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At least 19 recordsLinked to original sources
PubMed1985

Hexestrol residues and metabolites in the tissues of wethers injected with hexestrol dicaprylate or hexestrol.

Four young (23 kg body weight) and two mature wethers (52 and 92 kg body weight) were subcutaneously injected with hexestrol (HX) or HX dicaprylate (HX-D) and killed 41 d later. The HX residues, comprising free, glucuronide and KOH hydrolyzable forms plus metabolites were determined by gas chromatography after liquid-liquid extraction and silica gel chromatographic purification of tissue sample. The HX residues were observed to be at concentrations of .1 to 1.0 ppb in most of the tissues examined. Maturity of the animals and the two hormonal formulations resulted in little difference in residues. The KOH hydrolyzable fraction was hardly detected in the tissues examined. Free HX was a major residue in muscle, representing about 70% of HX residues. Glucuronide HX represented 70 to 80% of HX residues in liver and kidney. In lung, glucuronide and free HX were present in similar amounts. This study showed that the gross metabolic patterns of HX and its esters are similar to other estrogens and steroids.

Animals↗
PubMed1985

Carcinogenicity and metabolic activation of hexestrol.

The carcinogenic activity of the synthetic estrogen hexestrol was measured in male Syrian hamsters. Between 90% and 100% of the animals treated with hexestrol or with 3',3",5',5"-tetradeuteriohexestrol, implanted subcutaneously as 25-mg pellets, were found with renal carcinoma after 6-7 months. In vitro hexestrol metabolism, mediated by phenobarbital-induced rat liver microsomes, led to the formation of 3'-hydroxyhexestrol. This metabolite was identified by comparison with authentic reference material synthesized by oxidation of hexestrol with Fremy's salt. Diethylstilbestrol could not be detected as a metabolite. In urine of male Syrian hamsters, 3'-hydroxyhexestrol, 3'-methoxyhexestrol, 1-hydroxyhexestrol, and other hydroxylated and/or methoxylated hexestrol metabolites were identified. Again, diethylstilbestrol was not detectable as a hexestrol metabolite in vivo. The reactivity of 3'-hydroxyhexestrol was then studied to determine if this catechol estrogen played a role in hexestrol carcinogenicity. Horseradish peroxidase catalyzed the oxidation of 3'-hydroxyhexestrol to 3',4'-hexestrol quinone. This oxidation reaction could also be carried out non-enzymatically using silver oxide or silver carbonate on celite as oxidants. The quinone was unstable (t1/2 in methylene chloride: 53 min). It reacted with sulfur-containing compounds such as mercaptoethanol by Michael addition to form 3'-(2-hydroxyethylthio)-5'-hydroxyhexestrol. 3',4'-Hexestrol quinone reacted with simple amines such as ethylamine to form N-ethyl-aminohexestrol. The chemical reactions described above were carried out to test the reactivity of identified or suspected metabolic intermediates of hexestrol. It was concluded that carcinogenicity of hexestrol was not based on its conversion to diethylstilbestrol. Rather, catechol estrogen formation may be necessary for the carcinogenic action of hexestrol in analogy to events observed earlier with estradiol.

Animals↗
PubMed1990

Effects of synthetic estrogens, (R,R)-(+)-, (S,S)-(-)-, dl- and meso-hexestrol stereoisomers on microtubule assembly.

We previously reported on the inhibition of microtubule polymerization and the formation of ribbon structures by synthetic estrogens [Sato et al., J Biochem 101: 1247-1252, 1987]. The present investigation aimed to analyse these effects in vitro on stereochemical point of view, using hexestrol isomers ((R,R)-(+)-hexestrol, (S,S)-(-)-hexestrol and meso-hexestrol) and dl-hexestrol. Among hexestrols, dl-hexestrol showed the highest activity in ribbon formation from microtubule proteins at 100 microM. On the other hand, meso-hexestrol was distinguished from others by inhibition of microtubule assembly and formation of a large amount of aggregates from purified tubulin in the presence of MgCl2 and DMSO. These results were discussed with physico-chemical properties of hexestrols, e.g. absolute configurations as well as circular dichroism spectra and solid state carbon-13 nuclear magnetic resonance spectra.

Animals↗
PubMed1990

Effect of meso-hexestrol, a synthetic estrogen, on S-tubulin.

