Synthesis and biochemical evaluation of inhibitors of estrone sulfatase as potential anti-tumour agents

Patel, Chirag K (2003) Synthesis and biochemical evaluation of inhibitors of estrone sulfatase as potential anti-tumour agents. (PhD thesis), Kingston University,


In the treatment of hormone-dependent breast cancer, extensive research has been undertaken to produce compounds, which are both potent and selective inhibitors of the cytochrome P-450 enzyme aromatase. However, the use of aromatase inhibitors does not result in the inhibition of all of the biosynthetic processes, which lead to estrogen formation. That is, the enzyme estrone sulfatase converts the stored (sulfated) form of the estrogens to the active (non-sulfated) forms, thereby allowing the stimulation of tumours via a non-aromatase pathway and which, in general, is not blocked by aromatase inhibitors. In an effort to investigate further the structural requirements for estrone sulfatase (and thereby determine the probable mechanism of this enzyme), we designed a range of sulfonated compounds. Here, we report the synthesis and biochemical evaluation of the designed compounds. In general, the results of the study show that the sulfamated compounds are potent inhibitors, possessing greater inhibitory activity than COUMATE, but are weaker than EMATE and the recently reported derivatives of COUMATE, namely 667-COUMATE. However, a small range of compounds (124, 127, 130 and 133) based upon benzoic acid were found to be more potent than the latter compound, in particular, cyclooctyl 4-aminosulfonyl benzoate (133) (IC[sub]50 = 0.17[mu]M) was found to be 1.4 and 2.9 times more potent than 667- COUMATE (IC[sub]50 = 0.23[mu]M) and EMATE (IC[sub]50 = 0.5[mu]M) respectively. The non-sulfamated (for example, 4-nitrophenyl sulfonate based) compounds (52, 58, 61, 103, 131, 146, 170, 173 and 177) were either found to be non-inhibitors or possessed poor inhibitory activity against estrone sulfatase. Consideration of the structure activity relationship of the potent compounds within this study suggests a correlation between two major physicochemical factors [namely, hydrophobicity (logP) and the acid dissociation constant (pK[sub]a) of the parent phenol compound] and the biological activity possessed by sulfamated compounds. However, the present study also suggests another factor, which is presumed to play an important role in stabilising the enzyme-inhibitor complex, namely steric hindrance. That is, consideration of the cyclic ester based compounds against the corresponding straight chain compounds shows that the cyclic ester containing compounds possessed a much greater inhibitory activity. As such, these factors may be combined in an effort to design more potent inhibitors of estrone sulfatase.

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