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Judy L. Bolton - One of the best experts on this subject based on the ideXlab platform.
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The naphthol selective estrogen receptor modulator (SERM), LY2066948, is oxidized to an o-quinone analogous to the naphthol equine estrogen, equilenin.
Chemico-Biological Interactions, 2012Co-Authors: Teshome Gherezghiher, Bradley T. Michalsen, R. Esala P. Chandrasena, Johann Sohn, Gregory R J Thatcher, Judy L. BoltonAbstract:Abstract o -Quinone forming estrogens and selective estrogen receptor modulators (SERMs) have been associated with carcinogenesis. LY2066948, a novel SERM in development by Eli Lilly for the treatment of uterine fibroids and myomas, has structural similarity to the equine estrogen equilenin present in hormone replacement formulations; both contain a naphthol group susceptible to oxidative metabolism to o -Quinones. LY2066948 was synthesized and assayed for antiestrogenic activity, and in cell culture was confirmed to be a more potent antiestrogen than the prototypical SERM, 4-hydroxytamoxifen. Oxidation of LY2066948 with 2-iodoxybenzoic acid gave an o -quinone ( t 1/2 = 3.9 ± 0.1 h) which like 4-hydroxyequilenin- o -quinone ( t 1/2 = 2.5 ± 0.2 h) was observed to be exceptionally long-lived with the potential to cause cytotoxicity and/or genotoxicity. In model reactions with tyrosinase, the catechol metabolites of LY2066948 and equilenin were products; interestingly, in the presence of ascorbate to inhibit autoxidation, these catechols were formed quantitatively. Tyrosinase incubations in the presence of GSH gave the expected GSH conjugates resulting from trapping of the o- Quinones, which were characterized by LC–MS/MS. Incubations of LY2066948 or equilenin with rat liver microsomes also gave detectable o -quinone trapped GSH conjugates; however, as observed with other SERMs, oxidative metabolism of LY2066948 mainly occurred on the amino side chain to yield the N -dealkylated metabolite. CYP1B1 is believed to be responsible for extra-hepatic generation of genotoxic estrogen Quinones and o -quinone GSH conjugates were detected in equilenin incubations. However, in corresponding incubations with CYP1B1 supersomes, no o -quinone GSH conjugates of LY2066948 were detected. These studies suggest that although the naphthol group is susceptible to oxidative metabolism to long-lived o -Quinones, the formation of these Quinones by cytochrome P450 can be attenuated by the chemistry of the remainder of the molecule as in the case of LY2066948.
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The naphthol selective estrogen receptor modulator (SERM), LY2066948, is oxidized to an o-quinone analogous to the naphthol equine estrogen, equilenin.
Chemico-Biological Interactions, 2012Co-Authors: Teshome Gherezghiher, Bradley T. Michalsen, R. Esala P. Chandrasena, Johann Sohn, Gregory R J Thatcher, Judy L. BoltonAbstract:Abstract o -Quinone forming estrogens and selective estrogen receptor modulators (SERMs) have been associated with carcinogenesis. LY2066948, a novel SERM in development by Eli Lilly for the treatment of uterine fibroids and myomas, has structural similarity to the equine estrogen equilenin present in hormone replacement formulations; both contain a naphthol group susceptible to oxidative metabolism to o -Quinones. LY2066948 was synthesized and assayed for antiestrogenic activity, and in cell culture was confirmed to be a more potent antiestrogen than the prototypical SERM, 4-hydroxytamoxifen. Oxidation of LY2066948 with 2-iodoxybenzoic acid gave an o -quinone ( t 1/2 = 3.9 ± 0.1 h) which like 4-hydroxyequilenin- o -quinone ( t 1/2 = 2.5 ± 0.2 h) was observed to be exceptionally long-lived with the potential to cause cytotoxicity and/or genotoxicity. In model reactions with tyrosinase, the catechol metabolites of LY2066948 and equilenin were products; interestingly, in the presence of ascorbate to inhibit autoxidation, these catechols were formed quantitatively. Tyrosinase incubations in the presence of GSH gave the expected GSH conjugates resulting from trapping of the o- Quinones, which were characterized by LC–MS/MS. Incubations of LY2066948 or equilenin with rat liver microsomes also gave detectable o -quinone trapped GSH conjugates; however, as observed with other SERMs, oxidative metabolism of LY2066948 mainly occurred on the amino side chain to yield the N -dealkylated metabolite. CYP1B1 is believed to be responsible for extra-hepatic generation of genotoxic estrogen Quinones and o -quinone GSH conjugates were detected in equilenin incubations. However, in corresponding incubations with CYP1B1 supersomes, no o -quinone GSH conjugates of LY2066948 were detected. These studies suggest that although the naphthol group is susceptible to oxidative metabolism to long-lived o -Quinones, the formation of these Quinones by cytochrome P450 can be attenuated by the chemistry of the remainder of the molecule as in the case of LY2066948.
