Structure activity relationship of Aristolochic acid analogues: Inhibitory effect on human and rat gonadal 3β-Hydroxysteroid dehydrogenases.

Aristolochia species have been used in traditional Chinese medicine for over 1500 years to treat gynecological disorders. Recent pharmacological efforts focus on developing safer aristolochic acid derivatives (AAs) to retain therapeutic efficacy while minimizing toxicity. Human 3β-hydroxysteroid dehydrogenase 2 (h3β-HSD2) catalyzes the formation of precursors for sex hormones and corticosteroids, which play critical role in endocrine disorders such as polycystic ovary syndrome (PCOS) and Cushing's syndrome. This study aimed to evaluate AAs for their inhibitory effects on h3β-HSD2 and compared it with rat testicular 3β-HSD1. The inhibitory strength on h3β-HSD2 was AAB (IC50, 18.31 μM) > aristololactam I (28.52 μM) > AAC (39.73 μM) > AAD (164.76 μM). The inhibitory strength on rat 3β-HSD1 was AAB (IC50, 17.52 μM) > AAI (31.37 μM) > AAC (37.32 μM) > aristolone (89.66 μM). Docking showed that all chemicals bind to NAD+-binding site with the mix mode. AAs dose-dependently inhibited P4 synthesis in KGN cells, and ALI showed no cytotoxicity even at 100 μM. Overall, this study identifies AAs as potent inhibitors of h3β-HSD2 and r3β-HSD1, enzymes implicated in the pathophysiology of PCOS and Cushing's syndrome. Safe AAs-based therapeutics for endocrine disorders may be achievable.