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 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.
Owen
Caroline
C
School of Chemical and Pharmaceutical Sciences, Kingston University, Penrhyn Road, Kingston upon Thames, Surrey KT1 2EE, UK.
James
Karen
K
Sampson
Luther
L
Ahmed
Sabbir
S
D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry*; D001943:Breast Neoplasms / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry*; D004952:Esters / Q000737:chemistry; D006801:Humans; D006868:Hydrolysis; D012995:Solubility; D013429:Sulfatases / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D001565:Benzoates; D004791:Enzyme Inhibitors; D004952:Esters; D013429:Sulfatases; C020121:estrone sulfatase