中文摘要
多药耐药性(MDR)是癌症化疗的主要障碍，寻找低毒有效的逆转MDR 药物及深入研究MDR发生机制一直是亟需解决的关键问题。本课题研究内容包括肿瘤MDR 发生机制深入研究；申请者已发现的MDR 逆转剂（溴代汉防己甲素（W198），五味子甲素及新紫杉烷类衍生物）的深入研究；及以上述逆转剂为结构母核，再设计和筛选创新性的逆转MDR 先导化合物。目前研究任务已基本完成，并取得了几个重要成果：1.合成化合物284个，61个活性较好，对7个（NBP-014、NBP-036、NBP-071、Sy1611、H1、W6、W18）进行了系统研究，均有成药潜力，其中NBP-014作为候选药获得十一五重大新药创制科技重大专项的支持（2009ZX09103-033）。2.对已有化合物W198、LX2-30C等进行了系统研究，W198Ⅰ期临床试验已完成，LX2-30C有望成为新型的抗肿瘤耐药药物，相关研究也获得重大新药创制资金的支持。3. 建立MX-1耐紫杉醇裸鼠体内耐药株MX-1/T，属国内领先。同时建立A549/Taxol细胞株，并设计合成了基于高亲和力紫杉烷的小分子荧光探针。
英文摘要
Multidrug resistance (MDR) is the major obstacle in cancer chemotherapy. Studying the mechanisms of MDR and finding effective MDR reversal agents with low-toxicity are very important. This study included three parts: to study the mechanism of MDR; to further study the mechanisms of several potential MDR reversal agents, such as bromotetrandrine, schizandrin A and sinenxans, which were discovered by the applicants; and to synthesize and screen novel MDR reversal compounds based on the parent-structure of above-mentioned MDR reversal agents.At present, the tasks have been accomplished according to schedule. The achievements included: 1. 284 compounds were synthesized, and 61 compounds among them showed significant MDR reversal activities. Systemic studies on 7 of them (NBP-014、NBP-036、NBP-071、Sy1611、H1、W6、W18) have been done. The studies about the potential of NBP-014 as MDR reversal agent is supported by the National Ministry of Science and technology Eleventh 5-year Plan - Technical Platform for Drug Development. 2. Further studies about bromotetrandrine and LX2-30C have been done. Phase I clinical trials for bromotetrandrine have been finished. LX2-30C is a potential MDR reversal agent and its related study is supported by Technical Platform for Drug Development. 3. MX-1/T resistant cell line to taxol in nude
结题摘要
多药耐药性(MDR)是癌症化疗的主要障碍，寻找低毒有效的逆转MDR 药物及深入研究MDR发生机制一直是亟需解决的关键问题。本课题研究内容包括肿瘤MDR 发生机制深入研究；申请者已发现的MDR 逆转剂（溴代汉防己甲素（W198），五味子甲素及新紫杉烷类衍生物）的深入研究；及以上述逆转剂为结构母核，再设计和筛选创新性的逆转MDR 先导化合物。目前研究任务已基本完成，并取得了几个重要成果：1.合成化合物284个，61个活性较好，对7个（NBP-014、NBP-036、NBP-071、Sy1611、H1、W6、W18）进行了系统研究，均有成药潜力，其中NBP-014作为候选药获得十一五重大新药创制科技重大专项的支持（2009ZX09103-033）。2.对已有化合物W198、LX2-30C等进行了系统研究，W198Ⅰ期临床试验已完成，LX2-30C有望成为新型的抗肿瘤耐药药物，相关研究也获得重大新药创制资金的支持。3. 建立MX-1耐紫杉醇裸鼠体内耐药株MX-1/T，属国内领先。同时建立A549/Taxol细胞株，并设计合成了基于高亲和力紫杉烷的小分子荧光探针。