ANTICANCER LEADS FROM MARINE SPONGES AND THEIR SYMBIONTS

我们NCNPDDG项目的这个实验室项目的目标是获得 从海绵及其共生体中寻找抗癌药物的线索。 将特别注意：印度洋-太平洋和加勒比海绵 来自没有被很好研究的分类学家族，海绵是 富含蓝藻和可分离培养的放线菌 来自海绵。Sandoz的合作制药集团将 提供我们样品的化验工作。 该实验室的具体目标是：(A)继续探索 热带海绵寻找新的活性化合物。(B)研究潜在的 指海洋放线菌(尤其是从海绵中分离出来的) 新的活性化合物。(C)继续研究海绵 蓝藻共生体。(D)采用依赖机制的化验方法 具有抗新发现和抗细菌活性的提取物的筛选 临床上重要的分子靶点。(E)有效隔离 HIGH引导下活性粗提物的次生代谢产物 吞吐量屏幕。(F)完成对其总结构的澄清 活性化合物。(G)通过回忆以下情况启动扩大重新隔离 宏大生物体或大生物体的再培养，其小说 它们的结构和良好的生物活性决定了它们将在 次级屏幕。 将使用多阶段工艺来获得铅化合物。它的开头是 每年收集200多块新的印度洋-太平洋或加勒比海海绵 以便进一步提取。还将培养约100株海洋放线菌。 每年都在文化上。它们将完全从组织中获得 热带海绵。这些大型生物的提取物和 微生物将在寻找信号的初级筛查中进行评估 含SH2结构域蛋白的转导抑制物 核转录因子；转化剂的逆转；或 与细胞凋亡相关的药物。活性萃取物将经历一个循环 生物测定导向的溶剂分配，然后层析 净化。活性物质的结构将通过以下方式建立 以二维核磁为首的强大光谱工具 共鸣。主屏幕销售线索的另一个来源将是1,000 海绵和500多种化合物在我们的仓库里。主屏幕处于活动状态 我们将进一步研究化合物的效力、活性广度、 和体内疗效。总体而言，我们相信这种方法将导致 抗重要实体肿瘤活性新化合物的发现 包括乳房、结肠、肺、卵巢和前列腺。

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.