Mechanistic Study of Estriol Biosynthesis and Its Inhibitor

我们在人胎盘微粒体中雌三醇(E_3)生物合成的途径和动力学方面取得了一些有趣的结果，并开发了新的潜在芳香酶抑制剂。用高效液相色谱-电化学检测器测定了3个甾体化合物1-3与微粒体的芳香化反应，结果表明E_3的生成顺序为1-&gt；2-&gt；3，与雌酮(E_1)的生物合成类似。3芳构化反应的Km很大，表明E_1和E_3产物之间可能存在不同的芳构酶。在大鼠体内，每种情况下的血压都明显高于对照组。结果提示，2在控制孕期血压方面可能起着重要的作用。为了进一步阐明它们在怀孕期间的动态变化，我们合成了它们的氢化衍生物作为GC-MS分析的内标。我们合成了几种有效的芳香酶抑制剂，并评价了它们的抑制活性：1)不同位置上带有溴乙酰氧基的雄烯二酮衍生物，2)C_6上带有氧基的C_&lt；19&gt；-甾体，C-3，3)3-脱氧雄烯二酮衍生物上的各种取代基。得到了有趣的构效关系。

We have obtained interesting results concerning with the pathway and kinetics of the estriol (E_3) biosynthesis in human placental microsomes, and developed novel potential aromatase inhibitors.The 19-hydroxy (2)- and 19-oxo (3)-derivatives of 16chi-hydroxyandrostene- dione (1) were synthesized as the potent intermediates of the E_3 biosynthesis in the microsomes. The aromatizations of the three steroids 1-3 with the microsomes were determined using high-performance liquid chromatography with electrochemical detector, showing that E_3 would be produced in the sequence 1-> 2-> 3, similarly as that established in the estrone (E_1) biosynthesis. Extremely large Km for the aromatization of 3 suggested that different aromatases would be involved between the E_1 and E_3 productions.When 2 and its 3beta-hydroxy-5-ene derivative were injected s.c. into rats, the blood pressure was significantly elevated compared to the control in each case. The results suggested that 2 may play an interesting role in the control of the blood pressure of pregnancy. To further clarify their dynamic aspects in pregnancy, their deuterated derivatives were synthesized as internal standards for the GC-MS analysis.We have synthesized several potent aromatase inhibitors and evaluated their inhibition activities: 1) androstenedione derivatives having bromoacetoxy group at various positions, 2) C_<19> -steroids having an oxo group at C-6 and various substituents at C-3, 3) 3-deoxyandrostenedione derivatives. The interesting structure-activity relationships were obtained.