Stereochemistry and Reactions with Hydroxyl Ion and with Silver Oxide of the 2-Bromo-4-phenylcyclohexanols and the 1-Methyl-2-bromo-4-phenylcyclohexanols<sup>1</sup>

Curtin, David Y.; Harder, Robert J.

doi:10.1021/ja01494a061

Cited by 32 publications

(8 citation statements)

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“…Reactivity of Toremifene-o-quinone. Among the chemical and enzymatic agents that have been reported to oxidize catechols including manganese dioxide, lead (IV) oxide, and tyrosinase (40,41), we used silver oxide (35) as the chemical oxidizing agent and tyrosinase as the enzymatic agent to generate the o-quinone of 3,4dihydroxytoremifene. The UV spectra showed typical o-quinone chromophores at 375 and 460 nm.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Reactivity of Potential Toxic Metabolites of Tamoxifen Analogues: Droloxifene and Toremifene o-Quinones

Yao

Zhang

et al. 2001

Chem. Res. Toxicol.

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Tamoxifen remains the endocrine therapy of choice in the treatment of all stages of hormone-dependent breast cancer. However, tamoxifen has been shown to increase the risk of endometrial cancer which has stimulated research for new effective antiestrogens, such as droloxifene and toremifene. In this study, the potential for these compounds to cause cytotoxic effects was investigated. One potential cytotoxic mechanism could involve metabolism of droloxifene and toremifene to catechols, followed by oxidation to reactive o-quinones. Another cytotoxic pathway could involve the oxidation of 4-hydroxytoremifene to an electrophilic quinone methide. Comparison of the amounts of GSH conjugates formed from 4-hydroxytamoxifen, droloxifene, and 4-hydroxytoremifene suggested that 4-hydroxytoremifene is more effective at formation of a quinone methide. However, all three substrates formed similar amounts of o-quinones. Both the tamoxifen-o-quinone and toremifene-o-quinone reacted with deoxynucleosides to give corresponding adducts. However, the toremifene-o-quinone was shown to be considerably more reactive than the tamoxifen-o-quinone in terms of both kinetic data as well as the yield and type of deoxynucleoside adducts formed. Since thymidine formed the most abundant adducts with the toremifene-o-quinone, sufficient material was obtained for characterization by (1)H NMR, COSY-NMR, DEPT-NMR, and tandem mass spectrometry. Cytotoxicity studies with tamoxifen, droloxifene, 4-hydroxytamoxifen, 4-hydroxytoremifene, and their catechol metabolites were carried out in the human breast cancer cell lines S30 and MDA-MB-231. All of the metabolites tested showed cytotoxic effects that were similar to the parent antiestrogens which suggests that o-quinone formation from tamoxifen, droloxifene, and 4-hydroxytoremifene is unlikely to contribute to their cytotoxicity. However, the fact that the o-quinones formed adducts with deoxynucleosides in vitro implies that the o-quinone pathway might contribute to the genotoxicity of the antiestrogens in vivo.

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Section: Resultsmentioning

confidence: 99%

Synthesis and Reactivity of Potential Toxic Metabolites of Tamoxifen Analogues: Droloxifene and Toremifene o-Quinones

Yao

Zhang

et al. 2001

Chem. Res. Toxicol.

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“…The resulting solution was allowed to warm to 0 °C and was then cooled to −70 °C. 4-Phenyl-1,2-epoxycyclohexane (400 mg, 2.40 mmol) was added dropwise. The mixture was allowed to come to room temperature and then stirred for 4 h. Methanol was added dropwise.…”

Section: Methodsmentioning

confidence: 99%

Building with Cubane-1,4-diyl. Synthesis of Aryl-Substituted Cubanes, p-[n]Cubyls, and Cubane-Separated Bis(arenes)¹

et al. 1999

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On treatment with an organolithium 1,4-diiodocubane generates cubane-1,4-diyl, a highly reactive species, shown here to be a versatile precursor to numerous aryl substituted cubanes, available now for the first time in high yield. The diyl is demonstrated to provide a good route to bicubyl and its derivatives. A kind of “living polymerization” of the diyl is developed to give the p-[n]cubyls. These oligomers are rigid rods made up of cubanes linked together at the 1 and 4 positions, each cubane adding ∼4.15 Å to the length. The properties of these rods, some more than 15 Å long, are discussed, as are methods for modifying their solubility. X-ray crystallographic analyses of some of these compounds are presented, with emphasis on packing parameters.

