【作者】 田智勇；

【导师】 高文远； 王超杰；

【作者基本信息】 天津大学 ， 应用化学， 2009， 博士

【摘要】 目的:为了寻找新的酰亚胺类抗肿瘤药物,提高萘酰亚胺和邻苯酰亚胺的抗肿瘤活性,降低5-氟尿嘧啶毒副作用。方法:合成了34个目标化合物(其中酰亚胺-多胺缀合物21个,酰亚胺-5-氟尿嘧啶偶联物13个。除MNIS (2-10c)外,其余33个均为新化合物),对目标化合物进行了抗肿瘤活性评价并进行了化合物2-10f凋亡机制研究等。结果:(1)萘酰亚胺-多胺缀合物体外活性试验表明:7个多胺化合物(不含取代基)体外抗肿瘤活性均优于先导化合物萘酰亚胺,尤其是具有4-4-4多胺骨架的化合物(2-10f),对肝癌细胞和正常肝细胞具有选择性,对拓扑异构酶II有抑制作用,能够通过线粒体途径和膜死亡受体途径诱导肿瘤细胞(B16)凋亡;9个(含取代基)萘酰亚胺-多胺缀合物体外抗肿瘤活性优于Amonafide,对肝癌细胞和正常肝细胞具有选择性;取代基的有无及其种类、侧链的不同、链接链的长短、肿瘤细胞的不同对结果都有不同程度的影响。萘酰亚胺多胺缀合物对DNA有嵌入作用;(2)邻苯酰亚胺-多胺缀合物抗肿瘤活性很弱;(3)体内外活性试验表明部分酰亚胺-5-氟尿嘧啶偶联物对肿瘤细胞和肝癌H22有抑制作用,但由于13个酰亚胺-5-氟尿嘧啶偶联物的结构特殊性和化学稳定性,导致它们的体内外活性均不如5-氟尿嘧啶。结论:(1)萘酰亚胺-多胺缀合物具有较好的抗肿瘤活性和较好的选择性,表明萘酰亚胺-多胺缀合物作为抗肿瘤药具有良好的应用前景,值得作为先导化合物进一步研究;(2)邻苯酰亚胺-多胺抗肿瘤活性弱说明多胺对药物运载具有选择性;(3)酰亚胺-5-氟尿嘧啶偶联物的抗肿瘤活性不如5-氟尿嘧啶,说明它们能否释放出5-氟尿嘧啶是合成酰亚胺- 5-氟尿嘧啶偶联物的关键。更多还原

【Abstract】 Objective: It was to exploit new imide antitumor angents, enchance naphthalimide and phthalimide antitumor activitives and reduce 5-Fluorouracil side effects. Methodes: Thirty-four compounds including twenty-one imide polyamine and thirteen imide 5-Fluorouracil conjugates, which are new compounds exept MINS (2-10c), were synthesized, bioevaluated and studied on 2-10f inducing B16 cell apoptosis. Results: (1) Naphthalimide polyamine conjugates were evaluated in vitro cytotoxicity, the results revealed seven compounds without substitued groups have more effctive than naphthalimide while the others with different ones have more effctive than Amonafide. Importantly, compound 2-10f can inhibit Top.II and induce B16 cell apoptosis via both the mitochondrial and membrane death receptor pathways. Their antitumor activity was effected by substituent groups, chains and tumor cells. They have also exhibited cell selectivity to cancer cells through the human hepatoma BEL-7402 and human normal hepatocyte QSG-7701 screens and intercalated DNA. (2) Phthalimide polyamine conjugates have little antitumor activity. (3) 5-Fu imide conjugates were less effective than 5-Fu in vitro and in vivo because of their structural speciality and chemical stablity, although some of them effectively inhibited the growth of tumor cells in vitro and liver cancer H22 in vivo. Conclusion: (1) Naphthalimide polyamine conjugates which are insteresting anticaner would lead for further study; (2) It can be deduced that the polyamine has selectivity to carry phthalimide with regard that phthalimide polyamine conjugates have little antitumor activity; (3) It was vital that free 5-fluorouracil be released from imide 5-Fluorouracil conjugates under physiological pH conditions as a result that they were less effective than 5-Fu in vivo.更多还原