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摘 要：海洋微生物已成为海洋新天然产物的主要来源之一，从2009年开始发现的海洋新天然产物的1/3以上者是由海洋微生物产生的。从这些天然產物中寻找有重要作用的药物先导化合物，对于开发新的药物有重要的意义。该研究围绕其中成药性高的含氮和卤代化合物，展开研究，通过培养基优化和环境胁迫，从海洋微生物的发酵产物中获得结构新颖的、具有显著活性的含氮和卤代等海洋新天然产物。利用抗肿瘤等细胞或分子筛选模型，在细胞和分子水平上对具有生态学效应的次生代谢产物进行抗肿瘤、抗炎、抗病毒和抗菌等活性评价；探讨具有生态学效应的次生代谢产物与抗肿瘤、抗菌等药理活性之间的内在联系和规律性；发现生理活性先导化合物，并对某些具有显著生理活性的分子进行作用靶点和作用机制的探索，从而探讨海洋微生物次生代谢产物的生理活性机制。通过发酵优化、结构衍生和化学合成，从3株海洋微生物发酵产物中获得了29个生物碱和聚酮及其氯代化合物，其中13个为新化合物、4个新生物碱体外具有强抗甲型流感病毒（H1N1）活性。对2个具有显著抗肿瘤作用的化合物在体内外进行了深入的抗肿瘤作用的研究，并初步完成了1个药物先导化合物的成药性评价。首次发现吲哚二萜生物碱和脱氢苯丙氨酸构成的二酮哌嗪生物碱具有抗H1N1病毒活性，发现化合物Wentilactone A有较强的抗肺癌作用，其抗肿瘤作用效果优于阳性对照环磷酰胺。并对该化合物的制备工艺、理化性质、急性毒性、生殖毒性、剂型等进行了全面的研究，成药性前景良好，鉴于目前临床上尚未有非常有效地针对小细胞肺癌的化疗药物，该次研究发现的化合物具有对小细胞肺癌非常明确的疗效，且作用靶点明确，有望开发成为一类新药。
关键词：海洋微生物 天然产物 生理活性 药物先导化合物
Annual Report of the Activities and Mechanisms of Secondary Metabolites from Marine Microorganisms
Huang Caiguo
（The Second Military Medical University）
Abstract： Marine microorganisms have become a major source of natural products. Since 2009， over 1/3 new marine natural products were produced by marine microorganisms. Exploring leading compounds as candidates of new drugs from these natural products has important significance. Our subject is committed to the selection of Nitrogen compounds and Halogenated compounds with significant activity from fermentation products of marine microorganisms through medium optimization and environmental stress. Firstly， we use the tumor cell model and molecular screening model to evaluate the ecological effects of anti-tumor， anti-inflammatory， anti-viral and anti-bacterial activity of secondary metabolites at the cellular and molecular level； secondly， explore the intrinsic link and regularity between secondary metabolites and anti-tumor， anti-bacterial and other pharmacologically activities； thirdly， discover leading compounds which have physiological activity. Furthermore， investigate the molecular targets and mechanisms of these compounds for exploration of physiologically active mechanism of secondary metabolites from marine microorganisms. We derived 29 alkaloids， polyketide and chlorinated polyketide from three ermentation products of marine microorganisms though fermentation optimization， structured derivatives and chemical synthesis， in which 13 novel compounds and 4 novel alkaloids have strong anti-A influenza virus （H1N1） activity in vitro. We further studied the mechanisms of 2 novel compounds， which have significant anti-tumor effect in vitro and in vivo； and initially completed the evaluation of a pharmaceutical leading compound. We first discover indole diterpene alkaloids and dehydrogenation phenylalanine formed diketopiperazine alkaloids， which have anti-H1N1 activity. And Wentilactone A has significant anti-tumor effect， which is more effective than the positive control-cyclophosphamide. Furthermore， we have conducted a comprehensive study about the preparation， physicochemical properties， acute toxicity， reproductive toxicity， dosage forms， etc. of this compound. We find that Wentilactone A has good prospects of druggability. For there are no effective chemotherapy drugs against small cell lung cancer （SCLC） in the current clinical treatment， Wentilactone A which has clear effect and molecular targets against SCLC， is expected to be a promising novel， potent and selective anti-tumor drug candidate for lung cancer.
Key Words： Marine microorganisms； Natural products； Physiological activity； Pharmaceutical leading compounds
关键词：海洋微生物 天然产物 生理活性 药物先导化合物
Annual Report of the Activities and Mechanisms of Secondary Metabolites from Marine Microorganisms
Huang Caiguo
（The Second Military Medical University）
Abstract： Marine microorganisms have become a major source of natural products. Since 2009， over 1/3 new marine natural products were produced by marine microorganisms. Exploring leading compounds as candidates of new drugs from these natural products has important significance. Our subject is committed to the selection of Nitrogen compounds and Halogenated compounds with significant activity from fermentation products of marine microorganisms through medium optimization and environmental stress. Firstly， we use the tumor cell model and molecular screening model to evaluate the ecological effects of anti-tumor， anti-inflammatory， anti-viral and anti-bacterial activity of secondary metabolites at the cellular and molecular level； secondly， explore the intrinsic link and regularity between secondary metabolites and anti-tumor， anti-bacterial and other pharmacologically activities； thirdly， discover leading compounds which have physiological activity. Furthermore， investigate the molecular targets and mechanisms of these compounds for exploration of physiologically active mechanism of secondary metabolites from marine microorganisms. We derived 29 alkaloids， polyketide and chlorinated polyketide from three ermentation products of marine microorganisms though fermentation optimization， structured derivatives and chemical synthesis， in which 13 novel compounds and 4 novel alkaloids have strong anti-A influenza virus （H1N1） activity in vitro. We further studied the mechanisms of 2 novel compounds， which have significant anti-tumor effect in vitro and in vivo； and initially completed the evaluation of a pharmaceutical leading compound. We first discover indole diterpene alkaloids and dehydrogenation phenylalanine formed diketopiperazine alkaloids， which have anti-H1N1 activity. And Wentilactone A has significant anti-tumor effect， which is more effective than the positive control-cyclophosphamide. Furthermore， we have conducted a comprehensive study about the preparation， physicochemical properties， acute toxicity， reproductive toxicity， dosage forms， etc. of this compound. We find that Wentilactone A has good prospects of druggability. For there are no effective chemotherapy drugs against small cell lung cancer （SCLC） in the current clinical treatment， Wentilactone A which has clear effect and molecular targets against SCLC， is expected to be a promising novel， potent and selective anti-tumor drug candidate for lung cancer.
Key Words： Marine microorganisms； Natural products； Physiological activity； Pharmaceutical leading compounds