Synthesis and mechanism of hydrolysis of estrogen 6-sulfates: model compounds for demonstrating the carcinogenesis of estrogen.
To investigate the carcinogenesis of estrogen with respect to the chemical behavior of estrogen 6-sulfates, two epimeric 6-sulfates, pyridinium 3-methoxyestra-1,3,5(10)-trien-6 alpha-yl (8) and -6 beta-yl (11) sulfates, were synthesized as the model compounds, and their chemical reactivities were examined. These sulfates were shown to be highly reactive: in water, they were readily and quantitatively converted to a common product mixture, composed of 3-methoxyestra-1,3,5(10)-trien-6 alpha-ol (6) and -6 beta-ol (9) in an almost constant product ratio, with a predominant yield of the latter. The hydrolysis of both sulfates 8 and 11 proceeded in first-order kinetics with half-lives of 1.1 and 1.5 minutes, respectively. When the sulfates were hydrolyzed in 18O-water, the heavy-oxygen atom was shown to be incorporated quantitatively into the C-6 position of the products. These results demonstrate that estrogen 6-sulfates generate a highly reactive benzylic (C-6) carbocation in an aqueous solution, suggesting that the sulfates can act as carcinogens.
Takagi
H
H
Hokkaido Institute of Pharmaceutical Sciences, Japan.
Komatsu
K
K
Yoshizawa
I
I
D055598:Chemical Phenomena; D002621:Chemistry; D002851:Chromatography, High Pressure Liquid; D004963:Estrenes / Q000138:chemical synthesis / Q000737:chemistry*; D004967:Estrogens; D006868:Hydrolysis; D007700:Kinetics; D015394:Molecular Structure; D009369:Neoplasms / Q000139:chemically induced*; D010103:Oxygen Isotopes; D011726:Pyridinium Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D012996:Solutions; D014867:Water
D004963:Estrenes; D004967:Estrogens; D010103:Oxygen Isotopes; D011726:Pyridinium Compounds; D012996:Solutions; D014867:Water; C070233:pyridinium 3-methoxyestra-1,3,5(10)-trien-6-yl sulfate