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测定了15个原小檗碱衍生物(3-17)及小檗碱(1)和药根碱(2)抑制急性淋巴白血病细胞(包括Reh和Nalm-6细胞)增殖的活性。其中化合物4(9-溴乙基小檗碱),5(9-氯乙基小檗碱)和6(9-溴丙基小檗碱)表现出最为突出的抑制活性:在Reh细胞中,IC50值分别为0.45、0.39和0.57μmol/L;在Nalm-6细胞中,IC50值分别为3.6,4.3和1.17μmol/L。活性均强于先导化合物小檗碱和药根碱(后两者的IC50值均大于20μmol/L)。此外,化合物4和5能够剂量依赖的通过裂解PARP诱导急性淋巴白血病细胞凋亡,降低procaspase-3的浓度,增加活性caspase-3水平,同时提高细胞质中的细胞色素C水平。进一步,Reh细胞用0.5μmol/L的4和5处理36 h,能够显著下调β-catenin蛋白的表达,以上实验结果证明了这类化合物抑制肿瘤细胞增殖的作用机制可能与Wnt/β-catenin通路相关。化合物1、4、5、7和11的PAMPA膜渗透实验说明,C-9位取代的小檗碱衍生物可以提高化合物的细胞膜渗透性。
15 protoberberine derivatives (3-17) and berberine (1) and jatrorrhizine (2) were tested for their activity in inhibiting the proliferation of acute lymphoblastic leukemia cells, including Reh and Nalm-6 cells. Compounds 9 (9-bromoethylberberine), 5 (9-chloroethylberberine) and 6 (9-bromopropylberberine) showed the most prominent inhibitory activity. In Reh cells, The IC50 values were 0.45,0.39 and 0.57μmol / L, respectively. In Nalm-6 cells, the IC50 values were 3.6, 4.3 and 1.17μmol / L, respectively. Both of them were stronger than the lead compounds berberine and jatrorrhizine (IC50 values of the latter two were more than 20μmol / L). In addition, compounds 4 and 5 can induce apoptosis in acute lymphoblastic leukemia cells by cleaving PARP in a dose-dependent manner, reducing the concentration of procaspase-3, increasing the activity of caspase-3 and increasing the level of cytochrome C in the cytoplasm. Furthermore, Reh cells treated with 0.5μmol / L 4 and 5 for 36h could significantly down-regulate the expression of β-catenin protein. The above results demonstrate that the mechanism of action of these compounds on tumor cell proliferation may be related to Wnt / β-catenin pathway Related. PAMPA membrane permeation experiments of compounds 1, 4, 5, 7 and 11 demonstrated that the C-9 substituted berberine derivative can increase the cell membrane permeability of the compounds.