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“…( R,R )-2-Bromo-9-(1-methoxyethyl)fluorene (2a-OMe). Silver oxide was prepared by adding potassium hydroxide (0.15 g) in 3.5 mL of water to a solution of silver nitrate (0.39 g) in 3.5 mL of water . A mixture of the alcohol 2a-OH (20 mg), iodomethane (5 mL), and the freshly prepared silver oxide was refluxed.…”

Section: Methodsmentioning

confidence: 99%

Concerted and Stepwise Solvolytic Elimination and Substitution Reactions: Stereochemistry and Substituent Effects

1997

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Solvolysis of the R,R and R,S isomers 2a-X and 2b-X, respectively, (X = I, Br, OBs) in 25 vol % acetonitrile in water gives the elimination products 4, 5a, and 5b along with the substitution products 2a-OH, 2b-OH, 2a-NHCOMe, and 2b-NHCOMe. The rates of elimination (k E) increase with increasing acidity of the β-hydrogen of the substrate as expressed by a Brønsted parameter of α = 0.08 and 0.07 for the iodides and the bromides, respectively. In contrast, the brosylates, which give much smaller fractions of the stable alkenes, exhibit a negative Brønsted parameter for the elimination, α = −0.10. This shows that the brosylates, in contrast to the halides, do not give elimination exclusively by a solvent-promoted E1cB reaction or an E2 reaction with a large component of hydron transfer in the transition state and indicates a large amount of reaction through carbocation intermediates to give stable alkenes.

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Stereochemistry and Reactions with Hydroxyl Ion and with Silver Oxide of the 2-Bromo-4-phenylcyclohexanols and the 1-Methyl-2-bromo-4-phenylcyclohexanols¹

Cited by 32 publications

References 0 publications

Synthesis and Reactivity of Potential Toxic Metabolites of Tamoxifen Analogues: Droloxifene and Toremifene o-Quinones

Synthesis and Reactivity of Potential Toxic Metabolites of Tamoxifen Analogues: Droloxifene and Toremifene o-Quinones

Building with Cubane-1,4-diyl. Synthesis of Aryl-Substituted Cubanes, p-[n]Cubyls, and Cubane-Separated Bis(arenes)¹

Concerted and Stepwise Solvolytic Elimination and Substitution Reactions: Stereochemistry and Substituent Effects

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Stereochemistry and Reactions with Hydroxyl Ion and with Silver Oxide of the 2-Bromo-4-phenylcyclohexanols and the 1-Methyl-2-bromo-4-phenylcyclohexanols1

Cited by 32 publications

References 0 publications

Synthesis and Reactivity of Potential Toxic Metabolites of Tamoxifen Analogues: Droloxifene and Toremifene o-Quinones

Synthesis and Reactivity of Potential Toxic Metabolites of Tamoxifen Analogues: Droloxifene and Toremifene o-Quinones

Building with Cubane-1,4-diyl. Synthesis of Aryl-Substituted Cubanes, p-[n]Cubyls, and Cubane-Separated Bis(arenes)1

Concerted and Stepwise Solvolytic Elimination and Substitution Reactions: Stereochemistry and Substituent Effects

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Product

Resources

About

Stereochemistry and Reactions with Hydroxyl Ion and with Silver Oxide of the 2-Bromo-4-phenylcyclohexanols and the 1-Methyl-2-bromo-4-phenylcyclohexanols¹

Building with Cubane-1,4-diyl. Synthesis of Aryl-Substituted Cubanes, p-[n]Cubyls, and Cubane-Separated Bis(arenes)¹