Caroline P Owen

Novel inhibitors of the enzyme estrone sulfatase (ES)

We report the initial results of our study into a series of simple 4-sulfamated phenyl alkyl ketones as potential inhibitors of the enzyme estrone sulfatase. The results of the study show that these compounds are potent inhibitors, possessing greater inhibitory activity than COUMATE, but weaker activity than EMATE. Furthermore, the compounds are observed to be irreversible inhibitors.

Hydrophobicity, a physicochemical factor in the inhibition of the enzyme estrone sulfatase (ES)

We report the initial structure-activity relationship study (SAR) (in particular logP) of a series of compounds based upon 4-sulfamated phenyl ketones as potent inhibitors of the enzyme estrone sulfatase (ES). The results of the study show that these compounds are irreversible inhibitors of ES and that they are more potent than COUMATE, but weaker than EMATE. Analysis of the SAR data shows a strong correlation between IC(50) and logP but also supports our previous study, which suggests a very strong relationship between pK(a) and IC(50).

Acid dissociation constant, a potential physicochemical factor in the inhibition of the enzyme estrone sulfatase (ES)

We report the initial results of the synthesis and biochemical evaluation of a series of aminosulfonate based compounds of phenol and the determination of the pKa of the parent phenol in an attempt to investigate the role of this physicochemical factor in the irreversible inhibition of the enzyme estrone sulfatase (ES). The results of the study show that there is a strong correlation between the observed pKa and inhibitory activity. We postulate that the stability of the phenoxide ion, as indicated by the acid dissociation constant, is an important factor in the irreversible inhibition of this enzyme.

Synthesis and biochemical evaluation of some novel benzoic acid based esters as potential inhibitors of oestrone sulphatase

Oestrone sulphatase is an important target in the fight against hormone‐dependent breast cancer. In an effort to investigate the reported definitive pharmacophore for oestrone sulphatase and continue our search for potent inhibitors of this enzyme, we have undertaken extensive synthesis, biochemical evaluation and physicochemical property determination of a range of benzoic acid based esters. Here, we report the initial results of our study into a series of straight chain alkyl esters of 4‐sulphonylbenzoic acid. Using these compounds, we have investigated the involvement of two physicochemical properties, namely logP and pKa. The results of this study show that there was a strong correlation between the inhibitory activity and the logP of the parent compound. Within the series of compounds studied, hydrophobicity appears to be a more important factor than pKa in determining the overall inhibitory activity. In a previous report, we showed that pKa plays an important role in stabilizing the phenoxide ion resulting from the hydrolysis of the sulphamate group. Here, we propose that although pKa is an important factor in determining the overall inhibitory activity when a wide range of compounds are considered, both hydrophobicity and pKa need to be considered in the design of potential inhibitors of oestrone sulphatase.

Evidence for the mechanism of the irreversible inhibition of oestrone sulphatase (ES) by aminosulphonate based compounds.

In our search for the mechanism of the enzyme oestrone sulphatase (ES) we have synthesised and evaluated a number of compounds that were predicted to possess some inhibitory activity. Some of these compounds were indeed found to be inhibitors of ES, whilst other compounds were not. From a consideration of the structure-activity relationship (SAR) of the inhibitors and non-inhibitors of this enzyme, we discovered a factor which we now believe is the main inhibitory moiety within the aminosulphonated inhibitors. We therefore report the results of our study into a series of phenyl and alkyl sulphamated compounds as inhibitors of ES. The results of the study show that the substituted phenyl sulphamates are potent inhibitors, whereas the alkyl compounds are, in general, non-inhibitors. Using the results of our SAR study, we postulate the probable mechanism for the irreversible and reversible inhibition of ES, and rationalise the role of the different physicochemical factors in the inhibition of this crucial enzyme.

