小粘膜藻及其内生真菌次级代谢产物的化学多样性和PTP1B抑制活性研究

As the characteristic metabolites of alga, bromophenol derivatives have become a treasure of drug discovery due to its novel structure and unique bioactivity. Based on a large number of previous studies, bromophenol derivatives are found to have targeted PTP1B inhibitory activity. Our research team has ever used BPN that a natural compound isolated from alga with significant PTP1B inhibitory effect as the model compound, designed and synthesized a candidate anti-diabetic drug named HPN. Subsequent researches showed that a large number of BPN analogues also exist in Leathesia nana. However, due to the limitations of separation and analysis techniques at that time, the former study was not comprehensive or deep. This research aims to further seek halogenated phenols and other compounds with PTP1B inhibitory activity, taking advantage of the modern separation and analysis techniques. Additionally, in the interactional process of symbiosis and evolution with the host, endophytic fungus of alga can also produce similar or is completely different secondary metabolites from the host, which enrich its chemical diversity. Thus, the secondary metabolites of endophytic fungus from Leathesia nana were also explored in the present study. Utilizing some techniques such as epigenetic modifications to improve the expression ability of their internal silence genes, and to provide practical and effective ways to develop PTP1B inhibitors.

作为海洋藻类植物的特色代谢产物，溴酚类化合物独特的化学结构和生物活性成为新药研发的宝库。本课题组基于前期大量研究，发现溴酚类化合物具有靶向的PTP1B抑制活性；并以海藻中具有显著抑制活性的天然化合物BPN为先导物，通过合成修饰得到了抗糖尿病候选药物HPN。后续研究发现褐藻门粘膜藻科小粘膜藻中存在大量BPN类似物，但由于受当时分离和分析技术的限制，其化学成分研究仍不够系统。本项目旨在运用现代分离分析技术进一步挖掘小粘膜藻中具有PTP1B抑制活性的卤代酚类及其它类化学成分。由于海藻内生真菌在与宿主共生与进化的相互作用过程中也会产生类似于或完全不同于宿主的次级代谢产物，极大丰富天然产物的结构研究。本项目还针对小粘膜藻内生真菌的次级代谢产物进行多样性挖掘，利用表观遗传修饰等手段提高菌株内部沉默基因的表达能力，改变其次级代谢产物谱，为寻找PTP1B抑制剂提供切实有效的途径。

课题组前期研究发现，海藻溴酚类化合物具有靶向PTP1B抑制活性。本项目旨在借助现代分离分析技术进一步挖掘小粘膜藻及其内真菌中具有PTP1B抑制活性的代谢产物，并对活性产物进行靶向代谢组学研究。项目从小粘膜藻中共分离得到42个化合物，发现4个溴酚类化合物在体外对PTP1B酶表现出显著的抑制活性，进一步丰富了活性多样性溴酚类化合物库，也为探索小粘膜藻的系统发育提供了新的佐证。项目还从新鲜小粘膜藻中分离鉴定出57株内生真菌，并以PTP1B酶抑制活性和UPLC-MS分析结果为导向筛选出2株小粘膜藻内生高产菌株Aspergillus sp. XNM-4和Penicillium chrysogenum XNM-12，并完成了2株内生真菌次生代谢产物的分离，从真菌培养液中共分离鉴定出60个化合物（首次报道的新化合物4个），此类成分虽未有明显的PTP1B抑制活性，但展现出较好的抗肿瘤和抗菌活性。项目当前仍在对活性化合物进行代谢组学研究。在该项目的资助下，主持人以第一作者和通讯作者在Bioorganic Chemistry、Marine Drugs和Biochemical Systematics and Ecology期刊上共发表5篇SCI论文，包括1篇中科院分区1区论文，3篇2区论文，IF均大于5.0，超额完成了论文考核指标；还以第1完成人身份授权4件实用新型专利；以副主编身份出版1部专著；培养博士后研究人员1名。总体而言，项目按既定计划进行，完成了预期目标，研究内容进一步丰富了海藻药物化学研究。