摘要:
去氢骆驼蓬碱是一种β-咔啉类生物碱,能够显著地抑制秀丽隐杆线虫let-60(n1046gf)的多产卵器表型,具有治疗胰腺癌的潜在能力.本研究采用超高效液相色谱-四极杆-飞行时间质谱(UPLC-Q-TOF MS)法分析去氢骆驼蓬碱,确定其可能的裂解途径及特征碎片离子,同时研究其单体在线虫体内的代谢产物,并对给药后不同时间点的线虫成虫体内去氢骆驼蓬碱的含量进行半定量分析.结果显示,去氢骆驼蓬碱的裂解途径主要为RDA裂解,包括甲基、羟基等基团的丢失以及吲哚环的开裂.在电喷雾正离子模式下,检测到去氢骆驼蓬碱(m/z 213)的去甲基化(m/z 199)、羟基化(m/z 229)的代谢产物.半定量分析结果表明:0～5 h,线虫代谢旺盛,线虫体内去氢骆驼蓬碱的含量下降约80%;5 h后,代谢速率减慢.该方法适用于去氢骆驼蓬碱在线虫体内代谢产物的研究,能够为去氢骆驼蓬碱治疗胰腺癌的新药研发提供数据支持.
Abstract:
Harmine is one of β-carboline alkaloid that significantly inhibits the multivulva phenotype of let-60(n1046gf), a worm called Caenorhabditis elegans.Therefore, harmine has an important potential application in pancreatic cancer.Metabolic research in vivo is one of the important ways of pharmacodynamic substance research, which can illuminate the existent form medicine in vivo and confirm the real active constituent of medicine.The fragmentation pathway of harmine was analyzed by ultra performance liquid chromatography-quadrupole-time of flight mass spectrometry (UPLC-Q-TOF MS), and the possible fragmentation pathways and characteristic fragment ions were determined.The metabolites of harmane in Caenorhabditis elegans were studied by UPLC-Q-TOF MS.The MRM data acquisition model was used to study the content of harmine in the nematode worms at different time after administration by the semi-quantitative analysis.The results show that the fragment pathways of harmine are mainly RDA cleavage, including the loss of methyl groups and hydroxyl groups, and the cracking of indole ring.The metabolites of demethylated (m/z 199) and hydroxylated (m/z 229) of harmine (m/z 213) were detected in positive ion mode.The results of semi-quantitative study show that the metabolism of nematodes is strong in 0-5 h, and the content of harmine is decreased by about 80%, the metabolism rate slows down after 5 h.The study can lay the foundation for the development of new drugs for the treatment of pancreatic cancer.
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