We have reported that meso-hexestrol, a synthetic estrogen, inhibits microtubule assembly and induces microtubule proteins into twisted ribbon structures. On the other hand, Serrano et al. proved that S-tubulin, which lacks the C-terminal moiety of tubulin subunits, assembles into sheet structures in the absence of microtubule-associated proteins (MAPs). In the present investigation, we attempted to clarify whether meso-hexestrol could induce the ribbon structure from S-tubulin. meso-Hexestrol delayed the initiation of polymerization of S-tubulin into sheet structures in a dose-dependent manner below 50 microM. But the effect of meso-hexestrol on S-tubulin was reduced in the presence of either tau or microtubule-associated protein 2 (MAP2) in a MAPs-concentration-dependent manner. At concentrations higher than 100 microM, meso-hexestrol inhibited the polymerization of S-tubulin into sheet structures, without forming ribbon structures. The present results may indicate that moso-hexestrol interacts with S-tubulin, and its interaction is affected by MAPs.

Animals↗
PubMed1977

Estrogen photoaffinity labels. 1. Chemical and radiochemical synthesis of hexestrol diazoketone and azide derivatives; photochemical studies in solution.

Two photosensitive estrogen derivatives, hexestrol diazoketopropyl ether (5) and hexestrol azide (8a), have been synthesized in radiolabeled form, and their photochemical behavior in solution has been studied. The radiolabeled compounds were prepared in good yields according to improved synthetic procedures; they are stable and were obtained with specific activities in the range of 50-100 Ci per mmol and radiochemical purities in excess of 95%. A simpler model system, phenyl diazoketoprophyl ether, was used to study the photochemical behavior of the diazoketopropyl ether group. Direct irradiation of this compound at 254 nm in methanol led to 33% insertion product (methoxyketone) and 67% Wolff rearrangement product (ester). Irradiation of [3H]hexestrol diazoketopropyl ether (5) in methanol gives mainly nonpolar photoproducts (presumed to be the methoxy ketone and ester); however, irradiation in aqueous medium leads to large amounts of free hexestrol (52%). Photolysis of hexestrol azide (8a) in either methanol or water gives the corresponding amine in low yield as the only identifiable photoproduct.

Affinity Labels↗
PubMed1977

Carbon-14-labeled diethylstilbestrol synthesis by the McMurry method: concurrent formation of hexestrol.

Isotopically labeled diethylstilbestrol prepared from p-methoxypropiophenone by coupling with TiCl3-LiA1H4 contained approximately 50% hexestrol. Nonlabeled preparations and a subsequent labeled preparation had less than 2% hexestrol in them. Initial examinations for purity by gas-liquid chromatography, thin-layer chromatography, and isotope dilution did not show the presence of hexestrol. Specific ion monitoring of a gas chromatography-mass spectrometry determination revealed the presence of the deithylstilbestrol-hexestrol mixture.

Carbon Radioisotopes↗
PubMed1981

Gas-liquid chromatographic determination of hexestrol residues in adipose tissue.

A gas-liquid chromatographic (GLC) method is described for determining hexestrol residues in adipose tissue. The extraction and purification procedures were based on a published method for determining diethylstilbestrol. To increase precision and sensitivity, the sample was further cleaned up by silica gel column chromatography. The heptafluorobutyric (HFB) derivative of hexestrol was used for GLC analysis with HFB-docosanol as an internal standard. A variety of acetone-benzene mixtures were compared to determine the optimum ratio for hexestrol acylation. Acetone-benzene (90 + 10) or 100% acetone provided 16% higher GLC response than did a 50 + 50 mixture (P less than 0.001) and was selected for use in the acylation procedure. A system for evaporating excess reagents was also studied. Overall percent recovery reached 72 +/- 5. The method can be used to determine residual hexestrol at the 0.1 ppb level.

Acylation↗
PubMed1980

Synthesis of novel hexestrol and diethylstilbestrol derivatives as potential anticancer and estrogenic agents.

