含环庚三烯酮环的多环杂环类新化合物的理性发现及其调节自噬活性的构效关系探索

Streptomyces are well known for their ability to produce secondary metabolites, which are the major source of antibiotics in clinical use. Streptomyces sp. CPCC 204095 could produce tropolone-containing poly(hetero)cyclic compounds (TPCs), which were found to possess a common biological activity of inducing complete autophagy in our previous study. In this project, TPCs with diverse structures will be obtained by directed biosynthesis in Streptomyces sp. CPCC 204095 or glycosylation, and then isolated by flash column chromatography, and reversed-phase HPLC, etc. The structures of the TPCs will be determined by HRMS, NMR, etc. All the obtained TPCs will be tested for biological activity including cytotoxicity and autophagy regulation activity. Their water solubility will also be measured. Consequently, TPCs with high water solubility, low cytotoxicity and better autophagy activity will be screened. Meanwhile, the structure-activity relationship (SAR) of TPCs concerning autophagy activity may be systematically explored and analyzed. Autophagy is a mechanism of eukaryotic cells to degrade unnecessary or dysfunctional cellular organelles, and involves in various physiological and pathological processes. Dysfunctional autophagy promotes pathogenesis of many diseases, especially immunological disease, pathogenic infection, cancer, and neurodegenerative disease. Therefore, TPCs may serve as promising lead compound(s) for the prevention and treatment of the above diseases in the future.

本项目前期研究发现链霉菌CPCC 204095是一株产生含环庚三烯酮环的多环杂环类化合物（tropolone-containing poly(hetero)cyclic compounds, TPCs）产生菌，特别是国内外首次发现这类化合物具有调节自噬的生物活性。本项目拟采用体内定向生物合成与体外糖基化等策略，获得结构多样的TPCs衍生物，并通过比较所获得TPCs衍生物的理化性质和调节自噬生物活性，探索该类化合物的构效关系，有望为与自噬密切相关的人类疾病例如免疫、感染、肿瘤和神经退行性疾病等提供创新微生物药物先导化合物。

Isatropolones/isarubrolones是链霉菌CPCC 204095产生的含环庚三烯酮环的（tropolone-containing poly(hetero)cyclic compounds, TPCs）次级代谢产物，我们首次发现该类化合物具有调节自噬的生物活性。我们通过对链霉菌CPCC 204095发酵培养和分离纯化、体外酶促或定向衍生，获得了12个TPCs新化合物，并对这些化合物进行了自噬活性和药理活性探索。3个甲基化TPCs新化合物（isatropolone Cm、isatropolone Am、isarubrolone Cm）具有诱导不完全自噬的生物活性。糖基化TPCs新化合物与TPCs二聚体新化合物也具有调节自噬的活性。isarubrolone C以及体外酶促或定向衍生得到的TPCs化合物具有抗硝化应激损伤活性，可用于预防和/或治疗硝化应激导致的肝细胞或神经细胞损伤；isarubrolone C还表现出优异的预防和/或治疗非酒精性脂肪性肝病或肝炎的作用。因此，TPCs类化合物有望成为新药研发先导分子。此外，从链霉菌CPCC 204095中发现了isatropolone C的生物合成直接前体物7,12-dihydroisatropolone C。该化合物可自发氧化生成isatropolone C，为isatropolone C生物合成中的tropolone七元环构建提供新的认识。