西沙肉芝软珊瑚中多类型结构新颖化学成分及多靶点抗糖尿病活性谱研究

At present, the diabetes and its complications have been a serious threat to human health. Because of the toxicity and side effects of the existing drugs and their deficiency of improving complications, searching for new type of diabetes drug is a hot research topic in the world. Compared with the offshore soft corals, the species distributed in Xisha Islands, which are in urgent need of exploitation, have been attracting special attentions from scientists due to their unique chemical constituents with remarkable biological activities and potential medicinal values. Meanwhile, the poor studies in recent years indicated Xisha soft corals belonging to Sarcophyton featured a remarkable value in the discovery of novel lead compounds. Therefore, on the basis of literature analysis, we carried out preliminary chemical and biological studies on two unpublished species of Sarcophyton soft corals from Xisha, leading to obtain several potential anti-diabetic compounds. Based on the inspiring previous research, this project will systematically take the in-depth studies on the selected Xisha soft corals, focusing on the diverse chemical components and their anti-diabetic activities against novel targets such as FFAR-1, 11β-HSD1 for the treatment of diabetes mellitus and its complications. It is expected that several lead compounds with novel structural features will be discovered. The result of this project could lay a solid foundation for the research and development of new drugs for diabetes as well as provide an important suggestion for rational exploitation and utilization of soft corals distributed in the distant area of South China Sea.

糖尿病及其并发症严重威胁人类健康，但已有药物存在着毒副作用且不能有效改善并发症，因此开发新型糖尿病药物是国际上的研究热点。相对于近海，亟待开发的西沙海域的软珊瑚能产生生物活性显著的结构新颖化学成分，更因其潜在的药用价值被科学家所特别关注。近年来有限的研究表明，西沙肉芝软珊瑚在结构新颖先导化合物探索方面有重要的研究价值。通过充分的文献调研，我们选择2种未见研究报道的西沙肉芝软珊瑚开展了初步的化学和生物学研究，从中获得了具有良好的抗糖尿病活性成分。本项目拟在前期研究的基础上，以上述精心挑选的西沙肉芝软珊瑚为代表研究对象，选择FFAR-1、11β-HSD1等具有治疗糖尿病及其并发症的新型靶点，聚焦其中的多类型结构新颖化学成分及多靶点抗糖尿病活性谱，通过系统的研究，以期发现若干不同类型的结构新颖活性先导化合物，为新型糖尿病药物研发奠定基础，也为合理开发、利用我国远海软珊瑚资源提供重要参考。

本项目以采自我国南海不同海域的肉芝属软珊瑚Sarcophyton mililatensis等8个软珊瑚样品为研究材料，运用NMR等各种导向分离技术，获得一批结构新颖的化学成分，总计88个，其中新化合物53个。这些化学成分结构类型多种多样，包括西松烷型、sarsolenane型和capnosane型二萜和降西松烷型、inelegane型和yonarane型降二萜等区别明显的骨架类别，同时还存在醚化、内酯化等不同差异的结构特征。针对柔性复杂化合物分子的结构鉴定问题，集成了X-ray单晶衍射、Mosher反应、TDDFT ECD和QM-NMR量化计算技术，成功解决了部分柔性复杂结构的绝对构型。针对已获得的单体化合物，开展以PTP1B、TNF-α、BRD4、HDAC1和HDAC6等蛋白酯酶为研究对象的靶蛋白抑制作用、以THP-1、SNU-398、HT-29、Capan-1和A549细胞株为研究对象的抗肿瘤作用、以Con A或LPS诱导的T、B淋巴细胞为研究对象的免疫作用等多种不同范畴的高通量活性筛选，获得了31个活性化合物，包含6个与阳性对照药相当或比其略佳的高活性化合物。通过分子对接技术，分析了活性化合物分子与蛋白的作用模式。这些重要成果不仅为今后同种属或近缘软珊瑚样品的化学成分和生物功能的探索提供了重要的参考，也为相似结构类型的化合物分子的结构鉴定和功能分子结构导向型的药物研发奠定了扎实的基础。