Two novel series of potential anticancer agents derived from hexestrol and diethylstilbestrol have been synthesized. The first includes several alkylating agents containing sulphonic esters and nitrogen mustard functions attached through various chains to only one phenolic group in hexestrol. The second contains the N1-acetyl-N4-substituted thiosemicarbazide moieties attached to one phenolic group hexestrol or to the two phenolic oxygens in diethylstilbestrol. The tests of some of the products for antileukemic activity in P 388 Lymphocytic Leukemia indicated no significant activity over the parent nuclei. The estrogenic activity of some representative examples of the thiosemicarbazides was found to be dependent on the nature of the N4-substituent in the thiosemicarbazide moiety.

Animals↗
PubMed1992

Synthesis, receptor binding and target-tissue uptake of carbon-11-labeled carbamate derivatives of estradiol and hexestrol.

Carbon-11-labeled estradiol and hexestrol derivatives were prepared via the reaction of [11C]ethylchloroformate with the 2- and 4-amino derivatives of estradiol, the 3'-amino derivatives of hexestrol, and the 1-aminophenoxy derivatives of hexestrol and 1-norhexestrol. The corresponding nonradioactive carbamates were prepared for chemical characterization and in vitro receptor binding assays. The positions of the substituents on the parent molecules were selected with a view to minimize interference with the receptor binding process. In spite of this, affinity for the estrogen receptor was strongly impaired for all carbamate derivatives. Likewise, in vivo, the [11C]carbamate analogs failed to localize in receptor rich tissue via an estrogen receptor mediated process.

Amines↗
PubMed1981

Chemically reactive estrogens: synthesis and estrogen receptor interactions of hexestrol ether derivatives and 4-substituted deoxyhexestrol derivatives bearing alkylating functions.

A series of chemically reactive derivatives of the nonsteroidal estrogen hexestrol have been synthesized as potential affinity labels for the estrogen receptor or as cytotoxic agents with selective activity against receptor-containing cells. These compounds are hexestrol ethers with halo ketone, halohydrin, or epoxide functions or 4-substituted deoxyhexestrols with halo ketone, benzyl halide, nitro, azide, sulfonyl fluoride, or sulfonyl azide groups. The alkylating activity of the electrophilic derivatives was measured using the colorimetric reagent nitrobenzylpyridine, the bromo derivatives being considerably more reactive than the chloro ones. Their reversible binding to the lamb uterine estrogen receptor was measured by competitive binding assays, and their irreversible reaction with receptor was measured by exchange assays that determine the rate and extent of receptor inactivation. In general, monoetherification of hexestrol or substitution of deoxyhexestrol produces compounds with relatively low affinity for the estrogen receptor (0.3-10% that of estradiol). Most of the electrophilic derivatives are rapid and effective inactivators of receptor (24-70% inactivation within 0.5-5 h at 25 degrees C). Of the photosensitive derivatives, 4-azidodeoxyhexestrol appears to be the most efficient receptor inactivator (49%). The high reactivity of these compounds toward the estrogen receptor and the lack of interference by their reaction with other cellular nucleophiles suggest that these compounds may be useful as affinity-labeling agents or as selective cytotoxic agents in intact systems.

Affinity Labels↗
PubMed1983

Ring-substituted 1,2-dialkylated 1,2-bis(hydroxyphenyl)ethanes. 1. Synthesis and estrogen receptor binding affinity of 2,2'- and 3,3'-disubstituted hexestrols.

The syntheses of symmetrically 3,3'- and 2,2'-disubstituted meso hexestrol derivatives are described [3,3'-substituents: OH (1), F (2), Cl (3), Br (4), I (5), CH2N(CH3)2 (6), CH3 (7), CH2OCH3 (8), CH2OC2H5 (9), CH2OH (10), NO2 (11), NH2 (12), N(CH3)2 (13), COCH3 (14), and C2H5 (15); 2,2'-substituents: OH (16), F (17), Cl (18), Br (19), CH3 (20), and C2H5 (21)]. The synthesis of 1-3 was accomplished by reductive coupling of the propiophenones with TiCl4/Zn and subsequent hydrogenation of the cis-3,4-diphenylhex-3-enes. Compounds 4-15 were obtained by substitution of hexestrol, while compounds 16-21 were synthesized by coupling the 1-phenyl-1-propanols with TiCl3/LiAlH4 and separation of the meso diastereomers. The binding affinity of these compounds to the calf uterine estrogen receptor was measured relative to that of [3H]estradiol by a competitive binding assay. All test compounds showed relative binding affinity (RBA) values between 32 and less than 0.01% that of estradiol. Only meso-3,4-bis(2,4-dihydroxyphenyl)hexane (16) showed an estrogen receptor binding affinity comparable to that of hexestrol (32 and 27%, respectively). Compounds exhibiting RBA values of greater than 5% were evaluated in the mouse uterine weight test. All of them showed uterotrophic activity. Compounds 2, 7, 16, 17, and 20 were strongly active in very small doses (1 microgram per animal per day), while 1 and 12 produced full uterotrophic effects only in high doses and inhibited the estrone-stimulated uterine growth strongly in small doses (59 and 78% inhibition, respectively).

