设计,合成和生物评估含硫的epicaryolane衍生物作为FXR激活剂
Ji-Long Zou1, Da-Yu Shi1, Yi-Zhou Xiang2
1Shanghai Frontiers Science Center for TCM Chemical Biology, Innovation Research Institute of Traditional Chinese Medicine and School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Bioorganic chemistry
|January 28, 2026
概括
这项研究引入了一种新的仿生反应,以制造含硫的epicaryolane衍生物. 这些化合物显示出作为Farnesoid X受体 (FXR) 激动剂的前景,具有潜在的肝保护作用.
科学领域:
- 有机化学 有机化学
- 药用化学 医学化学
- 合成化学 合成化学
背景情况:
- (-) -β-糖烯是一种具有反应性碳酸介质的天然基烯.
- 开发高效的合成路径以获得新型衍生品对于药物发现至关重要.
- 含硫化合物往往表现出显著的生物活性.
研究的目的:
- 开发一种生物模拟的碳酸捕获反应,用于合成卡里奥兰衍生物.
- 评估合成的化合物对法尔内索伊德X受体 (FXR) 激素活性和肝脏保护作用的评估.
- 探索这些衍生品的多样化进入潜在的药理活性支架.
主要方法:
- 一种生物仿真反应,涉及 (-) -β-卡里奥菲伦和各种类硫醇/硫酸盐.
- 合成的硫和硫衍生物的特征,包括绝对配置.
- 在体外评估FXR激活剂活性和肝保护作用.
主要成果:
- 在温和的条件下有效合成基于epicaryolane的thioether和sulfone衍生物.
- 鉴定一种具有强大的FXR激活 (EC50 = 2.2μM) 的2-基替代硫乙烯.
- 证明氧化为硫,增强水友性,同时保持生物活性,并转化为共价核弹头.
结论:
- 建立了一个简洁而有效的战略,用于合成和多样化含硫的epicaryolane衍生物.
- 合成的衍生品表现出有前途的FXR激动剂活性和肝脏保护潜力.
- 这些化合物代表了开发新疗法的多功能支架.
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