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synthesis and reactivity of potential toxic metabolites of tamoxifen analogues droloxifene and toremifene o Quinones
Chemical Research in Toxicology, 2001Co-Authors: Fagen Zhang, Linning Yu, And Richard B Van Breemen, Yanan Yang, Judy L. BoltonAbstract: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 correspon...
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The reactivity of o-Quinones which do not isomerize to quinone methides correlates with alkylcatechol-induced toxicity in human melanoma cells.
Chemico-biological interactions, 1997Co-Authors: Judy L. Bolton, Li Shen, Emily Pisha, E. S. Krol, Suzanne L. Iverson, Zhiwen Huang, Richard B. Van Breemen, John M. PezzutoAbstract:Abstract Catechols are widespread in the environment, especially as constituents of edible plants. A number of these catechols may undergo oxidative metabolism to electrophilic o -Quinones (3,5-cyclohexadien-1,2-dione) by oxidative enzymes such as cytochrome P450 and peroxidases. Alkylation of cellular nucleophiles by these intermediates and the formation of reactive oxygen species, especially through redox cycling of o -Quinones, could contribute to the cytotoxic properties of the parent catechols. In contrast, isomerization of the o -Quinones to electrophilic quinone methides (4-methylene-2,5-cyclohexadien-1-one, QM) could cause cellular damage primarily through alkylation. In this investigation, we treated human melanoma cells with two groups of catechols. These cells have high levels of tyrosinase required to oxidize catechols to quinoids. For catechols which are oxidized to o -Quinones that cannot isomerize to quinone methides or form unstable quinone methides, plots of the cytotoxicity data (ED 50 ) versus the reactivity of the o -Quinones gave an excellent linear correlation; decreasing o -quinone reactivity led to a decrease in the cytotoxic potency of the catechol. In contrast, catechols which are metabolized by the o -quinone/ p -quinone methide bioactivation pathway were equally cytotoxic but showed no correlation between the reactivity of the o -Quinones and the cytotoxic potency of the catechols. The most likely explanation for this effect is a change in cytotoxic mechanism from o -quinone-mediated inhibition of cell growth to a bioactivation pathway based on both o -quinone and p -QM formation. These results substantiate the conclusion that the involvement of the o -quinone/QM pathway in catechol toxicity depends on a combination between the rate of enzymatic formation of the o -quinone, the rate of isomerization to the more electrophilic QM, and the chemical reactivity of the quinoids.
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p-Quinone methides are the major decomposition products of catechol estrogen o-Quinones.
Carcinogenesis, 1996Co-Authors: Judy L. Bolton, Li ShenAbstract:The mechanism of catechol estrogen-induced carcinogenesis could involve alkylation of critical cellular macromolecules by electrophilic quinoids. The o-Quinones formed from peroxidase/P450-catalyzed oxidation of catechol estrogens have previously been implicated as the ultimate carcinogens. In the present study, we have shown that additional reactive intermediates can be produced from isomerization of the catechol estrogen o-Quinones to highly electrophilic p-quinone methides (QMs). The o-Quinones of the catechol estrogens were incubated at 37 degrees C (pH 7.4) in the absence of GSH. Aliquots were removed at various times and combined with GSH. The GSH adducts were isolated and characterized by 1H-NMR, UV, and electrospray mass spectrometry. The o-quinone of 2-hydroxyestrone isomerized to two QMs; a QM stabilized by one alkyl substituent in the B ring, 2-OHE-QM1 (3-hydroxy-1-(10),3(4),5(6)-oestratrien-2,17-dione) and one having two alkyl substituents on the methylene group in the C ring, 2-OHE-QM2 (2-hydroxy-1(2),4(5),9(10)-oestratrien-3,17-dione). Only one QM was observed from the o-quinone of 4-hydroxyestrone, 4-OHE-QM2 (4-hydroxy-1(2),4(5),9(10)- oestratrien-3,17-dione) which is analogous to the C ring analog (2-OHE-QM2) from the o-quinone of 2-hydroxyestrone. The GSH adduct of 4-OHE-QM2 decomposed at pH 7.4 to give 9(11)-dehydro-4-hydroxyestrone as the major product. Finally, the disappearance of the estrogen o-quinone GSH adducts correlated with the formation of the GSH conjugates of the QMs. These data suggest that in cells with low levels of GSH, the formation of these potent electrophiles represents the major reaction pathway for estrogen o-Quinones. The implications of the o-quinone/QM pathway for the in vivo effects of catechol estrogens are not known; however, given the direct link between excessive exposure to endogenous estrogens and the enhanced risk of breast cancer, the potential for formation of additional reactive intermediates needs to be explored.
