ANTICANCER LEADS FROM MARINE SPONGES AND THEIR SYMBIONTS

我们的NCNPDDG项目的这个实验室计划的目标是获得 从海绵及其共生体中提取抗癌药物的线索。 将特别关注：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学家族， 富含蓝藻和可分离的培养放线菌 从海绵。山德士的合作制药集团将 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 热带海绵的新活性化合物。(b)To考察潜力 海洋放线菌（特别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)采用机制依赖性试验， 选择对新发现的和 临床上重要的分子靶点。(e)为了有效地隔离 活性粗提物的次级代谢产物， 吞吐量屏幕。(f)完成化合物的全结构解析 活性化合物(g)To通过回忆 活性物的大型生物体或大型生物体的再培养， 结构和有前途的生物活性决定了它们在 二级屏幕。 将采用多阶段工艺获得铅化合物。它首先 每年收集超过200种新的印度洋-太平洋或加勒比海海绵 以便进一步提取还将种植约100种海洋放线菌 每年的文化。这些将仅从组织中获得 热带海绵。这些大型生物的提取物， 将在初步筛选中评价微生物， 含SH 2结构域蛋白的转导抑制剂;抑制剂 核转录因子;转化逆转剂;或 与凋亡相关的药物。将对活性浸提液进行循环 生物测定导向的溶剂分配， 洁净.活性物质的结构将通过以下方式建立： 以二维核磁共振为主导的强大光谱工具 共振另一个主要屏幕线索来源将是1000 海绵和超过500种化合物主屏幕激活 将进一步研究化合物的效力，活性范围， 和体内功效。总的来说，我们认为这种方法将导致 发现对重要的实体瘤癌症有活性的新化合物 包括乳腺、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.