Animals↗
PubMed1979

[The effect of hexestrol on the breast in climacteric women (author's transl)].

In 176 women hexestrol was substituted during 12 month or longer after ovarectomy and hysterectomy. Changes of the breast were watched by mammography and plate-thermography during hexestrol treatment. Also blood cagulation was examined. No differencies were found between these women and 179 women of a control group. In the authors opinion the substitution of hexestrol is justified further on in climacteric periods.

Adult↗
PubMed1981

Thiourea and thiosemicarbazide derivatives structurally related to hexestrol: synthesis and anticancer and other pharmacological properties.

Two novel series of thio compounds bearing internal structural modifications of hexestrol were synthesized as potential anticancer agents. The first contains several N-substituted thiourea functions, and the second contains various N4-substituted-3-thiosemicarbazide moieties in place of one alpha-ethyl group of hexestrol dimethyl ether. The products showed no antileukemic activity in the P-388 lymphocytic leukemia system and did not exhibit any anticonvulsant or estrogenic properties.

Animals↗
PubMed2004

Formation of the depurinating N3adenine and N7guanine adducts by reaction of DNA with hexestrol-3',4'-quinone or enzyme-activated 3'-hydroxyhexestrol. Implications for a unifying mechanism of tumor initiation by natural and synthetic estrogens.

The nonsteroidal synthetic estrogen hexestrol (HES), which is diethylstilbestrol hydrogenated at the C-3-C-4 double bond, is carcinogenic. Its major metabolite is the catechol, 3'-OH-HES, which can be metabolically converted to the catechol quinone, HES-3',4'-Q. Study of HES was undertaken with the scope to substantiate evidence that natural catechol estrogen-3,4-quinones are endogenous carcinogenic metabolites. HES-3',4'-Q was previously shown to react with deoxyguanosine to form the depurinating adduct 3'-OH-HES-6'-N7Gua by 1,4-Michael addition [Jan S-T, Devanesan PD, Stack DE, Ramanathan R, Byun J, Gross ML, et al. Metabolic activation and formation of DNAadducts of hexestrol,a synthetic nonsteroidal carcinogenic estrogen. Chem Res Toxicol 1998;11:412-9.]. We report here formation of the depurinating adduct 3'-OH-HES-6'-N3Ade by reaction of HES-3',4'-Q with Ade by 1,4-Michael addition. The structure of the N3Ade adduct was established by NMR and MS. We also report here formation of the depurinating 3'-OH-HES-6'-N7Gua and 3'-OH-HES-6'-N3Ade adducts by reaction of HES-3',4'-Q with DNA or by activation of 3'-OH-HES by tyrosinase, lactoperoxidase, prostaglandin H synthase or 3-methylcholanthrene-induced rat liver microsomes in the presence of DNA. The N3Ade adduct was released instantaneously from DNA, whereas the N7Gua adduct was released with a half-life of approximately 3 h. Much lower (<1%) levels of unidentified stable adducts were detected in the DNA from these reactions. These results are similar to those obtained by reaction of endogenous catechol estrogen-3,4-quinones with DNA. The similarities extend to the instantaneously-depurinating N3Ade adducts and relatively slowly-depurinating N7Gua adducts. The endogenous estrogens, estrone and estradiol, their 4-catechol estrogens and HES are carcinogenic in the kidney of Syrian golden hamsters. These results suggest that estrone (estradiol)-3,4-quinones and HES-3',4'-Q are the ultimate carcinogenic metabolites of the natural and synthetic estrogens, respectively. Reaction of the electrophilic quinones by 1,4-Michael addition with DNA at the nucleophilic N-3 of Ade and N-7 of Gua is suggested to be the major critical step in tumor initiation by these compounds.