The mechanism of the irreversible inhibition of estrone sulfatase (ES) through the consideration of a range of methane- and amino-sulfonate-based compounds

We report the results of our study into a series of simple phenyl and alkyl sulfamates and alkyl methanesulfonates as potential inhibitors of the enzyme estrone sulfatase (ES). The results of the study show that the substituted phenyl sulfamates are good irreversible inhibitors; the alkyl sulfamate compounds were found to lack inhibitory activity; whilst the large alkyl chain containing methanesulfonate-based compounds were found to possess weak reversible inhibitory activity. Using the results of the inhibition study, we postulate the probable mechanism for ES and suggest that an attack by the gem-diol is a major requirement prior to the hydrolysis of the sulfamate group, following which, attack on the active site C=O occurs and which therefore leads to the production of an imine type functionality, resulting in irreversible inhibition.

The design, synthesis, and in vitro biochemical evaluation of a series of esters of 4-[(aminosulfonyl)oxy]benzoate as novel and highly potent inhibitors of estrone sulfatase

We report the initial results of our study into the use of a potential transition-state (TS) of the reaction catalysed by the enzyme estrone sulfatase (ES) in the design of a series of cyclic esters of 4-[(aminosulfonyl)oxy]benzoate as novel inhibitors of ES. The results of the study show that these compounds are some of the most potent inhibitors known todate, possessing greater inhibitory activity than the three standard compounds: 4-methylcoumarin-7-O-sulfamate (COUMATE); the tricyclic derivative of COUMATE, namely 667-COUMATE (which is in Phase I of clinical trials) and; the steroidal inhibitor estrone-3-O-sulfamate (EMATE).

Synthesis and biochemical evaluation of novel and potent inhibitors of the enzyme oestrone sulphatase (ES)

In an effort to investigate the structural requirements for the inhibition of the enzyme oestrone sulphatase (ES), we have previously undertaken extensive structure-activity relationship studies. Using the data from molecular modelling and structure-activity relationship determination studies, we have designed a number of compounds based upon 4-sulphamated phenyl ketones. Here, we report the results of our study into a series of these compounds as potential inhibitors of ES. The results of the study show that these compounds are potent inhibitors the possessing greater inhibitory activity than 4-methylcoumarin-7-O-sulphamate derivative (COUMATE) (a potent non-steroidal inhibitor), but are weaker than oestrone-3-sulphamate (EMATE) and the recently reported 667- and 669-COUMATE, however, they provide good lead compounds in the search for potent inhibitors of ES. Furthermore, the compounds are observed to be irreversible inhibitors. From the consideration of the structure-activity relationship of these novel compounds, we have attempted to rationalise the significance of the log P factor in the inhibition of ES and suggest that a log P requirement of approximately 3.5 aids the inhibition through the rapid expulsion of the carbon backbone from the active site. We also propose that the same factor is responsible for the hydrolysis of oestrone sulphate reaction, appearing to be an irreversible process.

Determination and use of a transition state for the enzyme estrone sulfatase (ES) from a proposed reaction mechanism

Using the postulated mechanism for the enzyme estrone sulfatase (ES), we have determined a possible transition state for the reaction catalysed by ES as a representation of the active site. Using the derived structure, we have undertaken the molecular modelling of several steroidal and non-steroidal inhibitors in an attempt to rationalise the inhibitory activity of a number of potent inhibitors.

Inhibition of estrone sulfatase (ES) by derivatives of 4-[(aminosulfonyl)oxy] benzoic acid

In our search for potent inhibitors of the enzyme estrone sulfatase (ES), we have undertaken the synthesis and biochemical evaluation of a range of straight chain alkyl esters of 4-[(aminosulfonyl)oxy] benzoic acid. The results of the study show that the synthesised compounds possess greater inhibitory activity when compared to COUMATE, although they were all found to possess lower inhibitory activity with respect to EMATE. Furthermore, the data suggest a strong correlation between logP and IC(50) and therefore adds further support to our previous report where we suggested a link between inhibitory activity and hydrophobicity.