β-卡巴林-肉桂酸骨架化合物B4的合成、含量测定和稳定性研究  

The synthesis,content determination and stability study of a β-carboline-cinnamic acid skeleton compound B4

作　　者：关丽 陈嘉欣 宋鹏飞 赵惠茹[1] 夏焱鑫 张胜杰 李伟泽[1] GUAN Li;CHEN Jia-xin;SONG Peng-fei;ZHAO Hui-ru;XIA Yan-xin;ZHANG Sheng-jie;LI Wei-ze(College of pharmacy,Xi an Medical University,Xi an 710021,China;School of Pharmaceutical Engineering,Shenyang Pharmaceutical University,Shenyang 110016,China)

机构地区：[1]西安医学院药学院,西安710021 [2]沈阳药科大学制药工程学院,沈阳110016

出　　处：《中国新药杂志》2025年第7期771-777,共7页Chinese Journal of New Drugs

基　　金：陕西省科技厅资助项目(2023-JC-QN-0827);西安市科协青年人才托举资助项目(959202413082);西安医学院科技创新团队配套资助项目(2021TDPT04);西安医学院大学生创新创业资助项目(121523038,121524024);西安医学院2022年度科研能力提升计划资助项目(2022NLTS059,2022NLTS075);陕西省教育厅项目(24JP172);西安市科技局项目(2025JH-ZRKX-0429)。

摘　　要：目的:合成β-卡巴林-肉桂酸骨架化合物B4,对其进行含量测定、人工胃肠液稳定性研究及溶血性评价。方法:以5-甲氧基色胺为原料,通过Pictet-spengler反应合成卡巴林,并与4-氯肉桂酸缩合反应形成目标化合物;利用HPLC法对化合物B4进行定性定量分析,优化色谱条件,并进行方法学验证,利用该检测方法对其在模拟人工肠胃液中的稳定性进行考察;并对该化合物B4进行溶血性评价。结果:化合物B4通过^(1)H-NMR,^(13)C-NMR和ESI-MS确定其结构,最佳色谱条件为色谱柱YMC-Pack ODS-A色谱柱(250 mm×4.6 mm,5μm),甲醇∶水=90∶10,等度洗脱,流速1.0 mL·min^(-1),检测波长278 nm。该方法线性范围为1~100μg·mL^(-1),线性方程为y=126.96x+199.85(R^(2)=0.9994),平均回收率为104%。该化合物甲醇溶液在25℃下24 h内保持稳定;在酸性的人工胃液中不稳定,在0 min被迅速降解至消失,而在人工肠液中相对稳定,缓慢降解,直至150 min后降解完全。同时化合物B4在溶血性试验中显示无肉眼可见溶血及凝集现象,符合《中华人民共和国药典》相关规定。结论:建立了化合物B4的完整含量测定方法,其作为一种新合成的创新小分子在碱性溶液比在酸性溶液中稳定。Objective:To synthesize the β-carboline-cinnamic acid skeleton compound B4,a new method for its determination was established and the stability and hemolytic characteristic of B4 were evaluated.Methods:β-Carboline was synthesized by the Pictet-Spengler reaction using tryptamine as the raw material.Subsequently,the β-carboline-cinnamic acid compound B4 was synthesized by the condensation reaction of β-carboline and 4-chlorocinnamic acid.Compound B4 was qualitatively and quantitatively analyzed by HPLC,with optimization of chromatographic conditions performed alongside methodological verification.The stability of compound B4 in simulated gastric and intestinal fluid was assessed using this detection method.The hemolytic evaluation of compound B4 was conducted in accordance with the relevant provisions of the hemolytic and coagulation test method.Results:The structural determination of compound B4 was conducted using ^(1)H-NMR,^(13)C-NMR,and ESI-MS.The optimal chromatographic conditions were established as:YMC-Pack ODS-A column(250 mm×4.6 mm,5 μm),with a mobile phase of methanol and water at V(methanol)∶V(water) of 90∶10,employing iso-degree elution at a flow rate of 1.0 mL·min^(-1) and detection wavelength of 278 nm.The linear range of the method was 1~100 μg·mL^(-1).The linear equation was y=126.96x+199.85(R^(2)=0.999 4).And the average recovery rate was 104%.The methanol solution of the compound remained stable for at least 24 h at 25 ℃.Compound B4 was unstable in acidic artificial gastric fluid where it rapidly degraded,while it was relatively stable and slowly degraded in artificial intestinal fluid until it was completely degraded after 150 min.At the same time,the hemolytic test of the compound B4 showed no visible hemolysis and coagulation phenomenon,thereby complying with the relevant provisions of pharmacopoeia.Conclusion:A method for content determination of compound B4 was established,which is a newly synthesized innovative small molecule.B4 exhibits greater stability in alkaline solution

关 键 词：β-卡巴林-肉桂酸骨架化合物 合成 含量测定 HPLC法 人工胃肠液 溶血试验 

分 类 号：R917[医药卫生—药物分析学]