The steroid sulfatase or steryl sulfatase is a microsomal enzyme widely distributed in human tissues that catalyzes the hydrolysis of sulfated 3-hydroxy steroids to the corresponding free active 3-hydroxy steroids. Since androgens and estrogens may be synthesized inside the cancerous cells starting from dehydroepiandrosterone sulfate (DHEAS) and estrone sulfate (E(1)S) available in blood circulation, the use of therapeutic agents that inhibit steroid sulfatase activity may be a rewarding approach to the treatment of androgeno-sensitive and estrogeno-sensitive diseases. In the present study, we report the chemical synthesis and biological evaluation of a new family of steroid sulfatase inhibitors. The inhibitors were designed by adding an alkyl, a phenyl, a benzyl, or a benzyl substituted at position 17alpha of estradiol (E(2)), a C18-steroid, and enzymatic assays were performed using the steroid sulfatase of homogenized JEG-3 cells or transfected in HEK-293 cells. We observed that a hydrophobic substituent induces powerful inhibition of steroid sulfatase while a hydrophilic one was weak. Although a hydrophobic group at the 17alpha-position increased the inhibitory activity, the steric factors contribute to the opposite effect. As exemplified by 17alpha-decyl-E(2) and 17alpha-dodecyl-E(2), a long flexible side chain prevents adequate fitting into the enzyme catalytic site, thus decreasing capacity to inhibit the steroid sulfatase activity. In the alkyl series, the best compromise between hydrophobicity and steric hindrance was obtained with the octyl group (IC(50) = 440 nM), but judicious branching of side chain could improve this further. Benzyl substituted derivatives of estradiol were better inhibitors than alkyl analogues. Among the series of 17alpha-(benzyl substituted)-E(2) derivatives studied, the 3'-bromobenzyl, 4'-tert-butylbenzyl, 4'-butylbenzyl, and 4'-benzyloxybenzyl groups provided the most potent inhibition of steroid sulfatase transformation of E(1)S into E(1) (IC(50) = 24, 28, 25, and 22 nM, respectively). As an example, the tert-butylbenzyl group increases the ability of the E(2) nucleus to inhibit the steroid sulfatase by 3000-fold, and it also inhibits similarly the steroid sulfatase transformations of both natural substrates, E(1)S and DHEAS. Interestingly, the newly reported family of steroid sulfatase inhibitors acts by a reversible mechanism of action that is different from the irreversible mechanism of the known inhibitor estrone sulfamate (EMATE).

译文

类固醇硫酸酯酶或甾基硫酸酯酶是一种广泛分布在人体组织中的微粒体酶,可催化硫酸化的3-羟基类固醇水解为相应的游离活性3-羟基类固醇。由于雄激素和雌激素可以从血液循环中可用的硫酸脱氢表雄酮 (DHEAS) 和硫酸雌酮 (E(1)S) 开始在癌细胞内部合成,使用抑制类固醇硫酸酯酶活性的治疗剂可能是治疗雄激素敏感和雌激素敏感疾病的有益方法。在本研究中,我们报告了一个新的类固醇硫酸酯酶抑制剂家族的化学合成和生物学评估。通过添加在雌二醇 (E(2)) 的17α 位被取代的烷基、苯基、苄基或苄基来设计抑制剂,C18-steroid,并且使用均质化JEG-3细胞或在HEK-293细胞中转染的类固醇硫酸酯酶进行酶促测定。我们观察到疏水取代基会强烈抑制类固醇硫酸酯酶,而亲水取代基则较弱。尽管17α 位的疏水基团增加了抑制活性,但空间因子却产生了相反的作用。如17α-癸基-e (2) 和17α-十二烷基-e (2) 所示,长的柔性侧链阻止了对酶催化位点的充分拟合,从而降低了抑制类固醇硫酸酯酶活性的能力。在烷基系列中,辛基基团 (IC(50) = 440 nM) 获得了疏水性和空间位阻之间的最佳折衷,但是侧链的明智支化可以进一步改善这一点。雌二醇的苄基取代衍生物比烷基类似物更好。在研究的17种 α-(苄基取代)-E(2) 衍生物系列中,3 '-溴苄基,4'-叔丁基苄基,4 '-丁基苄基,和4'-苄氧基苄基对类固醇硫酸酯酶将E(1)S转化为E(1) 提供最有效的抑制作用 (IC(50) 分别为24、28、25和22 nM)。例如,叔丁基苄基将E(2) 核抑制类固醇硫酸酯酶的能力提高了3000倍,并且它也类似地抑制了天然底物E(1) 和DHEAS的类固醇硫酸酯酶转化。有趣的是,新报道的类固醇硫酸酯酶抑制剂家族通过可逆的作用机制起作用,该作用机制不同于已知抑制剂氨基磺酸盐雌酮 (EMATE) 的不可逆机制。

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