Teshome Gherezghiher - One of the best experts on this subject based on the ideXlab platform.
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The naphthol selective estrogen receptor modulator (SERM), LY2066948, is oxidized to an o-quinone analogous to the naphthol equine estrogen, equilenin.
Chemico-Biological Interactions, 2012Co-Authors: Teshome Gherezghiher, Bradley T. Michalsen, R. Esala P. Chandrasena, Johann Sohn, Gregory R J Thatcher, Judy L. BoltonAbstract:Abstract o -Quinone forming estrogens and selective estrogen receptor modulators (SERMs) have been associated with carcinogenesis. LY2066948, a novel SERM in development by Eli Lilly for the treatment of uterine fibroids and myomas, has structural similarity to the equine estrogen equilenin present in hormone replacement formulations; both contain a naphthol group susceptible to oxidative metabolism to o -Quinones. LY2066948 was synthesized and assayed for antiestrogenic activity, and in cell culture was confirmed to be a more potent antiestrogen than the prototypical SERM, 4-hydroxytamoxifen. Oxidation of LY2066948 with 2-iodoxybenzoic acid gave an o -quinone ( t 1/2 = 3.9 ± 0.1 h) which like 4-hydroxyequilenin- o -quinone ( t 1/2 = 2.5 ± 0.2 h) was observed to be exceptionally long-lived with the potential to cause cytotoxicity and/or genotoxicity. In model reactions with tyrosinase, the catechol metabolites of LY2066948 and equilenin were products; interestingly, in the presence of ascorbate to inhibit autoxidation, these catechols were formed quantitatively. Tyrosinase incubations in the presence of GSH gave the expected GSH conjugates resulting from trapping of the o- Quinones, which were characterized by LC–MS/MS. Incubations of LY2066948 or equilenin with rat liver microsomes also gave detectable o -quinone trapped GSH conjugates; however, as observed with other SERMs, oxidative metabolism of LY2066948 mainly occurred on the amino side chain to yield the N -dealkylated metabolite. CYP1B1 is believed to be responsible for extra-hepatic generation of genotoxic estrogen Quinones and o -quinone GSH conjugates were detected in equilenin incubations. However, in corresponding incubations with CYP1B1 supersomes, no o -quinone GSH conjugates of LY2066948 were detected. These studies suggest that although the naphthol group is susceptible to oxidative metabolism to long-lived o -Quinones, the formation of these Quinones by cytochrome P450 can be attenuated by the chemistry of the remainder of the molecule as in the case of LY2066948.
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The naphthol selective estrogen receptor modulator (SERM), LY2066948, is oxidized to an o-quinone analogous to the naphthol equine estrogen, equilenin.
