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  2. Curcumin analogues exert potent inhibition on human and rat gonadal 3β-hydroxysteroid dehydrogenases as potential therapeutic agents: structure-activity relationship and in silico docking

Curcumin analogues exert potent inhibition on human and rat gonadal 3β-hydroxysteroid dehydrogenases as potential therapeutic agents: structure-activity relationship and in silico docking

  • J Enzyme Inhib Med Chem. 2023 Dec;38(1):2205052. doi: 10.1080/14756366.2023.2205052.
Xinyi Qiao 1 Lei Ye 1 Jialin Lu 1 Chengshuang Pan 1 2 Qianjin Fei 2 Yang Zhu 1 3 Huitao Li 1 3 Han Lin 1 Ren-Shan Ge 1 3 Yiyan Wang 1 3
Affiliations

Affiliations

  • 1 Department of Anesthesiology and Perioperative Medicine, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
  • 2 Reproductive Medicine Center, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 3 Key Laboratory of Structural Malformations in Children of Zhejiang Province, Key Laboratory of Environment and Male Reproductive Medicine of Wenzhou, Wenzhou, China.
Abstract

Curcuminoids are functional food additives, and the effect on gonadal hormone biosynthesis remains unclear. Gonads contain 3β-hydroxysteroid dehydrogenase isoforms, h3β-HSD2 (humans) and r3β-HSD1 (rats), which catalyse pregnenolone into progesterone. The potency and mechanisms of curcuminoids to inhibit 3β-HSD activity were explored. The inhibitory potency was bisdemethoxycurcumin (IC50, 1.68 µM) >demethoxycurcumin (3.27 µM) > curcumin (13.87 µM) > tetrahydrocurcumin (109.0 µM) > dihydrocurcumin and octahydrocurcumin on KGN cell h3β-HSD2, while that was bisdemethoxycurcumin (1.22 µM) >demethoxycurcumin (2.18 µM) > curcumin (4.12 µM) > tetrahydrocurcumin (102.61 µM) > dihydrocurcumin and octahydrocurcumin on testicular r3β-HSD1. All curcuminoids inhibited progesterone secretion by KGN cells under basal and forskolin-stimulated conditions at >10 µM. Docking analysis showed that curcuminoids bind steroid-active site with mixed or competitive mode. In conclusion, curcuminoids inhibit gonadal 3β-HSD activity and de-methoxylation of curcumin increases inhibitory potency and metabolism of curcumin by saturation of carbon chain losses inhibitory potency.

Keywords

Curcumin analogues; curcumin metabolite; docking analysis; gonad 3β-HSD; inhibition.

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