基于UPLC-Q-TOF-MS分析人参皂苷元新衍生物干预荷瘤小鼠的血清代谢组学特征  

Analysis of serum metabolomics characteristics of new ginsenoside derivatives in tumor-bearing mice based on UPLC-Q-TOF-MS technology

作　　者：刘芮 徐伟[1] 王彩虹 赵莹[1] 王振洲 LIU Rui;XU Wei;WANG Cai-hong;ZHAO Ying;WANG Zhen-zhou(Changchun University of Chinese Medicine,Changchun 130117,China)

机构地区：[1]长春中医药大学,长春130117

出　　处：《中国新药杂志》2023年第5期531-539,共9页Chinese Journal of New Drugs

基　　金：吉林省科技厅发展计划资助项目(20210204149YY)。

摘　　要：目的:采用糖基三氯乙酰亚胺酯法将D-核糖与拟人参皂苷元DQ半合成得到新型人参皂苷,对其体内外抗肿瘤活性以及作用机制进行研究,通过血清代谢组学分析其代谢途径及产物。方法:以D-核糖和拟人参皂苷元DQ为原料,通过化学方法合成得到新型人参皂苷衍生物,并对其进行结构鉴定;采用MTT比色法测定其对S180细胞、人肺腺癌SPC-A-1细胞、A549细胞的抗肿瘤活性以及对小鼠S180肿瘤细胞的抑制作用,基于细胞代谢组学分析探究其抗肿瘤作用机制。结果:首次通过化学方法半合成得到了新的奥克梯隆(Ocotillol)型人参皂苷,12-核糖基-拟人参皂苷DQ(12-riboside-pseudoginsengenin DQ,RPDQ),鉴定为(20S,24S)-12-O-α-D-呋喃核糖基-达玛-20,24-环氧-3β,12β,25-三醇,产率为38.6%,纯度为99.1%。MTT法检测RPDQ能够明显抑制3种肿瘤细胞的增殖;体内实验证明RPDQ对荷瘤小鼠的实体瘤有抑制作用,能够改善肿瘤细胞组织形态、降低荷瘤小鼠的脏脾和胸腺指数,延长小鼠的生存天数;代谢组学表明RPDQ通过调控花生四烯酸代谢、甘油磷脂代谢、色氨酸代谢等7个代谢途径达到抗肿瘤的作用,通过主成分分析(PCA)和正交偏最小方差判别分析(OPLS-DA)筛选鉴定出16个生物标记物,并研究出RPDQ在小鼠体内发挥抗肿瘤作用相关信号途径网络。结论:RPDQ的合成为此类人参皂苷衍生物的合成与活性研究提供了参考,RPDQ表现出较好的抗肿瘤活性,为拟人参皂苷的进一步研究与开发提供了理论和数据上的支撑。Objective:A new type of ginsenoside was semi-synthesized by D-ribose and ginsenoside DQ using glycosyl trichloroacetimide ester method.Its in vivo and in vitro anti-tumor activity and its mechanism of action were studied,and the metabolic pathways and products were analyzed by serum metabolomics.Methods:Using D-ribose and ginsenoside DQ as raw materials,new ginsenoside derivatives were synthesized by chemical methods,and their structures were identified.The effects on S180 cells,human lung adenocarcinoma SPC-A-1 cells,anti-tumor activity in A549 cells and inhibition to mouse S180 tumor cells were determined by MTT method.Its anti-tumor mechanism was explored based on cell metabolomics analysis.Results:For the first time,a new ocotillol-type ginsenoside,12-riboside-pseudoginsengenin DQ(RPDQ),was semi-synthesized by chemical methods,and was identified as(20S,24S)-12-O-α-D-ribofuranosyl-Dama-20,24-epoxy-3β,12β,25-triol,the yield is 38.6%,and the purity is 99.1%.MTT detection of RPDQ can significantly inhibit the proliferation of three kinds of tumor cells.In vivo experiments demonstrated that RPDQ inhibited solid tumors in tumor-bearing mice,improved the histomorphology of tumor cells,reduced the spleen and thymus indices in tumor-bearing mice and prolonged the survival days of mice.Metabolomics results showed that RPDQ exerted its anti-tumor effects by regulating seven metabolic pathways,including arachidonic acid metabolism,glycerophospholipid metabolism and tryptophan metabolism.Sixteen biomarkers were identified through principal component analysis(PCA)and orthogonal partial least squares discriminant analysis(OPLS-DA)screening,and a network of signaling pathways related to the anti-tumor effects of RPDQ in mice was investigated.Conclusion:The synthesis of RPDQ provides a reference for the synthesis and activity research of such ginsenoside derivatives.RPDQ shows good anti-tumor activity,which provides a theoretical basis and data support for the further research and development of pseudoginsengenin.

关 键 词：超高效液相色谱-四级杆-飞行时间串联质谱联用 抗肿瘤 代谢组学 12-核糖基拟人参皂苷元DQ 

分 类 号：R914.4[医药卫生—药物化学]