Owen Caroline, James Karen, Sampson Luther, Ahmed Sabbir
School of Chemical and Pharmaceutical Sciences, Kingston University, Penrhyn Road, Kingston upon Thames, Surrey KT1 2EE, UK.
J Pharm Pharmacol. 2003 Jan;55(1):85-93. doi: 10.1211/002235702568.
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.
硫酸雌酮酶是对抗激素依赖性乳腺癌的一个重要靶点。为了研究已报道的硫酸雌酮酶的确定药效团，并继续寻找该酶的强效抑制剂，我们对一系列苯甲酸酯进行了广泛的合成、生化评估和理化性质测定。在此，我们报告对一系列4-磺酰基苯甲酸直链烷基酯研究的初步结果。利用这些化合物，我们研究了两个理化性质，即脂水分配系数（logP）和酸度系数（pKa）。该研究结果表明，母体化合物的抑制活性与脂水分配系数之间存在很强的相关性。在所研究的一系列化合物中，在决定总体抑制活性方面，疏水性似乎比酸度系数是更重要的因素。在之前的一份报告中，我们表明酸度系数在稳定由氨基磺酸酯基团水解产生的酚氧离子方面起着重要作用。在此，我们提出，虽然在考虑多种化合物时酸度系数是决定总体抑制活性的一个重要因素，但在设计硫酸雌酮酶潜在抑制剂时，疏水性和酸度系数都需要考虑。
