel and very effective compound is found. 

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