Attempted synthesis and biochemical evaluation of non-steroidal estrone sulfatase inhibitors

Sampson, Luther (2000) Attempted synthesis and biochemical evaluation of non-steroidal estrone sulfatase inhibitors. (MPhil thesis), Kingston University, .


The use of inhibitors in the treatment of hormone dependent breast is discussed. Particular emphasis is placed on the inhibition of the enzymes 17[beta]- hydroxysteriod dehydrogenase, aromatase, and estrone sulfatase. The molecular modelling of known inhibitors has been undertaken in an attempt to develop a better understanding of the estrone sulfatase active site. The superimpositioning study has allowed us to firstly, rationalise the inhibitory activity of a number of inhibitors. Secondly, deliberated that the sulfonate group is the primary requirement for potent inhibition. Thirdly, hypothesised that the phenyl ring is not required for inhibitory activity and finally, considered that the importance of the hydrogen bonding group(s) within the ES active site corresponding to the C-17 area of the steroidal backbone. These hypotheses were then investigated through the attempted synthesis of the alkyl sulfamate and phosphonates. The latter proved difficult to synthesise although a number of sulfonates (methane- and amino-sulfonate) were synthesised and subsequently evaluated using placental microsomal enzyme. The biochemical evaluation showed these compounds to be poor inhibitors. However, a simple substituted ethyl alcohol based inhibitor was discovered to possess good inhibitory activity, possessing an IC[sub]50 valve of 0.74mM. This has allowed us to design and synthesis further novel and highly potent inhibitors of estrone sulfatase further novel and highly potent inhibitor of estrone sulfatase (not considered within the present study).

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