吡咯并[2,3-d]嘧啶类叶酸拮抗剂的设计与合成研究

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1、授予单位代码10089学号或申请号20122662HebeiMedicalUniversity硕士学位论文科学学位吡咯并[2，3-。嘧啶类叶酸拮抗剂的设计与合成研究研究生：张闯导师：杜玉民教授王磊副教授专业：药物化学2015年3月河北医科大学学位论文使用授权及知识产权归属承诺本学位论文在导师（或指导小组）的指导下，由本人独立完成。本学位论文研究所获得的研究成果，其知识产权归河北医科大学所有。河北医科大学有权对本学位论文进行交流、公幵和使用。凡发表与学位论文主要内容相关的论文，第一署名为单位河北医科大学，试验材料、原始数据、申报的专利等知识产权均归河北医科大学所有。否则，承担相应法律责任。河

2、北医科大学研究生学位论文独创性声明本论文是在导师指导下进行的研究工作及取得的研究成果，除了文中特别加以标注和致谢等内容外，文中不包含其他人已经发表或撰写的研究成果，指导教师对此进行了审定。本论文由本人独立撰写，文责自负。研究生签名：髮丨贫°导师签章：；年3月517日目录中文摘要··············································································1英文摘要············································································

3、···3英文缩写···············································································6研究论文吡咯并[2,3-d]嘧啶类叶酸拮抗剂的设计与合成研究前言·············································································7材料与方法··································································12结果·························

4、··················································32附图···········································································37讨论···········································································58结论···········································································59参考文献·····

5、································································60综述叶酸拮抗剂的研究进展···········································63致谢·················································································80个人简历··········································································81中文摘要吡咯并[2,

6、3-d]嘧啶类叶酸拮抗剂的设计与合成研究摘要叶酸代谢是人体内嘌呤核苷酸和嘧啶核苷酸生物合成中的重要环节。以叶酸代谢为作用靶点的叶酸拮抗剂在临床上已经应用于抗肿瘤、抗微生物、抗原生生物和抗炎治疗。已上市的多个药物，如甲氨喋呤（methotrexate,MTX），培美曲塞（pemetrexed,PMX），雷替曲塞（raltitrexed）和2009年获批的普拉曲沙（pralatrexate）作为抗肿瘤化疗药物已广泛被国内外临床使用。胸苷酸合成酶(TS)和二氢叶酸还原酶(DHFR)是叶酸拮抗剂的两个重要作用靶。二氢叶酸还原酶在细胞内催化二氢叶酸还原为四氢叶酸，而胸苷酸合成酶是催化单磷酸脱氧尿苷（

7、dUMP）从头合成单磷酸胸腺嘧啶核苷（dTMP）所需的酶。抑制二氢叶酸还原酶和胸苷酸合成酶将引起胞内还原态叶酸不足或者“胸苷酸缺陷状态”，从而使得细胞无法完成精确的DNA复制，最终导致细胞死亡。除二氢叶酸还原酶和胸苷酸合成酶外，嘌呤从头合成中依赖叶酸发挥作用的两个酶，甘氨酰核苷酸甲基转移酶（GARFTase）和氨基咪唑甲酰胺核苷酸甲基转移酶（AICARFTase）也可以作为叶酸拮抗剂的靶点。临床应用的经典叶酸拮抗剂作为一