Cartledge, Timothy (2008) Synthesis, biochemical evaluation and physiochemical property determination of a range of potential estrone sulfatase inhibitors in the treatment of hormone-dependent breast cancer. (PhD thesis), Kingston University, .
Abstract
The inhibition of enzymes within the steroidal cascade has been shown to lead to a reduction in tumour mass as a result of a reduction. in the levels of steroids present both within the plasma and within tumour cells. For example, 'in postmenopausal women, the use of enzyme inhibitors has led to the treatment of hormone-dependent breast cancer. Enzymes such as aromatase, 17ß-hydroxysteroid dehydrogenase [types 1 (17ß-HS01) and 3 (17ß-HS03)] and estrone sulfatase (ES) are some of the enzymes involved in the biosynthesis of steroids and have therefore become biochemical targets in the design and synthesis of novel drugs against this disease. Inhibitors of ES have thus far been investigated involving the use of the sulfamate moiety as the inhibiting moiety. Within the current study, the synthesis and biochemical evaluation of a number of compounds (both steroidal and non-steroidal) with varying structural features has been undertaken, in particular, the synthesis of sulfonate (as opposed to sulfamate) derivatives has been investigated. The results show that the sulfonate (methane sulfonate and trifluoromethanesulfonate) derivatives of 4-hydroxyphenyl ketone-based compounds were found to possess weak inhibitory activity against ES (from rat liver microsornes at a final inhibitor concentration of 100¡.JM) in comparison to the two standard compounds used within the study, namely EMATE and COUMATE. For example, within the methanesulfonate derivatives of 4-hydroxyphenyl ketone based compounds, the most potent compounds were: methanesulfonic acid 4-nonyl-phenyl ester (304) (which was found to possess -36% inhibitory activity against ES); methanesulfonic acid 4-decyl-phenyl ester (305) (which was found to possess -38% inhibitory activity against ES); methanesulfonic acid 4-cyclobutane carbonyl phenyl ester (307) (which was found to possess -38% inhibitory activity against ES) and methanesulfonic acid 4- cyclopentane carbonyl phenyl ester (308) (which was found to possess -38% inhibitory activity against ES). The trifluoromethanesulfonate derivatives of 4-hydroxyphenyl ketones were found to be extremely weak inhibitors of ES and were weak inhibitors in comparison to both standard compounds as well as the methanesulfonate derivatives of the 4-hydroxyphenyl ketone-based compound, indeed, the most potent compound was trifluromethanesulfonic acid 4-cyclobutane carbonyl phenyl ester (321) which was found to possess -29% inhibitory activity against ES. Within the estrone (E1)- and estradiol (E2)- based compounds, a number of different sulfonate derivatives were evaluated (but not synthesised) within this study, and a small number of these compounds was found to possess good inhibitory activity (at [1]=100¡.JM), however, in general, these compounds were also weak inhibitors in comparison to EMATE and COUMATE. Some of the more potent inhibitors within this range of compounds include: methanesulfonic acid E1 (369) (which was found to possess -47% inhibitory activity against ES); triffuoro-methanesulfonic acid E1 (370) (which was found to possess -58% inhibitory activity against ES) and; di-methanesulfonic acid E2 (371) (which was found to possess -41% inhibitory activity against ES). Within the range of E1- and E2-based compounds, it was observed that the inhibitory activity decreased with increasing size of the substituent on the sulfonate moiety, the introduction of a biphenyl ring on the sulfonate moiety resulted in a marked decrease in inhibitory activity. A range of thiosemicarbazone-based inhibitors were also evaluated and were shown to possess moderate inhibitory activity, however, they were weak inhibitors in comparison to the two standard compounds used. For example, compound 401 was found to possess -73% inhibitory activity against ES, whilst compound 381 was found to possess -70% inhibitory activity against ES - a major problem with these compounds is that they were found to rapidly degrade when dissolved in solution (such as ethanol or OMSO). In conclusion, the compounds synthesised proved to have weak levels of inhibitory activity, however, they have provided some insight into the design of novel inhibitors of ES.
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