一氧化氮供体型烷氧基联苯化合物的合成及抗肿瘤活性  

Synthesis and antitumor activity of NO-releasing alkoxylbiphenyl derivatives

作　　者：谷小珂[1,2] 唐孝波[2] 黄张建[2] 彭晖[3] 张奕华[2] 

机构地区：[1]徐州医学院江苏省新药研究与临床药学重点实验室,徐州221004 [2]中国药科大学新药研究中心,南京210009 [3]军事医学科学院卫生学环境医学研究所,天津300050

出　　处：《中国药科大学学报》2014年第6期657-661,共5页Journal of China Pharmaceutical University

基　　金：国家自然科学基金资助项目(No.81402789)~~

摘　　要：基于药物设计的拼合原理,将一氧化氮(NO)供体片段联接到烷氧基联苯结构中,设计、合成了一系列NO供体型烷氧基联苯化合物。采用MTT法评价了目标化合物对人肝癌细胞系Hep G-2、Bel-7402、SMMC-7721、QGY-7701及Bel-7404的增殖抑制作用。结果表明,目标化合物(4a^4g)对5种肝癌细胞均呈现出较好的抑制作用,其中对Hep G-2的活性最强(IC50=1.15~4.34μmol/L)。值得注意的是,除化合物4f外,其他化合物对正常肝细胞LO2的抑制作用较小(IC50=5.00~8.53μmol/L),提示NO供体型烷氧基联苯化合物对肝肿瘤细胞具有一定的选择性。此外,化合物4b对敏感及耐药的K562细胞均具有显著的增殖抑制作用,其IC50分别为1.32和1.28μmol/L。加入NO清除剂后,化合物4b的抑制活性显著降低,提示该化合物释放的NO对其抗肿瘤活性具有重要贡献。A series of NO-releasing alkoxylbiphenyl derivatives（ 4a-4g） were designed and synthesized by coupling the carboxyl group of alkoxylbiphenyl with NO donor. Their antitumor activities were evaluated by MTT assay in Hep G-2,Bel-7402,SMMC-7721,QGY-7701 and Bel-7404 cell lines. The results indicated that the target compounds exhibited significant inhibitory effects on the proliferation of tumor cells,especially on Hep G-2 cells（ IC50= 1. 15-4. 34 μmol / L）. Notably,the inhibitory effect of the target compounds on non-tumor liver LO2 cells was relatively weak（ IC50= 5. 00-8. 53 μmol / L） except compound 4f, suggesting that these compounds have selective inhibitory effects on tumor cells in vitro. Additionally,compound 4b could significantly inhibit the parental sensitive K562 and drug-resistant K562 / A02 cell proliferation, and the IC50 s were 1. 28 and 1. 32 μmol / L,respectively. Importantly,treatment with various concentrations of an NO scavanger significantly reduced the antitumor activity of compound 4b,suggesting that NO produced by compound 4b may play a significant role in inhibiting the proliferation of K562 and K562 / A02 cells.

关 键 词：一氧化氮供体 烷氧基联苯 抗肿瘤活性 肿瘤多药耐药 

分 类 号：R914.5[医药卫生—药物化学] R965[医药卫生—药学]