Sclerotiorin类天然产物的结构优化及其杀菌活性和作用机制研究

The selection and discovery of the lead structure play an important role during the development of novel pesticide. It is well known that natural products are the abundant source for the discovery of pesticide lead with an absolutely novel structure. The structure optimization of natural lead is an efficient approach to the innovation of pesticides. Sclerotiorin and its analogues are a representative class of natural products, structurally featured with a highly oxigenated backbone. Because of their broad spectrum biological properties, the total synthesis and isolation from different fungal species of this kind of natural products have received considerable attention of chemists. To the best of our knowledge, there is no publication describe the structure optimization of Sclerotiorin with an aim for the development of novel fungicide. In our previous research, we found that the antifungal activity was highly improved by replacement of the conjugated side chain of Sclerotiorin with a phenyl substituent. We envisioned that Sclerotiorin might be a good lead for the discovery of novel agricultural fungicides. In this project, we would like to get further insight into the structure-activity relationship of Sclerotiorin. We will focus on the structure optimization by changing the substituents pattern of the Sclerotiorin skeletone, at the same time, we also consider to modify the bicyclic core of Sclerotiorin by fusing with an another ring or by replacement of one of the six-member ring with a five membered lactone or lactam. We plan to construct a Sclerotiorin analogues library containing divers structural information. We hope to screen a novel fungicede lead based on several cycle endeavor of design-synthesis-bioassay-structure-activity analysis. We believe that the project implementation will bring a solid basis for the discovery of high potential, low toxicity, environmentally friendly green fungicide.

先导结构的选择和发现是创制新农药的关键要素，而天然产物则是发现具有新型骨架农药先导结构的宝库，对天然先导结构的优化是农药的重要创新之路。Sclerotiorin衍生物具有广谱生物活性，针对该天然产物的合成及从不同途径分离该天然产物的类似物引起了科学家的广泛兴趣。但是，以该类天然产物为先导进行结构优化来开发农用药物分子还没有文献报道，我们的前期研究表明，通过对该天然产物结构中3-位进行改变（用苯环取代共轭侧链）可显著提高其杀菌活性。本项目拟在前期工作的基础上进一步对该化合物结构进行改造，优化策略包括：保持其基本母核结构，优化不同侧位取代基以及通过并环、缩环等策略设计对其母核结构作有限改变，合成结构信息丰富的化合物库，筛选其杀菌活性，探索其作用机制。希望经过设计-合成-生测-构效关系的循环，找到具有新型骨架、优良生物活性的绿色杀菌剂先导结构。

先导结构发现是农药创制中最关键的科学问题之一。以天然产物为模板进行结构优化是发现具有新颖骨架和新颖作用机制农药分子的最有效途径。Sclerotiorin是一类具有广谱生物活性的天然产物，有关其全合成以及分离鉴定新型类似物的研究成为近年来的热点课题。本项目对Sclerotiorin开展系统的结构优化研究，共合成了八大类共234个Sclerotiorin衍生物，测试了所合成化合物的杀菌活性并总结了构效关系，发现了一些具有广谱杀菌活性的化合物，部分在20ppm的浓度下，对腐霉菌、番茄早疫病菌、葡萄灰霉病菌及玉米赤霉菌等测试病菌表现出100%的杀菌活性，远优于先导天然产物。通过结构修饰成功的简化了天然产物先导结构，提高了其杀菌活性。构效关系表明：1-位引入取代基则对活性不利；2-氧被氮取代对活性不利；3-芳基取代对抑菌活性较为重要；5-位可以容许多种取代基如卤素、芳基、烷基均可；7-位羟基是必需结构，若转化为酯基则活性基本丧失；开展了Sclerotiorin作用靶标研究，测试了部分化合物对猪心来源线粒体复合物抑制活性，发现部分3,5-二芳基Sclerotiorin衍生物是潜在的新型复合物II抑制剂，而呋喃并吡喃类衍生物则是潜在的新型复合物III抑制剂；研究了代表性Sclerotiorin衍生物光照稳定性研究，表明该类衍生物对随取代基不同光敏感性存在较大差异。研究了不同pH值对杀菌活性的影响，发现该类化合物在酸性环境下（pH = 5.5）和中性条件下显示非常优异的杀菌活性，而在弱碱性环境下（pH = 8）杀菌活性完全丧失。项目实施过程中，在国际SCI期刊 New Journal of Chemistry，RSC advance, Tetrahedron 等发表论文8篇。