【作者】 于志国；

【导师】 毕开顺； 郭跃伟；

【作者基本信息】 沈阳药科大学 ， 药物分析学， 2005， 博士

【摘要】 海绵是结构简单的低等动物，机体由多细胞组成，但细胞间仅有功能上的差异，还未形成组织或器官。海绵体内存在一种高效的过滤管系统，大量海水连同各种营养物质从中通过，经过滤后在各个功能细胞区被消化，进而为海绵的生长和繁殖提供养料和氧气。所以海绵可以在营养贫瘠的环境中生长，而且大多数海绵中有微生物与其共生。海绵广泛分布于海洋中，从热带海域到温带海域甚至极地海域都发现有海绵存在。海绵通常能够产生大量的活性次生代谢产物用于防止腐生生物的危害，这一特点也使海绵在与其它生物的竞争中处于优势地位，而人类则把海绵作为活性新药先导化合物的来源。运用正相硅胶柱、凝胶Sephadex LH-20柱以及高效液相等多种层析技术，对采自我国海南陵水海域的三种海绵进行了较深入的化学成分的研究，从中共分离鉴定了51个化合物，包括24个倍半萜、22个二倍半萜、1个三萜、3个吲哚类化合物和1个甾醇。通过综合波谱分析技术鉴定了上述化合物的结构，51个化合物中有10个新化合物，它们是二倍半萜hyrtiosin A-E；吲哚生物碱hyrtioindolealkaloid；螺环倍半萜spirofragilin；含甲酰胺基团的倍半萜acanformamide：含异硫腈基团的倍半萜acanisothiocynate和acanisothiobisabolene。另外还有3个化合物第一次从自然界分离得到。己知化合物中有18个是首次从我国南海海绵中分离得到。还发现新螺环倍半萜spirofragilin在氘代氯仿（CDCl₃）中室温下会发生化学变化，生成二聚体，并且通过单晶X-衍射分析确定了二聚体的结构。通过广泛的生物活性筛选，发现化合物204（heteronemin）对人肺癌A-549、人白血病HL-60、人宫颈癌HELA和人肝癌BEL-7402等四个细胞株的增殖有抑制作用，IC₅₀分别为2.31×10^-10M，1.92×10^-7M，2.42×10^-6M和1.72×10^-8M。还发现化合物222（hyrtiosal）、208（12，18-diepiscalaradial）、212（scalarafuran）具有PTP1B酶抑制作用，IC₅₀分别为6.04×10^-5M，3.16×10^-5M和5.42×10^-5M。更多还原

【Abstract】 The marine sponges are considered to be primitive organisms, with relative simple internal organization. The constituent cells of marine sponges form neither tissue layer nor organs, however, it dose perform specialized functions depending on the location within the sponge. Marine sponges have a very strong pumping capability of filtering a large volume of water through its tissues for food and oxygen, it is thus not surprising that marine sponges can live in a poor nutrient environment and many marine sponges contain symbiotic micro-organisms. Marine sponges occur in all oceans and have a wide distribution from tropical to temperate to arctic regions. They frequently produce large quantities of secondary metabolites to deter potential predators and to inhibit the growth of fouling organisms, and thus become one of important sources of bioactive marine natural products.In the process of searching for bioactive compounds, we have successively investigated three species of marine sponges collected off the Lingshui Bay, Hainan Province, China. By repeatedly chromatography on gel Sephadex LH-20 and silica gel columns, as well as purification by RP-HPLC, 51 compounds were obtained from the acetone extracts of the three species, including 24 sesquiterpens, 22 sesterterpenes, 1 triterpene, 3 indole compounds and 1 sterol. The structures of the compounds were elucidated on the basis of extensive spectroscopic analysis and comparison with reported data, one of which was secured by X-ray diffraction analysis experiment. Ten of the metabolites were identified as new compounds, and three were isolated from the natural source for the first time. The interesting fact is that the new spiro-sesquiterpene could convert to its dimer in dauterated chloroform solution under room temperature, which was further confirmed by X-ray diffraction analysis.All the compounds were subjected to a series of bio-screening experiments. Heteronemin was found to be cytotoxic against A-549, HL-60, HELA and BEL-7402 with IC₅₀ of 2.31×10^-10M, 1.92×10^-7M, 2.42×10^-6M and 1.72×10^-8M, respectively. Hyrtiosal, 12, 18-diepiscalaradial, and scalarafuran were found to show inhibitory activity against PTP1B with IC₅₀ of 6.04×10^-5M, 3.16×10^-5M, and 5.42×10^-5M, respectively.更多还原