脚骨脆属植物及其内生真菌中PI3K抑制剂的发现及抗肿瘤活性研究

As one of the most commonly activated signaling pathways in human cancer, the PI3K-Akt-mTOR pathway is a key signal transduction system that controls most hallmarks of cancer, including cell cycle, survival, metabolism, and genomic instability, which makes PI3K a hot target in anticancer therapy. In the preliminary study, we have discovered that the diterpenoid caseabalansin G from Casearia balansae exhibited significant PI3K inhibiting activity and caused cell cycle arrest and apoptosis of cancer cells, and the alkaloid dehydronotoamide C from Aspergillus versicolor, an endophytic fungus of C. balansae, also inhibited PI3K and proliferation of cancer cells significantly. Based on the above results, the aims of the present project are listed as follows: i) To separate the extracts of two Casearia species and two strains of fungal endophytes of C. balansae and rapidly obtain the novel bioactive metabolites and analogs under the guidance of PI3K-inhibiting assay. ii) To design and synthesize some derivatives of the active compounds, get the structure-activity relationship of PI3K inhibition, and find the most potent compound. iii) To test the anticancer activity of the active compounds in vitro and in vivo. To investigate its effect on the PI3K-Akt-mTOR pathway and cell functions such as proliferation, cell cycle, and apopotosis, and clarify its michanism of action. The results of this project will make basis for the discovery of new anticancer drugs.

作为肿瘤中最常见的被异常激活的通路之一，PI3K-Akt-mTOR途径是控制肿瘤的细胞周期、存活、代谢和基因不稳定性等的关键信号系统，这使得抑制PI3K成为抗肿瘤药物研究的热点。前期发现脚骨脆中以caseabalansin G为代表的二萜可显著抑制PI3K，并能阻滞肿瘤细胞周期和诱导细胞凋亡；其内生真菌Aspergillus versicolor中的生物碱dehydronotoamide C也可显著抑制PI3K并抑制肿瘤细胞增殖。本项目拟以PI3K抑制活性为指导，对筛选出有活性的两种脚骨脆属植物及两株脚骨脆内生真菌的提取物进行深入发掘，快速获得新的活性产物及其微量同系物。在此基础上进行衍生物设计与合成，研究其构效关系。针对活性强的分子，研究其体内、外抗肿瘤活性和作用机制，阐明其通过抑制PI3K-Akt-mTOR信号通路阻滞细胞周期和诱导细胞凋亡的作用机制，为新型抗肿瘤药物的发现奠定基础。

本项目完成了印度脚骨脆(Casearia kurzii)、脚骨脆(Casearia balansae)、脚骨脆内生真菌Aspergillus versicolor、Leptosphaeria sp. L1201、毛叶巴豆(Croton caudatus Geisel. var. tomentosus)、光叶巴豆(Croton laevigatus)、内生真菌Botrysphaeria laricina、Ulospora bilgramii的活性成分分离和结构鉴定，共分离获得各类化合物209个，采用NMR和HRMS等波谱学技术鉴定了其结构，其中包括新化合物73个，筛选发现具有较强抗肿瘤活性的化合物多个。对前期发现有活性的化合物进行了富集和结构修饰，制备衍生物7个，经筛选发现具有抗肿瘤活性的化合物多个，初步总结了其构效关系，筛选获得了强活性的化合物。对活性克罗烷型二萜化合物A4和A7进行了抗肿瘤活性研究，发现其细胞周期阻滞和诱导凋亡的活性。对克罗烷型二萜化合物B10和B11的活性进行了深入研究，发现该类化合物可抑制肿瘤细胞的PI3K激酶活性，进而引起肿瘤细胞周期阻滞和细胞凋亡。此外本项目还发现海松烷型二萜化合物BD对Nrf2信号通路的激活作用及其对As(III) 诱导的细胞损伤的保护作用。上述研究工作的完成，对阐明这几种植物或内生真菌的活性成分和新型抗肿瘤、化学预防药物的发现具有重要意义。

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