伊马替尼是目前治疗慢性粒细胞白血病（Chronic myeloid leukemia，CML）的一线药物，但容易耐药，而临床上针对此问题的药物选择性很少，故寻找逆转CML伊马替尼耐药的先导化合物很有必要。本项目前期确证了无明显细胞毒活性的莲子心总生物碱具有增强伊马替尼抑制K562/G01细胞增殖的作用，且发现其中甲基莲心碱能明显增强伊马替尼对CML原代细胞的敏感性。在此基础上，以LC-DAD-MS/MS技术为指导，综合运用制备高速逆流色谱、制备HPLC等分离手段以及NMR、X-射线单晶衍射等鉴定技术，通过活性跟踪对总生物碱的化学成分进行深入系统研究，并且采用逆转录实时定量荧光PCR（Real-time qPCR）法在多个基因靶点上研究强活性苄基异喹啉生物碱逆转CML伊马替尼耐药机制，期望发现结构新颖，活性强的先导化合物，为创新药物研究和开发奠定基础。

Imatinib is now the first-line drug to treatment of chronic myeloid leukemia (CML). On account of resistance and few drugs to reverse its resistance in clinically, it is indispensable to hunter for lead compounds to reverse imatinib resistance in CML. In our previous studies, it was confirmed that the total alkaloid without significant cytotoxic activity in embryo of the seed of Nelumbo nucifera GAERTN. can enhanced imatinib on the inhibition to proliferation of K562/G01 cell, and that neferine can significantly enhanced the sensitivity of imatinib to CML primitive cell. Based on the previous study and guided by the LC-DAD-MS/MS, we systematically study on the chemical composition of total alkaloid by activity guided with integrated use of various separation methods and kinds of identification technologies, such as preparative high speed countercurrent chromatography, preparative HPLC, NMR, and X-ray crystallography. This project adopts the reverse transcription real-time fluorescent quantitative PCR (Real-time qPCR) method to clarify the activity mechanism of benzylisoquinoline alkaloids with strong activity for reversing imatinib resistance in CML on multi-gene targets, expecting to find lead compounds with novel structure and strong activity, and to lay the foundation for innovative drug research and development.