Zhang F, Bolton J L
Department of Medicinal Chemistry and Pharmacognosy (M/C 781), College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231, USA.
Chem Res Toxicol. 1999 Feb;12(2):200-3. doi: 10.1021/tx980189g.
Equilin and equilenin make up approximately 20% of Premarin which is currently the most popular estrogen replacement therapy. Although there are numerous health benefits of estrogen replacement therapy, there are concerns over the link between estrogen replacement therapy and breast and endometrial cancer risk. One potential mechanism of estrogen carcinogenesis involves metabolism of estrogens to 2- and 4-hydroxylated catechols which are further oxidized to electrophilic/redox active o-quinones which have the potential to both initiate and promote the carcinogenic process. In this investigation, we have synthesized potential metabolites of equilin and equilenin, 2-hydroxyequilin and 2-hydroxyequilenin, respectively, as well as their methyl ether metabolites. These compounds were synthesized from commercially available optically pure equilin via a practical and efficient approach; five steps gave 2-methoxyequilin from which 2-hydroxyequilin was prepared by BBr3-catalyzed demethylation in one step. Similarly, treating 2-methoxyequilin with SeO2 followed by demethylation with BBr3 produced 2-hydroxyequilenin. The structures of the catechols as well as those of their methoxy ethers were unambiguously characterized by one-dimensional and two-dimensional NMR experiments, including 1H, 13C, APT, COSY, HMBC, and HMQC as well as mass spectrometry.
马萘雌酮和马萘雌酚约占目前最流行的雌激素替代疗法药物普雷马林的20%。尽管雌激素替代疗法有诸多健康益处，但人们仍担心雌激素替代疗法与乳腺癌和子宫内膜癌风险之间的联系。雌激素致癌的一种潜在机制涉及雌激素代谢为2-和4-羟基儿茶酚，这些儿茶酚进一步氧化为亲电/氧化还原活性邻醌，它们有可能启动和促进致癌过程。在本研究中，我们分别合成了马萘雌酮和马萘雌酚的潜在代谢物2-羟基马萘雌酮和2-羟基马萘雌酚及其甲醚代谢物。这些化合物通过一种实用高效的方法从市售的光学纯马萘雌酮合成；五步反应得到2-甲氧基马萘雌酮，然后通过BBr₃催化的脱甲基反应一步制备2-羟基马萘雌酮。同样，用SeO₂处理2-甲氧基马萘雌酮，然后用BBr₃脱甲基，得到2-羟基马萘雌酚。通过一维和二维核磁共振实验，包括¹H、¹³C、APT、COSY、HMBC和HMQC以及质谱，明确表征了儿茶酚及其甲醚的结构。
