基于海洋生物碱Aldisin的活性化合物库的构建及2-取代Aldisin合成方法学研究

The results already reported on the marine alkaloid aldisin and its analogs demostrated that aldisin and its derivatives (called aldisins) provides various bioactivities. Our recent research on the diversity of the structure and activity of aldisins preliminarily showed that some derivatives might be potent inhibitors against PTP1B and be of potent treatment for highly metastatic cancers. Hence, this project aims at construction of two aldisin-based libraries, which will be designed and constructed on the basis of drug discovery principles such as Lipinski and verb rules and the structural characteristics of PTP1B as well. All synthetic target molecules will be bioassayed in molecular and in cell levels, and the feedback results will in turn help us to improve the design of new target compounds, and finally at least two lead compounds will be obtained. Moreover, the focusing on the effective substitution of the 2-position of pyrrole, which will lead to the construction of 2-substituted aldisines, is one of the key points to implemen this proposal. In summary, the scientific significance of synthesis of 2-substituted aldisines and the obvious importance of furnishing lead compounds for PTP1B inhibitors and anticancer drugs urge us to carry out the suggested project.

已有的文献报道以及本课题组对海洋天然产物Aldisin的分子多样性研究所获得的初步研究结果表明，Aldisin的衍生物呈现出丰富多样的生物活性。本课题拟在本课题组已获得的具有PTP1B抑制活性和对高转移性的乳腺癌细胞、肝癌细胞及鼻咽癌细胞有明显的抑制活性的Aldisin衍生物的基础上，重点针对糖尿病和恶性肿瘤疾病靶，在PTP1B抑制活性和细胞水平的抗增殖活性测试指引下，设计、合成Aldisin的衍生物库和模拟物库。在库的构建过程中，将充分考虑分子多样性、药物先导化合物的Lipinski原则和Verb原则。同时，重点进行吡咯氮邻位衍生物的合成方法学的研究。最终构建两个功能性的海洋天然产物Aldisin的分子多样性库。其潜在应用价值和2-吡咯衍生物的合成方法学研究具有明确的科学意义，使得本课题值得实施。

已有的文献报道以及本课题组对海洋天然产物Aldisin的分子多样性研究所获得的初步研究结果表明，Aldisin的衍生物呈现出丰富多样的生物活性。本项目在本课题组已获得的具有PTP1B抑制活性和对高转移性的乳腺癌细胞、肝癌细胞及鼻咽癌细胞有明显的抑制活性的Aldisin衍生物的基础上，设计、合成C-2，C-5及C-4，5位改造的Aldisin的衍生物库和模拟物库。在库的构建过程中，重点进行了C-2位吡咯氮邻位衍生物的合成方法学的研究。同时，发展了C-N键的构建方法，并将这些方法应用于其他药物先导化合物的合成中。