Synthesis of potential inhibitors of estrone sulfatase in the treatment of hormone-dependent breast cancer
Estrone sulfatase (E 1 STS) belongs to a family of enzymes, namely the steroid sulfatases, which catalyse the conversion of the biologically inactive .cornpound to the more potent biologically active steroid. In particular, E1STS catalyses the conversion of estrone sulfate to estrone (E 1) and is therefore a pivotal enzyme in the progression of hormone-dependent breast cancer in postmenopausal women. The use of aromatase (AR) inhibitors, such as anastrozole, has led to the reduction of plasma levels of E1 by as much as 98%, however, it has been suggested that the high levels of E1 found within breast cancer cells are due 'to the activity of E1STS and is therefore a non-AR route which is not affected through the use of AR inhibitors. A number of compounds, both steroidal and non-steroidal, have been synthesised and subsequently evaluated as inhibitors of E1STS, however, from the ranges of compounds evaluated, 667-COUMATE remains the only compound to enter Phase I clinical trials. Within our own group, we have previously synthesised a number of compounds based on the 4-sulfamoylated derivatives of a series of alkyl 4- hydroxybenzoic acid esters, indeed, the cyclo-octyl derivative was found to be more potent than 667 -COUMATE. However, these compounds are known to be unstable in the plasma due to the presence (and action) of esterases. As such, we considered the synthesis of 4-sulfonated derivatives of both the mono- and di-substitiuted N-alkyl-4- hydroxybenzamide. In the synthesis of the target compounds, we utilised a reaction scheme which involved the initial synthesis of the mono- and di-substituted N-alkyl-4- hydroxybenzamide followed by the conversion of the 4-hydroxy moiety to the sulfamate, methansulfonate or trifluoromethansulfonate derivatives. However, a number of difficulties in the synthesis and purification of the N-alkyl-4-hydroxybenzamide from 4- hydroxybenzoic acid led us to consider the use of a protecting group for the' 4-hydroxy moiety. As such, we considered (and utilised) the initial synthesis of 4-acetoxybenzoic acid followed by the synthesis of N-alkyl-4-hydroxybenzamide via the appropriate acyl chloride. The conversion of the 4-hydroxy moiety to the sulfonate derivatives involved the reaction between N-alkyl-4-hydroxybenzamide and the appropriate sulfonyl chloride. In general, the reactions proceeded in moderate to good yield with a few problems, namely the purification of the target compounds. Although the sulfonated products are currently undergoing biochemical evaluation, initial pKa (a physicochemical factor which has been shown to play an important role in determining biochemical activity) studies suggest that the benzamide-based compounds are potentially weak inhibitors of E1STS. In an effort to produce novel inhibitors of E1STS, the synthesis of non-phenolic based inhibitors was also considered within the current study. In particular, synthesis of sulfamoylated derivatives of alkyl and benzyl alcohols was undertaken involving a reaction between the appropriate alcohol and aminosulfonyl chloride. In general, the reactions proceeded in low to good yield with the main problem once again being the purification of the product. These compounds are also currently undergoing biochemical evaluation, however, from molecular modelling studies undertaken within the group, they would initially appear to be weak inhibitors of E1STS. Within this range, however, the a-substituted halogen containing compounds (as these possess the potential to stabilise the alkoxide ion being formed as a result of the hydrolysis of the sulfamate moiety) may be the more potent inhibitors in comparison to the non-halogenated compounds.