Soltani-Khankahdani, Siamak (2011) Synthesis of biochemical evaluation of potential inhibitors of 17 [beta]-hydroxysteroid dehydrogenase for treatment of hormone-dependent prostate cancer. (PhD thesis), Kingston University, .
Abstract
It has been shown that the majority of benign prostatic hyperplasia (BPH) and prostate cancers are dependent on androgen production within the body. The biosynthesis of androgens is catalysed by different enzymes however one of the enzymes, 17 beta-hydroxysteroid dehydrogenase type 3 (17 beta-HSD3), converts the C(17)=O carbonyl moiety of androstenedione (1l4-dione) to the corresponding C(17)-OH hydroxyl group of testosterone (T). It has been hypothesised that inhibition of 17 beta-HSD3 may cause a decrease in the level of androgens which in turn leads to a reduction in the genesis of androgen-dependent prostatic diseases. The utilisation of enzyme inhibition as a therapeutic agent, in the treatment of breast cancer, has been tested on postmenopausal women by using aromatase inhibitors (e. g; exemestane, anastrazole and latrazole). This approach has proved to be successful and the impact of enzyme inhibition was led to a reduction in cancer growth. This process has now found a clinical application. From molecular modelling studies it was postulated that any potential inhibitor of 17 beta-HSD3 should contain a carbonyl moiety, mimicking the C(17)=O of the natural substrate, as well as an aromatic ring adjacent to the carbonyl group. With these criteria in mind results from our laboratories showed that from a library of candidates those based upon 4-hydroxyphenyl ketones showed some potential. The main focus of this prestn study was to fine tube the enzyme inhibitor analogues and hence optimise inhibitory activity of 4-hydroxyphenyl ketones. We have successfully synthesised a range of novel derivatives of 4-hydroxyphenyl ketones such as the 4-methanesulfonate and 4-acetate ester derivatives. In general, the reactions have proceeded very well with the yields ranging from 65% to 88% and 91% to 97% respectively. The results of biochemical evaluation studies suggested that the acetate ester derivatives, in particular compounds (149) and (150) exhibited good inhibitory activity against 17 beta-HSD type 3 of about 40% compared to standard inhibitors such as 7-hydroxyflavone and baicalein which resulted in about 13% and 14% inhibitory activity respectively. In addition a range of non-steroidal B, C, D ring mimics of the natural substrate of 17 beta-HSD type 3 were synthesised in good yields (65% to 85%). The biochemical evaluation of these compounds also showed good inhibitory activity; in fact compound (107) exhibited about 43% inhibition in comparison to the above standards which had inhibition of about 25% and 31 % respectively. In conclusion we have successfully synthesised and biochemically evaluated a number of enzyme inhibitors for the enzyme 17 beta-HSD type 3. The two types of active inhibitors were structurally dissimilar suggesting that they may have different modes of binding. This outcome requires further investigation in order to establish and identify how this inhibition is taking place.
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