中文摘要：

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。

英文摘要：

In the present study, 15 derivatives of protoberberine （3 - 17） along with berberine （ 1 ） and jatrorrhizine （2） were evaluated for their antineoplastic activities against acute lymphoid leukemia ceils （ including Reh and Nalm - 6 cells） in terms of proliferation inhibition. Compounds 4 （9 - bromoethylberberine）, 5 （9 - chloroethyl- berberine） and 6 （9 -bromopropylberberine） showed most significant inhibitory activities with IC50 values of 0.45, 0. 39, and 0.57 μmol/L against Reh cells, while Nalm - 6 cells were less sensitive to 4, 5, 6, with IC50 values of 3.6, 4. 3 and 1.17 μmol/L, respectively, which were both stronger than that of the lead compound berberine （1） and jatrorrhizine （2） （ 〉 20 μmol/L, respectively）. Furthermore, 4 and 5 could induce apoptosis in acute lymphoid leukemia cells as evidenced by cleavage of PARP in a dose-dependent manner, decrease of procaspase - 3, increase of active caspase - 3 and increase of the levels of cytochrome c in cytoplasm. Moreover, the Reh cells treated with 4 and 5 at the concentration of 0. 5 μmol/L for 36 h could significantly lead to the down regulation of β-catenin, and the result demonstrated that the mechanism of the derivatives on tumor were partially involved in the Wnt/ β-catenin signal pathway. A PAMPA permeability study of 1, 4, 5, 7 and 11 suggested that side chain substituted derivatives in 9 - position could improve the membrane permeability of berberine. It will be helpful for application in vivo assay. These findings suggest that these derivertives may be considered for future studies as promising therapeutic candidate for acute lymphoid leukemia.