鬼臼毒素类抗癌及抗艾滋病药物的设计、合成及活性研究-化学、有机化学专业论文.docxVIP

麓埘虫害博士掌位论文 麓埘虫害博士掌位论文 陈世武 物具有抗HIV—l活性的基本结构特征是：4’一位去甲基、A一环开环并甲醚化及 4一位为氮碳等小极性基团取代。 关键词： 鬼臼毒素·5一氟尿嘧啶·抗肿瘸·拼合原理·氨基酸· 细胞毒性·脂水分配系数·稳定性·DNA·拓扑异构酶．II·作用机制·核苷 ·司垣夫定d4T·抗．HIV活性·抗病毒·设计·合成 o、蔺料虫害博士掌位论文 o、蔺料虫害博士掌位论文 骧世武 Abstract Podophyllotoxin as well as its congeners and derivatives exhibit pronounced biological activity mainly as strong antineoplastic drugs and as antiviral agents，which is a good source of the arylteralin—type lignan．The podophyllotoxin derivatives etoposide(VP一16)，teniposide(VM一26)and EtopophOS(etoposide phosphate)，which are optimized from podophyllotoxin as lead compound，are thus successfully utilized in treatment of a variety of cancers，including small—cell lung cancer,testicular carcinoma，lymphoma，and Kaposi’S sarcoma．In addition，podophyllotoxin was used as antiviral agent in treatment of herpes simplex type I and condyloma acuminatum caused by human papilloma virus and others venereal and perianal warts。To obtain better the therapeutic agents with high activities and less toxic to namral celt，three kinds of derivatives of podophyllotoxin were designed，synthesized and evaluated for their biological activities in this thesis． 1．Based on antimetabolite 5-fluorourcial is one of the major anticancer agents used clinically,as well as amino acids with better biological activity and good water-solubility in the human body,27 Compounds were synthesized though associated 4-demethylepipodophyUotoxin and 5-FU with natural L-amino acid as linker．As the results，most target compounds showed more effective superior or comparable cytotoxicities than VP一16 and 5-FU，against human leukemic(HL一60， K562)and huaman lung carcinoma(A*549)in vitro．At the same time，they are stability in huaman plasma，mouse plasma and phosphate buffer solution，and they interacted weakly with calfthymus DNA． 2．To explore the range ofbiological activities ofthe podophyllotoxin compound class， another series of podophyllotoxin derivatives were designed and synthesized，which were conjugates of stavud