Structure-activity relationship and mechanistic study of organotins as inhibitors of human, pig, and rat gonadal 38-hydroxysteroid dehydrogenases

Organotins have been widely used in various industrial applications. This study investigated the structureactivity relationship as inhibitors of human, pig, and rat gonadal 38-hydroxysteroid dehydrogenases (38-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 38-HSD2 with IC50 values of 114.79, 106.98, and 5.40 mu M, respectively. For pig 38-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 mu M, respectively. Similarly, for rat 38HSD1, dipropyltin, diphenyltin, triethyltin, tributyltin, and triphenyltin displayed inhibitory activity with IC50 values of 81.35, 43.56, 55.55, 4.09, and 0.035 mu M, respectively. They were mixed inhibitors of pig and rat 38HSD, while triphenyltin was identified as a competitive inhibitor of human 38-HSD2. The mechanism underlying the inhibition of organotins on 38-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 38-HSD. The mechanistic investigation suggests that these compounds likely exert their inhibitory effects through binding to cysteine residues in the catalytic sites.