抗肿瘤活性汉防己甲、乙素衍生物的设计、合成及作用机制研究

Malignancy has been one of the most serious diseases endanger the health of all mankind, the mortality rate of cancer is only less then that of cardiovascular diseases, and hepatic cancer is one of the world's most common and most deadly cancer. The development of new chemotheraputic drugs, especially anti-tumor drugs with new mechanisms of action is an important means of dealing with cancer. Lead compounds of anti-tumor activity from natural sources is an important source for anti-tumor drug development. The applicant have dedicated recently in the preparation and anti-cancer activity of naturally occurring bisbenzylisoquinoline type alkaloids, and have found out that tetrandrine and fangchinoline isolated from Stephania tetrandrine S. Moore as well as some of their derivatives possessed potent anti-hepatic cancer and other malignancies cell activity with novel mechanisms of action. In this project, we will investigate the synthesis, anti-cancer activity and mechanisms of action for the novel derivatives of tetrandrine and fangchinoline on the basis of our preliminary studies. On the other hand, we will perform a liver cell targeted structural modification based on fangchinoline and its derivatives with potent anti-hepatic cancer activity, and evaluate their anti-hepatic cancer activity as well as structure-activity relationship (SAR) analysis. The main purpose of this project is to obtain 1-2 anti-tumor drug candidates with new anti-cancer drug development potential, and provide a scientific basis for the development of novel anti-cancer drugs with independent intellectual property lights and good market prospects.

恶性肿瘤一直是危害全人类健康最严重的疾病之一，其死亡率仅次于心脑血管疾病，其中的肝癌则是世界上最常见、最致命的癌症之一。研究化疗新药特别是具有全新作用机制的抗肿瘤新药是对付癌症的重要手段，而天然来源的抗肿瘤活性先导化合物是抗肿瘤新药研发的重要源泉。申请人近年来致力于天然双苄基异喹啉类生物碱及其衍生物的制备与抗肿瘤活性研究，并发现来源于粉防己的汉防己甲、乙素及其部分衍生物具有较好的抗肝癌等恶性肿瘤细胞活性，且具有较新颖的抗肿瘤作用机制。本项目拟在前期研究基础上进行汉防己甲、乙素新衍生物的合理化设计、合成、抗肿瘤活性、作用机制及构效关系研究，同时将对具有新作用机制的抗肝癌活性汉防己乙素及其衍生物进行以肝靶向为目的结构修饰、抗肝癌活性及构效关系相关研究，力争获得1-2个具有开发潜力的抗肿瘤新药候选药物分子，为具有重大市场前景及自主知识产权的抗肿瘤新药研发提供科学依据。

恶性肿瘤一直是危害全人类健康最严重的疾病之一，其死亡率仅次于心脑血管疾病，其中的肝癌则是世界上最常见、最致命的癌症之一。研究化疗新药特别是具有全新作用机制的抗肿瘤新药是对付癌症的重要手段，而天然来源的抗肿瘤活性先导化合物是抗肿瘤新药研发的重要源泉。申请人近年来致力于天然双苄基异喹啉类生物碱及其衍生物的制备与抗肿瘤活性研究，并发现来源于粉防己的汉防己甲、乙素及其部分衍生物具有较好的抗肝癌等恶性肿瘤细胞活性，且具有较新颖的抗肿瘤作用机制。本项对汉防己甲、乙素新衍生物的合理化设计、合成、抗肿瘤活性、作用机制及构效关系研究，同时将对具有新作用机制的抗肝癌活性汉防己乙素及其衍生物进行以肝靶向为目的结构修饰、抗肝癌活性及构效关系相关研究，目前总共得到汉防己甲素衍生物164个和汉防己乙素衍生物124个，发现了化合物LJJ-27、LJJ-54、LJJ-101、LJJ-102、LJJ-104等有良好的的抗肿瘤活性，初步作用机制研究证明多数化合物是通过诱导肿瘤细胞凋亡抑制肿瘤细胞增殖，目前已初步确定化合物LJJ-104为抗肿瘤新药候选药物分子，正在进行系统的临床前成药性评价研究。本项目的结果为具有重大市场前景及自主知识产权的抗肿瘤新药研发提供了科学依据。