| 刘洋,王皓,刘璐,等.抗流感病毒吲哚并喹啉硼酸化合物IQB-6的合成工艺及稳定性研究[J].中国海洋药物,2024,43(2):11-22. |
| 抗流感病毒吲哚并喹啉硼酸化合物IQB-6的合成工艺及稳定性研究 |
| Study on the synthesis process and stability of anti-influenza virus indoloquinoline boronic acid compound IQB-6 |
| 投稿时间：2023-01-11 修订日期：2023-04-19 |
| DOI：10.13400/j.cnki.cjmd.2024.02.006 |
| 中文关键词: 生物碱 硼酸 工艺研究 溶解度 稳定性 |
| English Keywords:alkaloids boronic acid synthesis technology solubility stability |
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| 中文摘要: |
| 目的 吲哚及喹啉类海洋生物碱具有独特的结构和优秀的生物活性，获得了药物化学家的广泛关注。课题组近年对海洋来源的吲哚类生物碱进行了大量研究，在此基础上发现了一个具有优秀体内外抗流感病毒活性的吲哚并喹啉硼酸候选化合物IQB-6，为了对该候选分子提供制剂、药效及药代动力学等方面的指导，遂对IQB-6进行了合成工艺、溶解性及稳定性研究。方法 首先，针对物料当量比、溶剂量、反应时间、反应温度、后处理及纯化方法等一系列反应条件，进行合成工艺优化，提高IQB-6收率及纯度；其次，测试了IQB-6在正己烷、水、乙醇、二甲基亚砜（DMSO）等八种溶剂中的溶解性；最后，考察了IQB-6在高温、高湿、光照、酸、碱及氧化条件下的稳定性，并且测试了其在人工胃液、肠液及体外大鼠血浆中的稳定性。结果 通过七步反应得到纯度大于99%的IQB-6产物，总收率可达到25%；溶解性研究表明，IQB-6在DMSO中溶解性最好，在其它有机溶剂中均有一定的溶解性，在水中最差；此外，在高温、高湿、光照等条件下的稳定性研究发现IQB-6具有一定的稳定性。结论 优化后的工艺成本低、易操作，便于放大。IQB-6的溶解特性，可为进一步的制剂研究提供指导。IQB-6理化性质稳定，便于储藏、运输和给药，相关稳定性试验则为后期的质量标准、药代动力学等研究提供一定的指导。 |
| English Summary: |
| Indole-drived and quinoline-drived marine alkaloids have attracted more and more attention of pharmaceutical chemists for their unique structures and excellent biological activities. In recent years our group has done a significant amount of research on indole alkaloids from Marine sources and based on this we have found a candidate compound IQB-6 of indolequinoline boronic acid with excellent anti-influenza virus activity in vitro and in vivo. In this paper, in order to provide guidance on the dosage form, pharmacodynamics and pharmacokinetics of indolequinoline boronic acid candidate IQB-6 with excellent activity of anti-influenza virus, the synthetic process, solubility and stability of IQB-6 were studied. Methods Firstly, for purpose of improving the yield and purity of IQB-6, a series of reaction conditions were optimized by controlling the material equivalent ratio, solvent volume, reaction time, reaction temperature, post-treatment and purification methods. Secondly, the solubility of IQB-6 in eight solvents such as n-hexane, water, ethanol and DMSO was tested. Finally, the stability of IQB-6 solid under high temperature, high humidity, light, acid, alkali and oxidation conditions was investigated, and the stability of IQB-6 solid in artificial gastric and intestinal fluids, plasma of SD rats was tested. Results The IQB-6 product with purity greater than 99% was obtained through seven steps, and the overall yield was 25%. Studies on the solubility of IQB-6 in organic solvents mentioned above showed that the solubility of IQB-6 in DMSO was the best and that in water was the worst, and it only had a certain solubility in others. In addition, stability studies under high temperature, high humidity, light and other conditions found that IQB-6 solid has a certain stability. Conclusion The optimized process had the advantages of low cost, simple operation and simple amplification. The dissolution characteristics of IQB-6 could provide guidance for further preparation research. The physical and chemical properties of IQB-6 are stable, which is convenient for storage, transportation and administration. The relevant stability test can provide certain guidance for the later quality standard and drug metabolism research. |
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