NOVEL CYTOTOXIC NATURAL PRODUCTS FROM MARINE SPONGES

来自海洋海绵的新型细胞毒性天然产品

• 批准号: 2092438
• 负责人: Phil Crews
• 金额: $ 25.22万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-04-01 至 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2092438
• 关键词: Porifera; alkaloids; alternatives to animals in research; animal extract; antineoplastics; carcinogen testing; chemical structure function; cytotoxicity; drug design /synthesis /production; drug screening /evaluation; laboratory mouse; nuclear magnetic resonance spectroscopy

This research has been designed to discover new paradigms of marine sponge-derived natural products chemistry. A long term focus is to isolate and study novel alkaloids and oxygen containing compounds. A further emphasis is to obtain compounds active against solid tumor cancers, for which there are few effective drugs. The specific aims are: (a) To discover new sponge derived anticancer agent candidates using the WSU in vitro disk-diffusion soft-agar-colony- formation-assay which detects agents with "cellular selectivity" for solid tumors by employing leukemia (L1210) cells, murine and human solid tumors (that are insensitive to conventional anticancer agents) and normal cells. (b)To continue the study of potent cytotoxic or antitumor active alkaloids or oxygen heterocycles discovered by our lab during prior research. (c) To emphasize under-explored sponge taxonomic orders such as the Choristida, Dendroceratida, Haplosclerida, Hadromerida, Lithistida, and Pioecilosclerida. (d) To explore sponge taxa which might have a broadened scope of nail products because of the presence of symbionts including photosynthetic microorganisms. (e) To efficiently purify solid tumor active cytotoxins (with emphasis on the cancers listed above) from active crude extracts by in vitro bioassay-guided isolation (f) To complete the structure elucidation of active compounds. (g)To develop new anticancer leads for future clinical trials by using in vivo evaluation in the mouse models at WSU to examine the in vitro active compounds once they have been characterized and isolated in sufficient amounts, with the highest priority given to compounds where selectivity is detected against a human tumor cell. Nonspecific cytotoxic agents have not been broadly useful in treating the common cancers noted above. Lead compounds, as potential solid tumor active agents, will be identified by a multistage process. Indo-Pacific sponges will be obtained from remote, relatively unexplored sites. Extracts and compounds will also be screened in the soft agar disk diffusion assays provided by Drs. Corbett and Valeriote at Wayne State University (WSU), and purified compounds will be evaluated, as appropriate, in the National Cancer Institute - Developmental Therapeutics Program (Na-DTP) in vitro 60-cell line panel. "Benchtop assays" are being developed at the University of California, Santa Cruz (UCSC) to speed-up the isolation of compounds from extracts active in the WSU assays. These will examine crude extracts for the ability to cause brine shrimp lethality, or to effect recombinant yeasts via mechanisms such as DNA damaging or cytoskeletal disruption. Structure determinations will emphasize contemporary NMR techniques applied in a concise fashion. Compounds active in the primary screens will be examined in secondary screens to test for selectivity, potency, mechanism of action and in vivo effects.

这项研究旨在发现海洋的新范式 海绵来源的天然产品化学。长期重点是 分离和研究新型生物碱和含氧化合物。一个 进一步的重点是获得对实体瘤的活性化合物 癌症，几乎没有有效的药物。 具体目的是：（a）发现新海绵衍生的抗癌 使用WSU在体外磁盘 - 扩散软胶合座的候选候选者 - 地层测定检测具有“细胞选择性”的药物 实体瘤通过使用白血病（L1210）细胞，鼠和人类固体 肿瘤（对常规抗癌药不敏感）和 正常细胞。 （b）继续研究有效的细胞毒性或抗肿瘤 我们实验室发现的活性生物碱或氧杂环 先前的研究。 （c）强调探索不足的海绵分类订单 例如Choristida，Dendroceratida，Haplosperida，Hadromerida， Lithistida和Pioecilesclerida。 （d）探索海绵类群 由于存在 共生体，包括光合微生物。 （e）有效 纯化实体瘤活性细胞毒素（重点是列出的癌症 上面的）通过体外生物测定引导的分离来自活性粗提取物 （f）完成活性化合物的结构阐明。 （g）到 通过使用体内开发新的抗癌引线供以后的临床试验 在WSU的小鼠模型中评估以检查体外活性 一旦将它们表征和隔离，化合物就足够 数量，优先级最高，在选择性的情况下 针对人肿瘤细胞检测到。 非特异性细胞毒性剂在治疗 上面指出的常见癌症。铅化合物，作为潜在的实体瘤 活性代理将通过多阶段过程来识别。印度太平洋 海绵将从远程，相对未探索的站点获得。 提取物和化合物也将在软琼脂盘中筛选 DRS提供的扩散测定。韦恩州的Corbett和Valeriote 大学（WSU）和纯化化合物将被评估为 适当，在国家癌症研究所 - 发展 在体外60细胞管线面板中的治疗计划（NA-DTP）。 “台式 分析”正在加利福尼亚大学圣克鲁斯分校开发 （UCSC）加快从活跃的提取物中的化合物分离 WSU测定法。这些将检查原油提取物，以便能够引起 盐水虾致死性，或通过机制实现重组酵母菌 例如DNA损伤或细胞骨架破坏。结构确定 将强调以简洁的方式应用的当代NMR技术。 主屏幕中活跃的化合物将在次级中检查 筛选以测试选择性，效力，作用机理和体内机理 效果。