新合成的7-氮杂异靛蓝的体内外抗肿瘤作用

The Antitumor Effect of a Novel 7-azaisoindigo in vitro and in vivo

对新合成的7-氮杂靛玉红类衍生物N／-（正-丁基）-7．氮杂异靛蓝[N1-（n-butyl）-7-azaisoindigo，7-AI—b1的体内外抗肿瘤作用的研究，为研发具有自主知识产权的靛玉红类抗肿瘤新药打下基础。以不同浓度的7．AI—b作用于肿瘤细胞，MTT法检测细胞活性；建立Heps／J5-癌荷瘤小鼠模型，评价7．AI_b的体内抗肿瘤作用；计算肝脏指数（1iverindex，LI）、胸腺指数（thymus index，TI）、脾脏指数（spleen index，sIL评价化合物的毒副作用；紫外法检测小鼠血清丙二醛（malondialdehyde，MDA）、谷胱甘hk（glutathione，GSH）的含量；HE染色观察肿瘤组织的变化；试剂盒检测细胞周期激酶（cyclin—dependent kinases，CDKs）的活性。结果发现，7-AI-b抑制肿瘤细胞增殖的Ic50值为28～40gmol／L，并以时间和剂量依赖性方式抑＊~]A549细胞的增殖。7-AI—b对Heps肝癌具有抑制作用且抑瘤率达到61．85％，与5-Fu~J相近；而7一AI—b对于小鼠的毒副作用明显小于后者，表现为体重正常增长，TI、sI和LI均无明显降低；等剂量的7．AI．b效果也明显优于靛玉红；并且7-AI山能增强荷瘤小鼠的抗氧化能力，使得MDA水平降低，GSH水平升高。另外，7-AI—b对于正常肝细胞株WRL-68和肝癌细胞HepG．2的毒性作用有明显差别，即具有一定的肿瘤细胞选择性。然而，7-AI—b对CDK2／cyclinA的抑制作用较弱。由此，7-AI—b可有效地抑制肿瘤的生长，且毒副作用较小，其机制可能与抑制细胞周期激酶CDKs有关，所以7-AI—b可以作为新型抗肿瘤药物进行研究。

The anticancer effect of a newly synthesized 7-azaisoindigo derivative （namely Nl-（n- butyl）-7-azaisoindigo, 7-AI-b） in vitro and in vivo were investigated, and the underlying mechanism of action was analyzed, which will be helpful for developing new anticancer agents with self-dominated intellectual property right. Cells proliferation was detected by MTT assay. The activity of 7-AI-b against human hepatoma carcinoma （Hepes） xenografts was examined. The thymus index （TI）, spleen index （SI） and liver index （LI） were calculated. The quantity of malondialdehyde （MDA） and glutathione （GSH） in the serum were measured by the MDA and GSH kits. HE staining was used to observe the tumor tissue. The activity of the cyclindependent kinases （CDKs） was measured by kit. It was found that the IC50 of 7-AI-b on different cells were between 28-40 ~tmol/L. 7-AI-b exhibited significant inhibition on cancer cell proliferation, especially on A549 cell proliferation in a dose- and time-dependent way. The anticancer activity of 7-AI-b against human hepatoma carcinoma （Heps） xenografts was comparable to that of 5-Fu and superior to indirubin standard substance, which was reached to 61.85%. 7-AI-b caused no significant adverse effects showing that the body weight grew commonly, and the TI, SI and LI were not decreased significantly. Also, 7-AI-b could elevate the oxidation resistance of the tumor-baring mice indicated by the quantity of MDA decrease and GSH increase. In addition, 7-AI-b showed significantly stronger cytotoxicity on cancer cells HepG-2 than normal cells WRL-68. However, it exerted low inhibited effect on the CDK2/cyclinD. These data suggest that 7-AI-b inhibits proliferation of human cancer cells in vitro and human hepatoma cancer xenograft in vivo. Also it has selective antitumor effects, and the mechanism may be related to inhibit the CDKs. So it would be a potential antitumor candidate.