Mechanistic Study of Estriol Biosynthesis and Its Inhibitor

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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.