有机化学 ›› 2024, Vol. 44 ›› Issue (7): 2305-2314.DOI: 10.6023/cjoc202312002 上一篇    下一篇

研究论文

25-羟基胆固醇及其类似物的合成与抗神经炎活性研究

蓝柳淞, 杨倩, 李永怡, 方淑君, 黄宇轩, 苏骏成*(), 潘成学*, 苏桂发*   

  1. 广西师范大学化学与药学学院 省部共建药用资源化学与药物分子工程国家重点实验室 广西桂林 541004
  • 收稿日期:2023-12-03 修回日期:2024-02-27 发布日期:2024-07-25
  • 作者简介:
    † 共同第一作者.
  • 基金资助:
    国家自然科学基金(81960638); 国家自然科学基金(82160656); 国家自然科学基金(82360695)

Synthesis and Anti-neuroinflammatory Activities of 25-Hydroxycholesterol and Its Analogues

Liusong Lan, Qian Yang, Yongyi Li, Shujun Fang, Yuxuan Huang, Juncheng Su(), Chengxue Pan, Guifa Su   

  1. School of Chemistry and Pharmaceutical Sciences/State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Guilin, Guangxi 541004
  • Received:2023-12-03 Revised:2024-02-27 Published:2024-07-25
  • Contact: E-mail: gfysglgx@163.com
  • About author:
    † These authors contributed equally to this work.
  • Supported by:
    National Natural Science Foundation of China(81960638); National Natural Science Foundation of China(82160656); National Natural Science Foundation of China(82360695)

25-羟基胆固醇(25HC)具有许多重要的生物活性, 也是合成骨化二醇、骨化三醇等药物的关键中间体, 开发其原料易得、工艺简单以及易于放大的新合成路线具有重要意义. 以廉价易得的猪去氧胆酸为原料, 经羟基酯化、脱羧碘代、与α-酮酸酯反应进而水解脱羧、羟基磺酸酯化及消除, 最后与格氏试剂反应共6步反应合成了3个25-羟基胆固醇及其类似物, 总产率为20.8%~23.0%. 新路线操作简单、易于放大, 有望进一步发展成工业化合成路线. 通过改变酮酸酯及格氏试剂可方便地得到不同的25-羟基胆固醇类似物. 合成所得到的15个化合物中, 有9个是新的化合物. 对15个化合物进行生物活性研究, 结果表明, 26,27-二乙基胆甾-5-烯-3β,25-二醇(8c)具有良好的抗神经炎活性, 可通过抑制核转录因子(NF-κB)和丝裂原活化蛋白激酶(MAPK/JNK)信号通路, 抑制LPS(脂多糖)诱导的小鼠小胶质瘤细胞(BV-2)细胞释放NO、下调白细胞介素6 (IL-6)、肿瘤坏死因子α (TNF-α)、白细胞介素1β (IL-1β)等炎症因子的信使核糖核酸(mRNA)水平, 表明8c是有潜力的抗神经炎症的化合物.

关键词: 25-羟基胆固醇, 25-羟基胆固醇类似物, 合成, 抗神经炎活性

25-Hydroxycholesterol (25HC) has many important biological activities and is also a key intermediate for the synthesis of calcifediol, calcitriol, etc. It is of great significance to develop a new synthetic route which is easy to available raw materials, simple process, and easy to scale up. In this report, three 25-hydroxycholesterol and its analogues were synthesized from hyodeoxycholic acid via esterification of hydroxyl groups, decarboxylation iodization of carboxyl groups, ketonic hydrolysis after nucleophilic substitution with α-ketoester, sulfonate esterification then elimination, and finally reaction with Grignard reagent. The total yield was 20.8%~23.0%. The new route is simple to operate and easy to scale up, and is expected to be further developed into an industrial synthetic route. Similar analogues of 25-hydroxycholesterol can be easily prepared by changing α-ketoesters and Grignard reagents. Among the 15 compounds synthesized, there are 9 new compounds. Their biological activities were evaluated. The results showed that 26,27-diethylcholest-5-ene-3β,25-diol (8c) has good anti-neuritis activity and can inhibit NO release from LPS (lipopolysaccharides)-induced BV-2 (mouse microglia) cells by inhibiting Nuclear Factor kappa-B (NF-κB) and Mitogen-activated protein kinase/c-Jun N-terminal Kinase (MAPK/JNK) signaling pathways, and down-regulating mRNA-levels of inflammatory cytokines such as Interleukin-6 (IL-6), Tumor Necrosis Factor-α (TNF-α) and Interleukin-1β (IL-1β), indicating that 8c is a potential anti-neuroinflammatory compound.

Key words: 25-hydroxycholesterol, 25-hydroxycholesterol analogues, synthesis, anti-neuritis activity