5-烯去甲斑蝥素氧代单乙酸及其盐的合成和抗肝癌活性

The synthesis and anti-hepatoma activity of 5-en-norcantharidin oxo-mono-acetic acid and its salt

目的为降低斑蝥素毒副作用并改善其水溶性,设计合成新型斑蝥素的衍生物及其盐。方法以呋喃为原料,与顺丁烯二酸酐在有机溶剂中反应得到5-烯去甲斑蝥素,此产物在有机溶剂中经Li Al H4还原反应得到5-烯去甲斑蝥素二醇,后者与溴乙酸乙酯反应得到5-烯去甲斑蝥素氧代单乙酸乙酯,该酯在碱性条件下水解生成相应的去甲斑蝥素氧代单乙酸及其盐。用磺酰罗丹明(sulforhodamine B,SRB)染色法对最终产物进行抗肝癌活性测试。结果新型斑蝥素的衍生物——5-烯去甲斑蝥素氧代单乙酸及其盐抗肝癌活性测试的结果表明,5-烯去甲斑蝥素氧代单乙酸及其盐的浓度5μg/m L对人肝癌细胞Hep G2具有一定抑制效果,抑制率分别为50%和65%。结论本研究方法制得的5-烯去甲斑蝥素氧代单乙酸及其盐具有一定的抗肝癌效果。

Objective A new type of norcantharidin derivatives and its salt were designed and synthesized to reduce the toxicity and improve the water solubility of the cantharidin. Methods Furan reacted with maleic anhydride to generate 5-en-norcantharidin in organic solvent In. the following,5-en-norcantharidin was reduced by lithium aluminium hydride（ Li Al H4） to afford 5-en-norcantharidin glycol; Then,using tetrahydrofuran as the solvent,5-en-norcantharidin glycol was reacted with ethyl bromoacetate in the catalysis of sodium hydride to produce 5-en-norcantharidin oxo-mono-acetate. Finally the oxo-mono-acetate was hydrolyzed in alkaline condition,to generate the target compound oxo-mono-acetic acid and its salt. Anti hepatoma activity was tested by sulforhodamine B staining method. Results The result of anti-hepatoma activity showed that the 5-en-norcantharidin oxo-mono-acetic acid and its salt had shown 50% and 65% inhibition on hepatoma Hep G2 cells respectively when its concentration of 5 μg / ml. Conclusion The 5-en-norcantharidin oxo-mono-acetic acid and its salt showed a moderate inhibition on Hep G2 cells,which can be used as a kind of high efficiency and low toxicity of cantharidin antitumor drug candidate.