TY - JOUR
T1 - Synthesis and structure elucidation of estrogen quinones conjugated with cysteine, N-acetylcysteine, and glutathione
AU - Cao, Kai
AU - Stack, Douglas E.
AU - Ramanathan, Ragulan
AU - Gross, Michael L.
AU - Rogan, Eleanor G.
AU - Cavalieri, Ercole L.
PY - 1998
Y1 - 1998
N2 - Catechol estrogen quinones (CE-Q) have been implicated as ultimate carcinogenic metabolites in estrogen-induced carcinogenesis. CE-Q may covalently bind to DNA to initiate cancer. These quinones can also be conjugated with glutathione, a reaction that prevents damage to DNA by CE-Q. The glutathione conjugates are then catabolized through mercapturic acid biosynthesis to cysteine and N-acetylcysteine conjugates. This may be the most important detoxification pathway of CE-Q. The chemical synthesis and characterization of these conjugates are the first essential steps to better understand their function in biological systems. Eighteen conjugates were synthesized by reaction of estrone-3,4-quinone (E1-3,4-Q), estradiol-3,4- quinone (E2-3,4-Q), estrone-2,3-quinone (E1-2,3-Q), or estradiol-2,3- quinone (E2-2,3-Q) with various sulfur nucleophiles, RSH, in which R is the cysteine, N-acetylcysteine, or glutathione moiety. Reactions of E1-3,4-Q and E2-3,4-Q produce regiospecifically 4-OHE1-2-SR and 4-OHE2-2-SR, respectively, in almost quantitative yield. E1-2,3-Q and E2-2,3-Q react regioselectively and quantitatively to form 2-OHE1(E2)-1-SR and 2- OHE1(E2)-4-SR, in which the 1-isomers are always the major products. The ratio between 1 and 4 isomers is 3.5 for cysteine, 2.7 for N-acetylcysteine, and 2.5 for glutathione. The synthesized conjugates will be used as standards in the identification of these compounds formed in biological systems.
AB - Catechol estrogen quinones (CE-Q) have been implicated as ultimate carcinogenic metabolites in estrogen-induced carcinogenesis. CE-Q may covalently bind to DNA to initiate cancer. These quinones can also be conjugated with glutathione, a reaction that prevents damage to DNA by CE-Q. The glutathione conjugates are then catabolized through mercapturic acid biosynthesis to cysteine and N-acetylcysteine conjugates. This may be the most important detoxification pathway of CE-Q. The chemical synthesis and characterization of these conjugates are the first essential steps to better understand their function in biological systems. Eighteen conjugates were synthesized by reaction of estrone-3,4-quinone (E1-3,4-Q), estradiol-3,4- quinone (E2-3,4-Q), estrone-2,3-quinone (E1-2,3-Q), or estradiol-2,3- quinone (E2-2,3-Q) with various sulfur nucleophiles, RSH, in which R is the cysteine, N-acetylcysteine, or glutathione moiety. Reactions of E1-3,4-Q and E2-3,4-Q produce regiospecifically 4-OHE1-2-SR and 4-OHE2-2-SR, respectively, in almost quantitative yield. E1-2,3-Q and E2-2,3-Q react regioselectively and quantitatively to form 2-OHE1(E2)-1-SR and 2- OHE1(E2)-4-SR, in which the 1-isomers are always the major products. The ratio between 1 and 4 isomers is 3.5 for cysteine, 2.7 for N-acetylcysteine, and 2.5 for glutathione. The synthesized conjugates will be used as standards in the identification of these compounds formed in biological systems.
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U2 - 10.1021/tx9702291
DO - 10.1021/tx9702291
M3 - Article
C2 - 9705753
AN - SCOPUS:0031843615
SN - 0893-228X
VL - 11
SP - 909
EP - 916
JO - Chemical Research in Toxicology
JF - Chemical Research in Toxicology
IS - 8
ER -