Study On The Synthesis Of 7-oxygen Or Nitrogen Substituted Steroidal Aromatase Inhibitors

Breast cancer is the second major cause of mortality in women. Aromatase inhibitors can treat breast cancer through inhibiting the synthesis of the estrogen, which nowdays has taken over the anti-estrogen because of their superior efficacy and favorable safety profile. Especially steroidal AIs, have attracted a great deal of attention because of their irreversible, high selectivity and persistence. This dissertation is focused on the synthesis of 7-oxygen or nitrogen substituted derivatives of androstenedione and dehydroepiandrosterone, for the purpose of structure-activity relationship and drug discovery in this field.1. 9 novel 3,3-ethylenedioxy-7β-acyloxy-5-androstene-17-one from AD were synthesized by ketal reaction, allylic oxidation, selective reduction, deprotection and esterification. The structures of all intermediates and compounds were identified by MS, 1H NMR and 13C NMR.2. 9 3β-acetoxy-7β-acyloxy-5-en-17-one and 7 3β-acetoxy-7α-acyloxy-5-en-17- one were obtained from DHEA through the following reaction: acetylation, ketal reaction, allylic oxidation, selective reduction, deprotection and esterification. Six of target compounds were never reported in the literature. The structures of all intermediates and compounds were identified by MS, 1H NMR and 13C NMR.3. 18 novel 7-amide-AD derivatives were synthesized from AD by ketal reaction, allylic oxidation, oximation, reduction, N-acetylation and deprotection. The reduction of oxime were investigated and the 7-amino steroid was obtained via reduction with sodium in enthol. The structures of all target compounds were identified by MS, 1H NMR, 13C NMR and HRMS. Their stereo configuration was confirmed by DEPT, HMQC and NOE.4. The reduction of oxime which was obtained from the staring material DHEA were investigated and the reaction could be conducted using LiAlH4, but the by-products were so many that the target product could not be separated.5. Some of target compounds were evaluated for their anti-tumor activitiy against MCF-7, but the result was not satisfied.