海洋微生物次生代謝產物的生理活性和作用機制年度報告

黃才國

摘 要：海洋微生物已成為海洋新天然產物的主要來源之一，從2009年開始發(fā)現(xiàn)的海洋新天然產物的1/3以上者是由海洋微生物產生的。從這些天然產物中尋找有重要作用的藥物先導化合物，對于開發(fā)新的藥物有重要的意義。該研究圍繞其中成藥性高的含氮和鹵代化合物，展開研究，通過培養(yǎng)基優(yōu)化和環(huán)境脅迫，從海洋微生物的發(fā)酵產物中獲得結構新穎的、具有顯著活性的含氮和鹵代等海洋新天然產物。利用抗腫瘤等細胞或分子篩選模型，在細胞和分子水平上對具有生態(tài)學效應的次生代謝產物進行抗腫瘤、抗炎、抗病毒和抗菌等活性評價；探討具有生態(tài)學效應的次生代謝產物與抗腫瘤、抗菌等藥理活性之間的內在聯(lián)系和規(guī)律性；發(fā)現(xiàn)生理活性先導化合物，并對某些具有顯著生理活性的分子進行作用靶點和作用機制的探索，從而探討海洋微生物次生代謝產物的生理活性機制。通過發(fā)酵優(yōu)化、結構衍生和化學合成，從3株海洋微生物發(fā)酵產物中獲得了29個生物堿和聚酮及其氯代化合物，其中13個為新化合物、4個新生物堿體外具有強抗甲型流感病毒（H1N1）活性。對2個具有顯著抗腫瘤作用的化合物在體內外進行了深入的抗腫瘤作用的研究，并初步完成了1個藥物先導化合物的成藥性評價。首次發(fā)現(xiàn)吲哚二萜生物堿和脫氫苯丙氨酸構成的二酮哌嗪生物堿具有抗H1N1病毒活性，發(fā)現(xiàn)化合物Wentilactone A有較強的抗肺癌作用，其抗腫瘤作用效果優(yōu)于陽性對照環(huán)磷酰胺。并對該化合物的制備工藝、理化性質、急性毒性、生殖毒性、劑型等進行了全面的研究，成藥性前景良好，鑒于目前臨床上尚未有非常有效地針對小細胞肺癌的化療藥物，該次研究發(fā)現(xiàn)的化合物具有對小細胞肺癌非常明確的療效，且作用靶點明確，有望開發(fā)成為一類新藥。

關鍵詞：海洋微生物 天然產物 生理活性 藥物先導化合物

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