Chemico-Biological Interactions, 2012Co-Authors: Teshome Gherezghiher, Bradley T. Michalsen, R. Esala P. Chandrasena, Johann Sohn, Gregory R J Thatcher, Judy L. BoltonAbstract:Abstract o -Quinone forming estrogens and selective estrogen receptor modulators (SERMs) have been associated with carcinogenesis. LY2066948, a novel SERM in development by Eli Lilly for the treatment of uterine fibroids and myomas, has structural similarity to the equine estrogen equilenin present in hormone replacement formulations; both contain a naphthol group susceptible to oxidative metabolism to o -Quinones. LY2066948 was synthesized and assayed for antiestrogenic activity, and in cell culture was confirmed to be a more potent antiestrogen than the prototypical SERM, 4-hydroxytamoxifen. Oxidation of LY2066948 with 2-iodoxybenzoic acid gave an o -quinone ( t 1/2 = 3.9 ± 0.1 h) which like 4-hydroxyequilenin- o -quinone ( t 1/2 = 2.5 ± 0.2 h) was observed to be exceptionally long-lived with the potential to cause cytotoxicity and/or genotoxicity. In model reactions with tyrosinase, the catechol metabolites of LY2066948 and equilenin were products; interestingly, in the presence of ascorbate to inhibit autoxidation, these catechols were formed quantitatively. Tyrosinase incubations in the presence of GSH gave the expected GSH conjugates resulting from trapping of the o- Quinones, which were characterized by LC–MS/MS. Incubations of LY2066948 or equilenin with rat liver microsomes also gave detectable o -quinone trapped GSH conjugates; however, as observed with other SERMs, oxidative metabolism of LY2066948 mainly occurred on the amino side chain to yield the N -dealkylated metabolite. CYP1B1 is believed to be responsible for extra-hepatic generation of genotoxic estrogen Quinones and o -quinone GSH conjugates were detected in equilenin incubations. However, in corresponding incubations with CYP1B1 supersomes, no o -quinone GSH conjugates of LY2066948 were detected. These studies suggest that although the naphthol group is susceptible to oxidative metabolism to long-lived o -Quinones, the formation of these Quinones by cytochrome P450 can be attenuated by the chemistry of the remainder of the molecule as in the case of LY2066948.
Gregory R J Thatcher - One of the best experts on this subject based on the ideXlab platform.
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The naphthol selective estrogen receptor modulator (SERM), LY2066948, is oxidized to an o-quinone analogous to the naphthol equine estrogen, equilenin.
Chemico-Biological Interactions, 2012Co-Authors: Teshome Gherezghiher, Bradley T. Michalsen, R. Esala P. Chandrasena, Johann Sohn, Gregory R J Thatcher, Judy L. BoltonAbstract:Abstract o -Quinone forming estrogens and selective estrogen receptor modulators (SERMs) have been associated with carcinogenesis. LY2066948, a novel SERM in development by Eli Lilly for the treatment of uterine fibroids and myomas, has structural similarity to the equine estrogen equilenin present in hormone replacement formulations; both contain a naphthol group susceptible to oxidative metabolism to o -Quinones. LY2066948 was synthesized and assayed for antiestrogenic activity, and in cell culture was confirmed to be a more potent antiestrogen than the prototypical SERM, 4-hydroxytamoxifen. Oxidation of LY2066948 with 2-iodoxybenzoic acid gave an o -quinone ( t 1/2 = 3.9 ± 0.1 h) which like 4-hydroxyequilenin- o -quinone ( t 1/2 = 2.5 ± 0.2 h) was observed to be exceptionally long-lived with the potential to cause cytotoxicity and/or genotoxicity. In model reactions with tyrosinase, the catechol metabolites of LY2066948 and equilenin were products; interestingly, in the presence of ascorbate to inhibit autoxidation, these catechols were formed quantitatively. Tyrosinase incubations in the presence of GSH gave the expected GSH conjugates resulting from trapping of the o- Quinones, which were characterized by LC–MS/MS. Incubations of LY2066948 or equilenin with rat liver microsomes also gave detectable o -quinone trapped GSH conjugates; however, as observed with other SERMs, oxidative metabolism of LY2066948 mainly occurred on the amino side chain to yield the N -dealkylated metabolite. CYP1B1 is believed to be responsible for extra-hepatic generation of genotoxic estrogen Quinones and o -quinone GSH conjugates were detected in equilenin incubations. However, in corresponding incubations with CYP1B1 supersomes, no o -quinone GSH conjugates of LY2066948 were detected. These studies suggest that although the naphthol group is susceptible to oxidative metabolism to long-lived o -Quinones, the formation of these Quinones by cytochrome P450 can be attenuated by the chemistry of the remainder of the molecule as in the case of LY2066948.
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The naphthol selective estrogen receptor modulator (SERM), LY2066948, is oxidized to an o-quinone analogous to the naphthol equine estrogen, equilenin.
