Synthesis Of Steroidal Drugs From AD/DHEA And Studies On Their Biological Activities

Steroid drugs for their specific characteristic physiological activities have been widely used in treating different kinds of diseases, such as rheumatism, anti-tumor, skin disease, and so on. During the past 50 years, the discovery and synthesis of steroid drugs is one of the two remarkable developments in medical industry, which has become the second large drug inferior to antibiotics. Androstenedione(AD) and dehydroepiandrosterone(DHEA) as a new steroid material attracts people's attention because of the shortage of diosgenin resource and successful synthesis of AD by degradation of sterols. The followings were included in this thesis:1. 24 new oxime-ether and oxime-ester compounds from AD were synthesized by cleavage of A-ring through NaIO₄/KMnO₄ oxidation, ring closure by amination, oximation with hydroxylaminechloride in C-17 position. The structures of all intermediates and compounds were identified by IR, MS, 1H NMR and 13C NMR.2. The reduction of oxime were investigated and the 17-amino steroid was obtained via reduction with Ni-Al alloy in yield of 90%. The 17-amino steroids were subsequently substituted by substituted acylchloride and carboxylic acids and 15 acylamide compounds were obtained in C-17 position. The structures of all intermediates and compounds were identified by IR, MS, 1H NMR and 13C NMR.3. The side chains of DHEA were achieved with different wittig reagents at C-17 position and the methylene, ethyl, ethoxycarbonylmethylene, methoxymethylene groups were successfully introduced into DHEA in total yield of 96%, 95%, 53%,10%, respectively.4. The important intermediate 17β-carboxyl steroid 3-62 and progesterone 3-64 from DHEA were synthesized by wittig reaction, hydroboration-oxidation, oppenauer oxidation, Jone's oxidation in total yield of 23.0%, 5.7%, respectively. The hydroxymethyl group was introduced into 17-ethylene steroid at C-20 position and unexpected trihydroxymethyl steroid compound was obtained.5. Some of target compounds were evaluated for their anti-tumor activitiy and inhibitory activity of rat 5α-reductase in vitro. In the test for inhibitory activity of rat liver microsomal 5α-reductase, all compounds showed more or less inhibition to rat 5α-reductase. several compounds 301, 302, 304, 305, 306 showed good and potent inhibition to rat 5α-reductase, the compounds 301, 305, 306 was found to be almost identical to Epristeride in same testing condition and have been selected for further development. In anti-tumor test, the accepted testing compounds showed little inhibition to human mammary cancer MDA-MB-468 cell line.