Carcinogens↗
PubMed1990

Analysis of diethylstilbestrol, dienestrol and hexestrol in biological samples by immunoaffinity extraction and gas chromatography-negative-ion chemical ionization mass spectrometry.

A method has been developed for the detection of diethylstilbestrol, together with dienestrol and hexestrol, using extraction with a single immunoaffinity column containing antibodies raised against diethylstilbestrol, followed by gas chromatography-negative-ion chemical ionization mass spectrometry. Immunoaffinity columns were prepared by coupling immunoglobulin G fractions obtained from rabbit antisera with a Sepharose matrix. The immunizing agent was synthesized by introducing a carboxyl group into the diethylstilbestrol molecule and coupling this product to bovine serum albumin. The columns were used for immunoadsorption of diethylstilbestrol and other estrogens, after dilution of samples with phosphate buffer, and were eluted with acetone-water (95:5 v/v). A derivatization method suitable for gas chromatographic-mass spectrometric analysis of diethylstilbestrol and other estrogens was developed using pentafluorobenzyl bromide and ethanolic potassium hydroxide as reagents. The derivatives obtained were detectable at the sub-picogram level using gas chromatography with negative-ion chemical ionization mass spectrometry. Recoveries of cis- and trans-diethylstilbestrol, dienestrol and hexestrol from the immunoaffinity columns, determined after extraction from urine, plasma and buffer, ranged from 28 to 96%. The sensitivity for diethylstilbestrol in urine samples was ca. 10 ppt. The method was applied to the analysis of urine from calves given a single dose of 10 mg of diethylstilbestrol. Free and glucuronic acid conjugated diethylstilbestrol decreased with time, but their ratio was variable.

Animals↗
PubMed1977

Estrogen photoaffinity labels. 2. Reversible binding and covalent attachment of photosensitive hexestrol derivatives to the uterine estrogen receptor.

The ability of two radiolabeled, photoreactive estrogen analogues, [3H]hexestrol diazoketopropyl ether ([3H]Hex-DKP) and [3H]hexestrol azide ([3H]Hex-N3), to covalently label the uterine estrogen receptor is studied. Lamb uterine estrogen receptor preparations that have been partially purified (ammonium sulfate precipitation, Sephadex G-200 chromatography) and disaggregated by limited trypsinization can be electrophoresed on polyacrylamide gels under conditions where binding activity is preserved. This electrophoretic procedure was used to fractionate the proteins labeled by the two photoreactive estrogen analogues. Prior to photolysis, peaks of radioactivity indicating estrogen specific binding of [3H]-Hex-N3 and [3H]Hex-DKP are evident on the gels, although dissociation of the latter compound is extensive. When preparations of uterine estrogen receptor that contain the photoreactive derivatives are irradiated and then electrophoresed, reversibly labeled proteins can be distinguished from irreversibly labeled ones (covalently bonded), by extraction of the individual gel slices with organic solvents. While no irreversible binding to receptor appears to result from irradiation with [3H]Hex-DKP, irradiation with [3H]Hex-N3 does covalently label the estrogen receptor. The receptor covalently labeled with [3H]Hex-N3 has the same electrophoretic mobility as the unlabeled receptor; the covalent labeling process is estrogen-site specific, and the efficiency of labeling (15-20%) is consistent with the inactivation efficiency of Hex-N3, previously measured by an indirect assay. This is the first example of the labeling of a steroid hormone receptor by photoaffinity labeling.

Affinity Labels↗
PubMed1975

Iodohexestrols. I. Synthesis and photoreactivity of iodinated hexestrol derivatives.

The five possible ortho-iodinated hexestrols, containing from 1-4 iodines per molecule, have been synthesized as potential iodine-containing estrogenic ligands. After chromatographic separation and purification, each derivative has been fully characterized by spectroscopic methods. [3-H]-3-Iodohexestrol, [131-I]- and [125-I]-3-iodohexestrol, and [125-IA1-3,5-diiodohexestrol have also been prepared. Photolysis of 3,5-diiodohexestrol in methanol results in rapid deiodination to 3-iodohexestrol; further reduction to hexestrol is slower. Photolysis of 3-iodohexestrol in benzene gives 3-phenylhexestrol.

Benzoates↗