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NO供体型大黄酸衍生物的合成及抗肿瘤活性

Synthesis and antitumor activities of NO-donating rhein derivatives

  • 摘要: 以大黄酸为原料,利用其羧基通过不同的连接臂与呋咱氮氧化合物偶联,得到7个NO供体型大黄酸衍生物,其结构经红外光谱、核磁共振氢谱和质谱确证。采用MTT法测试了目标化合物对人肝癌细胞HepG2、Bel-7402,人结肠癌细胞HCT116,人骨肉瘤细胞U2OS,耐药细胞Bel-7402/5-FU及正常肝细胞LO2的体外抗细胞增殖活性。结果显示,所有目标化合物对受试的肿瘤细胞和耐药细胞均具有较强的增殖抑制活性,其中化合物4g对人肝癌细胞HepG2、Bel-7402,人骨肉瘤细胞U2OS及耐药细胞Bel-7402/5-FU具有强的增殖抑制活性,而且对正常细胞影响很小,表现出较好的选择性。采用Griess法测定了目标化合物4g在肿瘤细胞HepG2中对NO释放的影响。结果表明,化合物4g在细胞中能释放高浓度的NO,其抗肿瘤作用可能与NO的释放相关。NO清除剂验证实验表明,化合物4g的抗肿瘤活性部分来自于NO的释放。

     

    Abstract: Seven target compounds coupled by rhein and furoxan were synthesized and their chemical structures were confirmed by 1H NMR, IR, and MS. All target compounds were evaluated for anti-proliferative activity against human hepatoma cells HepG2 and Bel-7402, human colon cancer cells HCT116, human osteosarcoma cells U2OS, drug-resistant cells Bel-7402/5-FU and normal hepatocytes cells LO2 in vitro by thiazolyl blue(MTT) colorimetry. The results indicated that all target compounds had more potent anti-proliferative activity than their parent compound rhein. Additionally, compound 4g had stronger proliferation inhibitory activity on HepG2, Bel-7402, U2OS and Bel-7402/5-FU,with little effect on the proliferation of normal cells, exhibiting selective inhibitory activity. Griess assay was used to measure the release of nitric oxide in vitro. Results showed that compound 4g could increase the releases NO in HepG2 cells, which may be associated with its antitumor effects. Furthermore, the antitumor activity of compound 4g was attenuated by NO scavenger (hemoglobin), which indicates that the antitumor activity of compound 4g may be partly related to the release of NO.

     

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