权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanistic Study of Estriol Biosynthesis and Its Inhibitor

雌三醇生物合成及其抑制剂的机理研究

基本信息

批准号：
63571056
负责人：
NUMAZAWA Mitsuteru
金额：
$ 1.09万
依托单位：
Tohoku College of Pharmacy
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1988
资助国家：
日本
起止时间：
1988 至 1989
项目状态：
已结题

项目摘要

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.

本工作对人胎盘微粒体合成雌三醇（E_3）的途径和动力学进行了研究，并开发了新的芳香化酶抑制剂。用高效液相色谱-电化学检测器测定了3种甾体化合物1-3与微粒体的芳构化反应，结果表明E_3的生成顺序为1-> 2-> 3，与雌酮（E_1）的合成顺序相似。3的芳构化Km值很大，表明E_1和E_3的生成可能涉及不同的芳构化酶。在每种情况下，与对照组相比，大鼠的血压显著升高。结果提示，2可能在控制妊娠期血压中起重要作用。为了进一步阐明它们在妊娠中的动态变化，我们合成了它们的氘代衍生物作为GC-MS分析的内标物，并评价了它们的抑制活性：1）在不同位置上具有溴乙酰氧基的雄烯二酮衍生物，2）<19>在C-6上具有氧代基和在C-3上具有不同取代基的C_ -甾体，3）3-脱氧雄烯二酮衍生物。得到了有趣的构效关系。