Synthesis of steroid AB ring mimics

Aidoo-Gyamfi, Kwabina (2002) Synthesis of steroid AB ring mimics. (MSc(R) thesis), Kingston University, .


Prostate diseases are a serious threat to the health and quality of life of ageing males. Prostate cells are hormone-dependent and as such are stimulated by androgens, for example testosterone (T) and dlhydrotestcsterone (DHT). Of the androgens, it is DHT that is the more potent. DHT is formed through the enzyme catalysed reduction of T by 5a-reductase (5AR) and requires NADPH as a co-factor. This enzyme is one of the major targets in androgen therapy for the treatment of prostate diseáses since a reduction in DHT levels would result in a subsequent decrease in the stimulation of hormone-dependent prostate cells without affecting the amount of T produced by the prostate or the testes. As such, 5AR inhibitors would be expected to possess less side-effects, such as loss of libido. A number of compounds (steroidal and non-steroidal) have previously been reported as potent inhibitors of 5AR but only a few have entered clinical trials and even fewer have entered the clinic. As such, the development 'of a potent non-steroidal inhibitor is crucial in the fight against hormone-dependent prostatic diseases. In the current study, we have reviewed the strategy for the treatment of hormone¬dependent prostate diseases and, in particular, we have considered the reported inhibitors of two of the most important enzymes, namely 17a-hydroxylase/17,20- lyase (P45017a) and 5AR. Within the research group, we have undertaken extensive studies into the molecular modelling of compounds against 5AR and therefore 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 coumarin backbone would undergo a reduction reaction (i.e. mimic the natural substrate) and therefore possess inhibitory activity. We have therefore synthesised a number of coumarin based compounds. In particular, we have synthesised a wide range of esters of the hydroxylated coumarin backbone. That is, using 4- and 7- hydroxycoumarin as starting material we reacted the. hydroxy compound with a range of acyl chlorides (from acetyl to decanoyl). In general, the reactions using 7-hydroxycoumarin proceeded in good yield and without major problems, although the larger alkyl chain containing acyl chlorides proved to be slow in reacting with 7 -hydroxycoumarin, and the time of reaction needed to be extended. The esters resulting from the use of 4-hydroxycoumarin proved to be relatively unstable and were observed to undergo hydrolysis with standing, however, it was possible to undertake spectral analysis (except elemental analysis) prior to degradation of the esters. The range of potential inhibitors were purified and fully characterised. A second aim of the study was to evaluate the synthesised compounds against 5AR, however, due to a lack of time, this was not achieved.

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