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Please use this identifier to cite or link to this item: http://hdl.handle.net/1993/804

Title: Studies in the synthesis of mechanism-based steroid enzyme inhibitors and related compounds
Authors: Majgier-Baranowska, Helena
Issue Date: 1-Oct-1997
Abstract: The main goal of the thesis was to synthesize compounds which would selectively inhibit a function of steroid enzymes. Three enzymes have been targeted; 3$\alpha,20\beta$- (EC 1.1.1.53) and 17$\beta,20\alpha$-hydroxy dehydrogenases ("cortisone reductase") (EC 1.1.1.62) and estrogen synthetase (aromatase) (P450 XIXA1). The first part of the research was aimed at the synthesis of substituted cyclosteroid derivatives designed as substrates for the above enzymes which are able to act as mechanism-based inhibitors. The second part of the thesis dealt with the synthesis of 4-hydroxyestrogen derivatives, which are the natural metabolites of estrogens. For the synthesized compounds, $\sp1$H and $\sp{13}$C NMR spectra as well as electron ionization mass spectra were determined. The structures of synthesized compounds were analysed by COSY, HSQC, HMBC, NOE experiments, and were confirmed by X-ray crystallographic analysis. Two spirocyclopropanol steroid isomers, 20$\alpha$- and 20$\beta$-hydroxy-17$\alpha,21\alpha$-cyclopregn-4-en-3-one, have been synthesized as potential mechanism-based inhibitors of 17$\beta,20\alpha$- and 3$\alpha,20\beta$-hydroxysteroid dehydrogenase, respectively. Inhibitors of aromatase have been synthesized via reductive cyclization of androst-4-ene-3,17-dian-19-al and 5$\alpha$-androst-1-ene-3,17-dion-19-al with Zn in 50% aqueous acetic acid or Li in liquid ammonia followed by acetylation and oxidation. 19(R/S)-Acetoxy-5$\beta$,19-cyclo-androst-1-ene-3, 17-diones have been synthesized via palladium oxidation of trimethylsilyl enol ethers. Attempts to synthesize unsaturated analogues of 19(R/S)-acetoxy-1$\beta$,19-cyclo-5$ \alpha$-androstane-3,17-dione, by the same procedure, were not successful. Enzyme evaluation studies showed that 19(S)- and 19(R)-acetoxy-5$\beta$,19-cycloandrost-1-ene-3,17-dione showed 8% and 44% of inhibitory activity, respectively. The synthesized 19(R)-hydroxy- and 9(R)-acetoxy-1$\beta$,19-cyclo-5$\alpha$-androstane-3,17-dione showed 40-50% of inhibition when tested on human placental aromatase microsomes. The ratio of products with the hydroxy group above ring A upon reductive cyclization was investigated. It was discovered that reductive cyclization of androst-4-ene-3,17-dion-19-al both in Zn/50% aqueous acetic acid and Li/NH$\sb3$ gave the same product, namely the thermodynamically less stable 19(R)-hydroxy-5$\beta$,19-cycloandrost-3,17-dione. However, reductive cyclization of androst-1-ene-3,17-dion-19-al with Zn/50% acetic acid gave thermodynamically more stable product, the 19(R)-hydroxy-1$\beta$,19-cyclo-5$\alpha$-androstane-3,17-dione, but with i/NH$\sb3$ the thermodynamically less stable, 19(S)-hydroxy-1$\beta$,19-cyclo-5$\alpha$-androst-3,17-dione (70%), was produced. Mechanisms for the reductive cyclization of androst-4-ene-3,17-dion-19-al and 5$\alpha$-androst-1-ene-3,17-dion-19-al as well as for epimerization of 19(R)-hydroxy-5$\beta$,19-cycloandrostane-3,17-dione have been proposed. Investigations of the reductive cyclization were also extended to androst-4-ene-3,17-dione derivatives with different functional groups at C-19, namely the 19-protected oxime and 19-methyl ester. In the pursuit of a more efficient method for the synthesis of 4-hydroxyestrogens from estr-4-ene-3,17-dione via 4$\xi,5\xi$-epoxysteroid derivatives, two different strategies were applied: (1) acidic aromatization of 4$\xi,5\xi$-epoxyestr-1-ene-3,17-dione, and (2) pyrolysis of 4-chloro-4$\xi,5\xi$-epoxyestra-3,17-dione. (Abstract shortened by UMI.)
URI: http://hdl.handle.net/1993/804
Appears in Collection(s):FGS - Electronic Theses & Dissertations (Public)

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