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

Ahmed, Sabbir; Owen, Caroline P.; James, Karen; Patel, Chirag; Sampson, Luther

doi:10.1016/s0960-0760(02)00036-5

Cited by 11 publications

(10 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, this mechanism did not require the cleavage of the S ¾ OAr bond until after the irreversible production of the imine, and as such, this mechanism contradicts the results of this study. Recently, we reported (Ahmed et al 2002) an alternative mechanism (Figure 4) for the irreversible inhibition of oestrone sulfatase by sulfamate-based com-pounds, where we proposed that cleavage of the S ¾ OAr bond was the crucial step to the inhibition of this enzyme and occurred before the formation of the imine product.…”

Section: Biochemical Evaluation and Structure-activity Relationshipmentioning

confidence: 99%

Structure-activity relationship determination within a group of substituted phenyl sulfamate based compounds against the enzyme oestrone sulfatase

Patel

Galisson

James

et al. 2003

Journal of Pharmacy and Pharmacology

Self Cite

View full text Add to dashboard Cite

The enzyme oestrone sulfatase (ES) is responsible for the conversion of the stored (sulfated) form of oestrogens to the active form, namely oestrone. In our continuing quest to synthesize potent inhibitors of oestrone sulfatase and to determine the structural requirements for such inhibition, we have synthesized and evaluated several derivatives of phenyl sulfamate. We report the results of the synthesis and biochemical evaluation of a series of 3- and 4-aminosulfonated derivatives of phenol in an effort to investigate the role of the acid dissociation constant (pK(a)), and therefore the stability of the phenoxide ion, on the inhibitory activity of compounds against this enzyme. The results showed that there was a strong correlation between the observed pK(a) and inhibitory activity within the aminosulfonated compounds considered. This suggested that in the inhibition of oestrone sulfatase by these compounds, pK(a) was an important physicochemical property, and as such, the stability of the O(-) ion was a crucial factor in the inhibition, and therefore the drug design process.

show abstract

Section: Biochemical Evaluation and Structure-activity Relationshipmentioning

confidence: 99%

Structure-activity relationship determination within a group of substituted phenyl sulfamate based compounds against the enzyme oestrone sulfatase

Patel

Galisson

James

et al. 2003

Journal of Pharmacy and Pharmacology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Our interest in the synthesis of α-fluorosulfonamides stemmed from our desire to prepare benzylic α,α-difluorosulfonamides, such as compound 2 , to test as reversible inhibitors of the enzyme estrone sulfatase (ES) and as probes to test mechanisms proposed for the irreversible inhibition of this therapeutically significant enzyme by sulfamates, such as compound 3 . Here we report that compound 2 , as well as other primary, secondary, and tertiary sulfonamides of type 1 , can be prepared by electrophilic fluorination of α-carbanions of protected sulfonamides.…”

mentioning

confidence: 99%

Synthesis of α-Fluorosulfonamides by Electrophilic Fluorination

2004

View full text Add to dashboard Cite

show abstract

“…Inhibitors of oestrone sulphatase containing an aminosulphonate group are also believed to undergo a similar process. Recently, we reported a mechanism for the inhibition of oestrone sulphatase by sulphamate containing compounds where we proposed that the cleavage of the S-OR bond (and thus pK a ) was a crucial step in the inhibition process so as to produce sulphamic acid and the anion containing the carbon backbone (RO ) (Ahmed et al 2002). The destabilization of the RO (due to the relatively high hydrophobicity of the R group) would therefore appear to aid the overall inhibitory process.…”

Section: Resultsmentioning

confidence: 99%

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

Owen

James

Sampson

et al. 2003

Journal of Pharmacy and Pharmacology

Self Cite

View full text Add to dashboard Cite

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 pK(a). 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 pK(a) in determining the overall inhibitory activity. In a previous report, we showed that pK(a) plays an important role in stabilizing the phenoxide ion resulting from the hydrolysis of the sulphamate group. Here, we propose that although pK(a) is an important factor in determining the overall inhibitory activity when a wide range of compounds are considered, both hydrophobicity and pK(a) need to be considered in the design of potential inhibitors of oestrone sulphatase.

show abstract

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

Cited by 11 publications

References 12 publications

Structure-activity relationship determination within a group of substituted phenyl sulfamate based compounds against the enzyme oestrone sulfatase

Structure-activity relationship determination within a group of substituted phenyl sulfamate based compounds against the enzyme oestrone sulfatase

Synthesis of α-Fluorosulfonamides by Electrophilic Fluorination

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

Contact Info

Product

Resources

About