Synthesis and structure elucidation of estrogen quinones conjugated with cysteine, N-acetylcysteine, and glutathione.
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(E 2)-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.
Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA.
K
K
Cao
D E
DE
Stack
R
R
Ramanathan
M L
ML
Gross
E G
EG
Rogan
E L
EL
Cavalieri
D000111:Acetylcysteine / Q000737:chemistry*; D003545:Cysteine / Q000737:chemistry*; D002393:Estrogens, Catechol / Q000737:chemistry*; D005978:Glutathione / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011809:Quinones / Q000737:chemistry*
D002393:Estrogens, Catechol; D011809:Quinones; D005978:Glutathione; D003545:Cysteine; D000111:Acetylcysteine