Synthesis of thiosemicarbazone-based and 3,5-dibromo-4-hydroxyphenyl ketone compounds as potential non-steroidal inhibitors of the enzyme estrone sulfatase

Bordbar, Hadi (2011) Synthesis of thiosemicarbazone-based and 3,5-dibromo-4-hydroxyphenyl ketone compounds as potential non-steroidal inhibitors of the enzyme estrone sulfatase. (PhD thesis), Kingston University,


Estrone sulfatase (STS) has been shown to play a major role in the biosynthesis of estrogens [in particular estrone (E 1) which subsequently leads to the biosynthesis of estradiol (E2)] and therefore the initiation and progression of hormone-dependent breast cancer in post menopausal women. Recently, a range of thiosemicarbazone-based compounds have been reported as inhibitors of STS, however, due to the mode of action of these inhibitors, no detailed structure-activity relationship (SAR) was offered. In an effort to investigate the SAR within the thiosemicarbazone-based compounds, the current project considered the synthesis and biochemical evaluation of a range of novel thiosemicarbazone-based compounds. The target compounds were synthesised through a reaction between a carbonyl containing starting material (benzaldehyde- or acetophenone-based starting material) with N-cyclohexylhydrazinecarbothioamide using ethanol as the reaction solvent. When benzaldehyde was used for the reaction to produce benzaldehyde N-cyclohexylthiosemicarbazone-based compounds, the target compounds were obtained in good to excellent yield -the target compounds were obtained in a range of 60% [for 1-(4-methylphenyl) ethan-1-one Ncyclohexylthiosemicarbazone (218)] to 92% [for benzaldehyde Ncyclohexylthiosemicarbazone (201)]. However, when acetophenone-based starting material was used, for example 1-phenylethan-1-one Ncyclohexylthiosemicarbazone- based compounds, the target inhibitors were obtained in poor yield (30% or lower)- it was postulated that steric hindrance was the major factor in the reduced yield, indeed, in the most hindered case no product was obtained. Attempts to increase the yield, involving the use of a higher boiling point solvent such as toluene resulted in the production of a by-product, namely, N,N -dicyclohexylhyd razine-1 ,2 -d icarbothioam ide(200). The biochemical evaluation (using STS from rat liver) of a small range of the thiosemicarbazone-based compounds showed that these compounds are weak inhibitors of STS in comparison to the sulfamate-based standard compounds, namely COUMATE and EMATE, however, the evaluation of these compounds suggested that hydrogen bond interaction between the inhibitor and the binding site was important in the inhibition of STS. A range of sulfonate-based potential inhibitors were also synthesised using a multistep synthetic route with the initial synthesis of a range of 4-hydroxyphenyl ketone-based compounds. The phenyl ring was then derivatised involving the synthesis of the 3,5-dibrominated derivatives which were subsequently derivatised to both the methanesulfonate- or the trifluoromethanesulfonatederivatives. These compounds were produced without any major difficulties (except for the dibromination step where the larger alkyl chain containing compounds could not be synthesised in sufficient quantity to proceed to the sulfonate derivatives). The sulfonate-based compounds were not evaluated against STS due to the relocation of the research group, however, they are currently undergoing biochemical evaluation at the University of the West of Scotland.

Actions (Repository Editors)

Item Control Page Item Control Page