Chemico-Biological Interactions, 2012Co-Authors: Teshome Gherezghiher, Bradley T. Michalsen, R. Esala P. Chandrasena, Johann Sohn, Gregory R J Thatcher, Judy L. BoltonAbstract:Abstract o -Quinone forming estrogens and selective estrogen receptor modulators (SERMs) have been associated with carcinogenesis. LY2066948, a novel SERM in development by Eli Lilly for the treatment of uterine fibroids and myomas, has structural similarity to the equine estrogen equilenin present in hormone replacement formulations; both contain a naphthol group susceptible to oxidative metabolism to o -Quinones. LY2066948 was synthesized and assayed for antiestrogenic activity, and in cell culture was confirmed to be a more potent antiestrogen than the prototypical SERM, 4-hydroxytamoxifen. Oxidation of LY2066948 with 2-iodoxybenzoic acid gave an o -quinone ( t 1/2 = 3.9 ± 0.1 h) which like 4-hydroxyequilenin- o -quinone ( t 1/2 = 2.5 ± 0.2 h) was observed to be exceptionally long-lived with the potential to cause cytotoxicity and/or genotoxicity. In model reactions with tyrosinase, the catechol metabolites of LY2066948 and equilenin were products; interestingly, in the presence of ascorbate to inhibit autoxidation, these catechols were formed quantitatively. Tyrosinase incubations in the presence of GSH gave the expected GSH conjugates resulting from trapping of the o- Quinones, which were characterized by LC–MS/MS. Incubations of LY2066948 or equilenin with rat liver microsomes also gave detectable o -quinone trapped GSH conjugates; however, as observed with other SERMs, oxidative metabolism of LY2066948 mainly occurred on the amino side chain to yield the N -dealkylated metabolite. CYP1B1 is believed to be responsible for extra-hepatic generation of genotoxic estrogen Quinones and o -quinone GSH conjugates were detected in equilenin incubations. However, in corresponding incubations with CYP1B1 supersomes, no o -quinone GSH conjugates of LY2066948 were detected. These studies suggest that although the naphthol group is susceptible to oxidative metabolism to long-lived o -Quinones, the formation of these Quinones by cytochrome P450 can be attenuated by the chemistry of the remainder of the molecule as in the case of LY2066948.
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Quinone formation as a chemoprevention strategy for hybrid drugs: balancing cytotoxicity and cytoprotection.
Chemical research in toxicology, 2007Co-Authors: Tareisha L. Dunlap, R. Esala P. Chandrasena, Zhiqiang Wang, Vaishali Sinha, Zhican Wang, Gregory R J ThatcherAbstract:Cellular defense mechanisms that respond to damage from oxidative and electrophilic stress, such as from Quinones, represent a target for chemopreventive agents. Drugs bioactivated to Quinones have the potential to activate antioxidant/electrophile responsive element (ARE) transcription of genes for cytoprotective phase 2 enzymes such as NAD(P)H-dependent quinone oxidoreductase (NQO1) but can also cause cellular damage. Two isomeric families of compounds were prepared, including the NO-NSAIDs (NO-donating nonsteroidal anti-inflammatory drugs) NCX 4040 and NCX 4016; one family was postulated to release a quinone methide on esterase bioactivation. The study of reactivity and GSH conjugation in model and cell systems confirmed the postulate. The quinone-forming family, including NCX 4040 and conisogenic bromides and mesylate, was rapidly bioactivated to a quinone, which gave activation of ARE and consequent induction of NQO1 in liver cells. Although the control family, including NCX 4016 and conisogenic brom...
R. Esala P. Chandrasena - One of the best experts on this subject based on the ideXlab platform.
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The naphthol selective estrogen receptor modulator (SERM), LY2066948, is oxidized to an o-quinone analogous to the naphthol equine estrogen, equilenin.
