摘要
目的设计合成鬼臼毒素4β-(1,3,4-噁二唑-2-氨基)衍生物,并寻求具有高效低毒抗癌活性的新化合物。方法鬼臼毒素经叠氮化、还原、加成、消除得到4β-异硫氰酸酯-4-脱氧鬼臼毒素(4),再与酰肼化合物反应得到氨基硫脲衍生物,最后经环化得到目标化合物。采用MTT法,以5-氟尿嘧啶、鬼臼毒素、VP-16为阳性对照药,评价目标化合物对人前列腺癌细胞(DU-145)、人胃癌细胞(SGC-7901)、人非小细胞肺癌细胞(A549)、神经母细胞瘤细胞(SH-SY5Y)、人肝癌细胞(HepG2)、子宫颈癌细胞(HeLa)6种肿瘤细胞以及1种正常细胞小鼠成纤维细胞(L929)的细胞毒活性。结果合成了9个新化合物,其结构经IR、1H-NMR、13C-NMR和MS确证。体外抗癌活性实验表明,目标化合物对正常细胞的毒性均远远小于阳性对照,部分化合物显示出较好的抗癌活性。结论在这一系列衍生物中,化合物6b对所测试细胞系的细胞毒活性显示了突出的生物活性。
Objective To design and synthesize 4β-（ 1,3,4-oxadiazole-2-amino）-podophyllotoxin derivatives in order to seek new anticancer agents with low toxicity. Methods Podophyllotoxin was converted into 4β- isothiocyanate-4-desoxypodophyllotoxin through azidization, reduction, addition and elimination reactions. Then a series of thiosemicarbazide derivatives were readily prepared by reacting the isothiocyanate （ 4 ） with hydrazide compounds. Upon treatment with tosyl chloride and pyridine in refluxing THF, the thiosemicarbaz- ides were transformed into the corresponding oxadiazole derivatives. Using fluorouracil as positive control, all the newly synthesized 4β-（ 1,3,4-oxadiazole-2-amino）-podophyllotoxin derivatives were screened for cy- totoxicity against six human cancer cell lines（ DU-145, SGC-7901, A549, SH-SY5Y, HepG2 and HeLa）and a normal cell line （ L929 ） in vitro by MTT method. Results Nine novel compounds were synthesized, and their structures were characterized by IR, 1H-NMR, 13 C-NMR and MS. The MTT results indicated that most of the new compounds exhibited much lower cytotoxicity toward the normal cell line （L929）than podophyl- lotoxin, VP-16 and 5-fluorouracil. Some of the new compounds （ 6a, 6b ） showed good cytotoxicity against the tested cancer cells. Conclusions In this series of novel 4β-（ 1,3,4-oxadiazole-2-amino） -podophyllotoxin derivatives, compound 6b displays a prominent anticancer activity toward the tested cancer cell lines.
出处
《沈阳药科大学学报》
CAS
CSCD
北大核心
2012年第6期427-433,共7页
Journal of Shenyang Pharmaceutical University
基金
2011常州市科技支撑计划(社会发展)资助项目(CE20115050)
2010江苏省企业博士集聚计划资助项目
关键词
鬼臼毒素
1
3
4-噁二唑
合成
抗癌活性
podophyllotoxin
1,3,4-oxadiazole
synthesis
anticancer activity
