马兜铃酸类似物的构效关系：对人和大鼠性腺3β-羟基类固醇脱氢酶的抑制作用

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2025-05-24 DOI:10.1016/j.bioorg.2025.108630

Weijian Zhu , Zhuoqi Chen , Shaowei Wang , Yang Zhu , Ren-shan Ge

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引用次数: 0

摘要

马兜铃属植物在中医中用于治疗妇科疾病已有1500多年的历史。最近的药理学努力集中在开发更安全的马兜铃酸衍生物（AAs），以保持治疗效果，同时尽量减少毒性。人3β-羟基类固醇脱氢酶2 （h3β-HSD2）催化性激素和皮质类固醇前体的形成，在多囊卵巢综合征（PCOS）和库欣综合征等内分泌疾病中起重要作用。本研究旨在评价AAs对h3β-HSD2的抑制作用，并将其与大鼠睾丸3β-HSD1进行比较。对h3β-HSD2的抑制强度为AAB (IC50, 18.31 μM)；马兜铃内酰胺I (28.52 μM) >；AAC (39.73 μM) >；Aad （164.76 μm）对大鼠3β-HSD1的抑制强度为AAB (IC50, 17.52 μM)；AAI (31.37 μM) >；AAC (37.32 μM) >；马兜铃酮（89.66 μM）；对接表明，所有化学物质都以混合模式结合到NAD+结合位点。AAs剂量依赖性地抑制KGN细胞P4合成，ALI在100 μM下无细胞毒性。总的来说，本研究确定了AAs是h3β-HSD2和r3β-HSD1的有效抑制剂，这些酶与PCOS和库欣综合征的病理生理有关。安全的基于aas的内分泌疾病治疗方法是可以实现的。

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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.

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来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.