Synthesis of a series of aminosulfonated compounds as potential inhibitors of estrone sulfatase

In an effort to investigate further the pharmacophoric requirements for the inhibition of the enzyme estrone sulfatase, we designed a range of sulfamic acid 2,6-dibromophenyl esters and 3,5-dibromo-4-sulfamoyloxy-benzoic acid esters as potential inhibitors of this crucial enzyme. Here we report the synthesis of these compounds, the determination of the pK[sub]a of the non-sulfamoylated derivatives and the initial screening data. The results show these compounds, in general, to be poor inhibitors of estrone sulfatase and weaker inhibitors than the three standard compounds, namely COUMATE, 667-COUMATE and EMATE. Furthermore, the results of the current study appear to suggest that the incorporation of the bromine moiety within the phenyl ring of the general 0-sulfamoylated phenyl derivatives does not increase the inhibitory activity, indeed a decrease in the inhibitory activity is observed. For example, sulfamic acid 4-nonanoylphenyl ester (55) was found to possess 67% inhibition at 10[mu]M final assay inhibitor concentration, however, the dibrominated derivative of this compound, sulfamic acid 2,6-dibromo-4-cyclobutanecarbonylphenyl ester (96) was found to possess 96% inhibition at a much increased inhibitor concentration (50[mu]M). Whilst possessing poor inhibitory activity, the results show the synthesised compounds to be good lead compounds in the search for more potent inhibitors of estrone sulfatase.