Chemico-Biological Interactions, 2012Co-Authors: Teshome Gherezghiher, Bradley T. Michalsen, R. Esala P. Chandrasena, Johann Sohn, Gregory R J Thatcher, Judy L. BoltonAbstract:Abstract o -Quinone forming estrogens and selective estrogen receptor modulators (SERMs) have been associated with carcinogenesis. LY2066948, a novel SERM in development by Eli Lilly for the treatment of uterine fibroids and myomas, has structural similarity to the equine estrogen equilenin present in hormone replacement formulations; both contain a naphthol group susceptible to oxidative metabolism to o -Quinones. LY2066948 was synthesized and assayed for antiestrogenic activity, and in cell culture was confirmed to be a more potent antiestrogen than the prototypical SERM, 4-hydroxytamoxifen. Oxidation of LY2066948 with 2-iodoxybenzoic acid gave an o -quinone ( t 1/2 = 3.9 ± 0.1 h) which like 4-hydroxyequilenin- o -quinone ( t 1/2 = 2.5 ± 0.2 h) was observed to be exceptionally long-lived with the potential to cause cytotoxicity and/or genotoxicity. In model reactions with tyrosinase, the catechol metabolites of LY2066948 and equilenin were products; interestingly, in the presence of ascorbate to inhibit autoxidation, these catechols were formed quantitatively. Tyrosinase incubations in the presence of GSH gave the expected GSH conjugates resulting from trapping of the o- Quinones, which were characterized by LC–MS/MS. Incubations of LY2066948 or equilenin with rat liver microsomes also gave detectable o -quinone trapped GSH conjugates; however, as observed with other SERMs, oxidative metabolism of LY2066948 mainly occurred on the amino side chain to yield the N -dealkylated metabolite. CYP1B1 is believed to be responsible for extra-hepatic generation of genotoxic estrogen Quinones and o -quinone GSH conjugates were detected in equilenin incubations. However, in corresponding incubations with CYP1B1 supersomes, no o -quinone GSH conjugates of LY2066948 were detected. These studies suggest that although the naphthol group is susceptible to oxidative metabolism to long-lived o -Quinones, the formation of these Quinones by cytochrome P450 can be attenuated by the chemistry of the remainder of the molecule as in the case of LY2066948.
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The naphthol selective estrogen receptor modulator (SERM), LY2066948, is oxidized to an o-quinone analogous to the naphthol equine estrogen, equilenin.
Chemico-Biological Interactions, 2012Co-Authors: Teshome Gherezghiher, Bradley T. Michalsen, R. Esala P. Chandrasena, Johann Sohn, Gregory R J Thatcher, Judy L. BoltonAbstract:Abstract o -Quinone forming estrogens and selective estrogen receptor modulators (SERMs) have been associated with carcinogenesis. LY2066948, a novel SERM in development by Eli Lilly for the treatment of uterine fibroids and myomas, has structural similarity to the equine estrogen equilenin present in hormone replacement formulations; both contain a naphthol group susceptible to oxidative metabolism to o -Quinones. LY2066948 was synthesized and assayed for antiestrogenic activity, and in cell culture was confirmed to be a more potent antiestrogen than the prototypical SERM, 4-hydroxytamoxifen. Oxidation of LY2066948 with 2-iodoxybenzoic acid gave an o -quinone ( t 1/2 = 3.9 ± 0.1 h) which like 4-hydroxyequilenin- o -quinone ( t 1/2 = 2.5 ± 0.2 h) was observed to be exceptionally long-lived with the potential to cause cytotoxicity and/or genotoxicity. In model reactions with tyrosinase, the catechol metabolites of LY2066948 and equilenin were products; interestingly, in the presence of ascorbate to inhibit autoxidation, these catechols were formed quantitatively. Tyrosinase incubations in the presence of GSH gave the expected GSH conjugates resulting from trapping of the o- Quinones, which were characterized by LC–MS/MS. Incubations of LY2066948 or equilenin with rat liver microsomes also gave detectable o -quinone trapped GSH conjugates; however, as observed with other SERMs, oxidative metabolism of LY2066948 mainly occurred on the amino side chain to yield the N -dealkylated metabolite. CYP1B1 is believed to be responsible for extra-hepatic generation of genotoxic estrogen Quinones and o -quinone GSH conjugates were detected in equilenin incubations. However, in corresponding incubations with CYP1B1 supersomes, no o -quinone GSH conjugates of LY2066948 were detected. These studies suggest that although the naphthol group is susceptible to oxidative metabolism to long-lived o -Quinones, the formation of these Quinones by cytochrome P450 can be attenuated by the chemistry of the remainder of the molecule as in the case of LY2066948.
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Quinone formation as a chemoprevention strategy for hybrid drugs: balancing cytotoxicity and cytoprotection.
