ANTICANCER LEADS FROM MARINE SPONGES AND THEIR SYMBIONTS

海洋海绵及其共生体具有抗癌作用

• 批准号: 6102633
• 负责人: Phil Crews
• 金额: $ 10.92万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6102633
• 关键词: Actinomycetales; Dinoflagellates; Porifera; antineoplastics; apoptosis; aquatic organism; bioassay; biological products; biological signal transduction; cooperative study; inhibitor /antagonist; microorganism culture; neoplasm /cancer pharmacology; nuclear magnetic resonance spectroscopy; oncogenes; photosynthetic bacteria; saltwater environment; symbiosis; transcription factor; tumor suppressor genes

The goal of this laboratory program of our NCNPDDG project is to obtain leads for anticancer drugs from marine sponges and their symbionts. Special attention will be given to: Indo-Pacific and Caribbean sponges from taxonomic families that have not been well studied, sponges that are rich in cyanobacteria and cultured actinomycetes that can be separated from sponges. The collaborating Pharmaceutical group at Sandoz will provide the assay work on our samples. Specific aims of this laboratory are: (a) To continue the exploration of tropical sponges for novel active compounds. (b)To examine the potential of marine actinomycetes (especially those separated from marine sponges) for novel active compounds. (c) To continue the study of sponges with cyanobacterial symbionts. (d) To employ mechanism-dependent assays for selection of extracts with activity against newly discovered and clinically important molecular targets. (e) To efficiently isolate secondary metabolites from active crude extracts guided by high throughput screens. (f) To complete the total structure elucidation of active compounds. (g)To initiate scale-up reisolation by recollection of macroorganism or reculture of macro organisms of actives whose novel structure and promising bioactivity dictate their further study in the secondary screens. A multistage process will be used to obtain lead compounds. it begins by collecting annually, more than 200 new Indo-Pacific or Caribbean sponges for further extraction. About 100 marine actinomycetes will also be grown in culture each year. These will be obtained exclusively from the tissue of tropical sponges. The extracts of these macroorganisms and microorganism will be evaluated in primary screens which seek: signal transduction inhibitors of the SH2 domain containing proteins; inhibitors of nuclear transcription factors; reversal of transformation agents; or drugs relevant to apoptosis. Active extracts will be subjected to a cycle of bioassay-directed solvent partitioning and then chromatographic purification. The structures of the actives will be established by powerful spectroscopic tools headed by two-dimensional nuclear magnetic resonance. Another source for primary screen leads will be the 1,000 sponges and over 500 compounds in our repository. Primary screen active compounds will be further studied for their potency, breadth of activity, and in vivo efficacy. Overall, we believe this approach will lead to the discovery of new compounds active against important solid tumor cancers including breast, colon, lung, ovarian and prostate.

我们的NCNPDDG项目的实验室计划的目标是获得 来自海洋海绵及其共生体的抗癌药物的铅。 将特别注意：印度太平洋和加勒比海海绵 来自尚未得到很好研究的分类家庭，海绵是 富含蓝细菌和可以分开的培养的放线菌 来自海绵。 Sandoz的合作制药小组将 在我们的样品上提供测定工作。 该实验室的具体目的是：（a）继续探索 新型活性化合物的热带海绵。 （b）检查潜力 海洋放线菌（尤其是那些与海绵分离的菌） 用于新型活性化合物。 （c）继续研究海绵 蓝细菌共生体。 （d）采用机制依赖性测定 选择具有针对新发现的活动的提取物和 临床上重要的分子靶标。 （e）有效隔离 由高高指导的活性原油提取物的二级代谢产物 吞吐量屏幕。 （f）完成总结构 活性化合物。 （g）通过回忆起来 宏观生物或宏观生物的宏观生物，其小说 结构和有希望的生物活性决定了他们在 次级屏幕。 多阶段过程将用于获得铅化合物。它始于 每年收集200多个新的印度太平洋或加勒比海 用于进一步提取。大约100个海洋放线菌也将种植 每年的文化。这些将仅从组织中获得 热带海绵。这些宏观生物的摘录和 微生物将在寻求的主要屏幕中进行评估：信号 含有蛋白质的SH2结构域的转导抑制剂；抑制剂 核转录因子；转换剂的逆转；或者 与凋亡有关的药物。主动提取物将经历一个周期 生物测定指导的溶剂分配，然后色谱法 纯化。活跃人士的结构将由 强大的光谱工具以二维核磁力为首 谐振。主要屏幕线索的另一个来源将是1,000 我们的存储库中的海绵和500多种化合物。主屏幕活动 将进一步研究化合物的效力，活动广度， 和体内功效。总体而言，我们相信这种方法将导致 发现活跃的重要实体瘤癌的新化合物 包括乳房，结肠，肺，卵巢和前列腺。