Abstract：
Organotins have been widely used in various industrial applications. This study investigated the structure-activity relationship as inhibitors of human, pig, and rat gonadal 3β-hydroxysteroid dehydrogenases (3β-HSD). Human KGN cell, pig, and rat testis microsomes were utilized to assess the inhibitory effects of 18 organotins on the conversion of pregnenolone to progesterone. Among them, diphenyltin, triethyltin, and triphenyltin exhibited significant inhibitory activity against human 3β-HSD2 with IC50 values of 114.79, 106.98, and 5.40 μM, respectively. For pig 3β-HSD, dipropyltin, diphenyltin, triethyltin, tributyltin, and triphenyltin demonstrated inhibitory effects with IC50 values of 172.00, 100.19, 87.00, 5.75, and 1.65 μM, respectively. Similarly, for rat 3β-HSD1, dipropyltin, diphenyltin, triethyltin, tributyltin, and triphenyltin displayed inhibitory activity with IC50 values of 81.35, 43.56, 55.55, 4.09, and 0.035 μM, respectively. They were mixed inhibitors of pig and rat 3β-HSD, while triphenyltin was identified as a competitive inhibitor of human 3β-HSD2. The mechanism underlying the inhibition of organotins on 3β-HSD was explored, revealing that they may disrupt the enzyme activity by binding to cysteine residues in the catalytic sites. This proposition was supported by the observation that the addition of dithiothreitol reversed the inhibition caused by all organotins except for triethyltin, which was partially reversed. In conclusion, this study provides valuable insights into the structure-activity relationship of organotins as inhibitors of human, pig, and rat gonadal 3β-HSD. The mechanistic investigation suggests that these compounds likely exert their inhibitory effects through binding to cysteine residues in the catalytic sites.
摘要：
有机锡已广泛用于各种工业应用中。这项研究调查了作为人类抑制剂的结构-活性关系，猪,和大鼠性腺3β-羟基类固醇脱氢酶（3β-HSD）。人KGN细胞,猪,和大鼠睾丸微粒体用于评估18种有机锡对孕烯醇酮转化为孕酮的抑制作用。其中,二苯基锡,三乙基锡,和三苯基锡对人3β-HSD2表现出明显的抑制活性，IC50值为114.79、106.98和5.40μM，分别。对于猪3β-HSD，二丙基锡,二苯基锡,三乙基锡,三丁基锡,和三苯基锡表现出抑制作用，IC50值为172.00、100.19、87.00、5.75和1.65μM，分别。同样，对于大鼠3β-HSD1，二丙基锡，二苯基锡,三乙基锡,三丁基锡,三苯基锡显示出抑制活性，IC50值为81.35、43.56、55.55、4.09和0.035μM，分别。它们是猪和大鼠3β-HSD的混合抑制剂，而三苯基锡被确定为人3β-HSD2的竞争性抑制剂。探索了有机锡抑制3β-HSD的潜在机制，揭示它们可能通过与催化位点的半胱氨酸残基结合来破坏酶活性。观察到添加二硫苏糖醇逆转了除三乙基锡以外的所有有机锡引起的抑制作用，这一观点得到了支持。这是部分逆转的。总之,这项研究为有机锡作为人类抑制剂的结构-活性关系提供了有价值的见解，猪,和大鼠性腺3β-HSD。机理研究表明，这些化合物可能通过与催化位点中的半胱氨酸残基结合而发挥其抑制作用。