Chemical research in toxicology, 2007Co-Authors: Tareisha L. Dunlap, R. Esala P. Chandrasena, Zhiqiang Wang, Vaishali Sinha, Zhican Wang, Gregory R J ThatcherAbstract:Cellular defense mechanisms that respond to damage from oxidative and electrophilic stress, such as from Quinones, represent a target for chemopreventive agents. Drugs bioactivated to Quinones have the potential to activate antioxidant/electrophile responsive element (ARE) transcription of genes for cytoprotective phase 2 enzymes such as NAD(P)H-dependent quinone oxidoreductase (NQO1) but can also cause cellular damage. Two isomeric families of compounds were prepared, including the NO-NSAIDs (NO-donating nonsteroidal anti-inflammatory drugs) NCX 4040 and NCX 4016; one family was postulated to release a quinone methide on esterase bioactivation. The study of reactivity and GSH conjugation in model and cell systems confirmed the postulate. The quinone-forming family, including NCX 4040 and conisogenic bromides and mesylate, was rapidly bioactivated to a quinone, which gave activation of ARE and consequent induction of NQO1 in liver cells. Although the control family, including NCX 4016 and conisogenic brom...
Kazumasa Wakamatsu - One of the best experts on this subject based on the ideXlab platform.
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Tyrosinase-Catalyzed Oxidation of the Leukoderma-Inducing Agent Raspberry Ketone Produces (E)-4-(3-Oxo-1-butenyl)-1,2-benzoquinone: Implications for Melanocyte Toxicity.
Chemical Research in Toxicology, 2017Co-Authors: Shosuke Ito, Maki Hinoshita, Erina Suzuki, Makoto Ojika, Kazumasa WakamatsuAbstract:The exposure of human skin to 4-(4-hydroxyphenyl)-2-butanone (raspberry ketone, RK) is known to cause chemical/occupational leukoderma. RK has a structure closely related to 4-(4-hydroxyphenyl)-2-butanol (rhododendrol), a skin whitening agent that was found to cause leukoderma in the skin of consumers in 2013. Rhododendrol is a good substrate for tyrosinase and causes a tyrosinase-dependent cytotoxicity to melanocytes, cells that are responsible for skin pigmentation. Therefore, it is expected that RK exerts its cytotoxicity to melanocytes through the tyrosinase-catalyzed oxidation to cytotoxic o-Quinones. The results of this study demonstrate that the oxidation of RK by mushroom tyrosinase rapidly produces 4-(3-oxobutyl)-1,2-benzoquinone (RK-quinone), which is converted within 10–20 min to (E)-4-(3-oxo-1-butenyl)-1,2-benzoquinone (DBL-quinone). These Quinones were identified as their corresponding catechols after reduction by ascorbic acid. RK-quinone and DBL-quinone quantitatively bind to the small thio...
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Tyrosinase-Catalyzed Oxidation of the Leukoderma-Inducing Agent Raspberry Ketone Produces (E)‑4-(3-Oxo-1-butenyl)-1,2-benzoquinone: Implications for Melanocyte Toxicity
2017Co-Authors: Shosuke Ito, Maki Hinoshita, Erina Suzuki, Makoto Ojika, Kazumasa WakamatsuAbstract:The exposure of human skin to 4-(4-hydroxyphenyl)-2-butanone (raspberry ketone, RK) is known to cause chemical/occupational leukoderma. RK has a structure closely related to 4-(4-hydroxyphenyl)-2-butanol (rhododendrol), a skin whitening agent that was found to cause leukoderma in the skin of consumers in 2013. Rhododendrol is a good substrate for tyrosinase and causes a tyrosinase-dependent cytotoxicity to melanocytes, cells that are responsible for skin pigmentation. Therefore, it is expected that RK exerts its cytotoxicity to melanocytes through the tyrosinase-catalyzed oxidation to cytotoxic o-Quinones. The results of this study demonstrate that the oxidation of RK by mushroom tyrosinase rapidly produces 4-(3-oxobutyl)-1,2-benzoquinone (RK-quinone), which is converted within 10–20 min to (E)-4-(3-oxo-1-butenyl)-1,2-benzoquinone (DBL-quinone). These Quinones were identified as their corresponding catechols after reduction by ascorbic acid. RK-quinone and DBL-quinone quantitatively bind to the small thiol N-acetyl-l-cysteine to form thiol adducts and can also bind to the thiol protein bovine serum albumin through its cysteinyl residue. DBL-quinone is more reactive than RK-quinone, as judged by their half-lives (6.2 min vs 10.5 min, respectively), and decays rapidly to form an oligomeric pigment (RK-oligomer). The RK-oligomer can oxidize GSH to GSSG with a concomitant production of hydrogen peroxide, indicating its pro-oxidant activity, similar to that of the RD-oligomer. These results suggest that RK is cytotoxic to melanocytes through the binding of RK-derived Quinones to thiol proteins and the pro-oxidant activity of the RK-oligomer
