Synthesis of mimics of steroid A ring as potential enzyme inhibitors

Makwana, Vaidehi (2002) Synthesis of mimics of steroid A ring as potential enzyme inhibitors. (MSc(R) thesis), Kingston University, .


Prostate cells are generally hormone-dependent and are stimulated by androgens, for example testosterone (T) and the more potent androgen dihydrotestosterone (DHT). DHT is formed through the reduction of T by the enzyme 5a-reductase (5[alpha]R) and this enzyme has become one of the major targets in the treatment of hormone-dependent prostate diseases [such as benign prostate hyperplasia (BPH) and prostate cancer] since a reduction in DHT levels would result in a subsequent decrease in the stimulation of androgen-dependent prostate cancer cells. Inhibitors of 5[alpha]R (both steroidal and non-steroidal) have previously been reported but only a few have entered clinical trials and even fewer have entered the clinic (for example, finasteride). As such, the development of a potent non-steroidal inhibitor is crucial in the fight against hormone-dependent prostatic diseases. In the present study, we have reviewed the strategies for the treatment of hormone-dependent prostate diseases and, in particular, have considered the reported inhibitors of two of the most important enzymes in the biosynthesis of androgens, namely 17[alpha]-hydroxylase/17,20-lyase (P450[sub][17][alpha]) and 5[alpha]R. We have previously undertaken extensive studies into the molecular modelling of compounds against 5[alpha]R and have gained an insight into the active site of this enzyme. From our studies, we determined the mimicking of the steroid A-ring was an important feature of a potential inhibitor. Furthermore, we determined that the carbon-carbon double bond and the ketone moiety within the A-ring of the steroid backbone were the basic requirements for inhibition, in particular the C=C, as this is involved in the reduction reaction. We therefore concluded that compounds based on cinnamic acid would possess inhibition as this type of compound possesses the appropriate characteristics and would therefore undergo the reduction reaction (i.e. mimic the natural substrate). We have therefore synthesised a wide range of esters and amides of 4-substituted cinnamic acid - the results of the molecular modelling study showed that hydrogen bonding may be possible between the 4-substituted group and parts of the active site. That is, using 4-substituted cinnamic acid (e.g. 4-nitro cinnamic acid) as starting material, we converted the carboxylic acid to the more reactive acid chloride which was subsequently reacted with a range of straight chain alkyl alcohols (from methyl to pentyl) to give us the esters and with alkyl amines (from methyl to pentyl) to give us the amides. In general, the reactions leading to the esters proceeded in good yield and without major problems. The production of the amides, however, proved to be troublesome, in particular the use of methylamine, however, through extensive purification steps, it was possible to obtain the target N-methyl compounds. The range of potential inhibitors were all purified and fully characterised, including elemental analysis. A second aim of the study was to evaluate the synthesised compounds against 5[alpha]R, however, due to a lack of time, this was not achieved.

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