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: 2092437
• 负责人: Phil Crews
• 金额: $ 15.39万
• 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 1995-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2092437
• 关键词: Porifera; Tunicata; X ray crystallography; alkaloids; alternatives to animals in research; animal extract; antineoplastics; chemical models; chemical structure function; computer simulation; cytotoxicity; drug design /synthesis /production; drug screening /evaluation; heterocyclic compounds; nuclear magnetic resonance spectroscopy; saltwater environment; Porifera; Tunicata; X ray crystallography; alkaloids; alternatives to animals in research; animal extract; antineoplastics; chemical models; chemical structure function; computer simulation; cytotoxicity; drug design /synthesis /production; drug screening /evaluation; heterocyclic compounds; nuclear magnetic resonance spectroscopy; saltwater environment

DESCRIPTION (Investigator's Abstract): The project aim is to contribute to the search of new cancer chemotherapy agents. This research will discover and study novel marine sponge-derived compounds possessing in vitro potency against slow growing tumor cells. Cancer assay models are provided by two collaborators, Dr. Jake Clement of Abbott Laboratories, and the National Cancer Treatment (NCI-DCT) group, coordinated by Dr. Ven Narayanan. The long term goals are: (a) to uncover new structural concepts for cytotoxic active natural products, (b) to employ a concise approach which involves rapid in vitro assays as a tool to screen extracts from meagerly explored marine sponge families, (c) to isolate cytotoxic principles from sponge taxa predicted as being a source of natural products biosynthesized by symobionts including photosynthetic microogranisms or heterotrophic bacteria, (d) to efficiently elucidate the structures of active compounds, (e) to pursue and modify potent cytotoxic alkaloids discovered during the investigators prior research, and (f) to forward the most selective in vitro active natural product or semisynthetic derivatives to the collaborators for in vivo assay follow-up. An innovative experimental plan is in place to guide this project. Special emphasis is being devoted to taxa from two sponge orders, Choristida and Poecilosclerida. The investigator's work to date has shown that sponges of the former order can be considered as a prime source for novel cytotoxic alkaloids. The literature provides justification for the belief that sponges of the latter order are a source of diverse heterocyclics possibly derived from symbiotic heterotrophic microorganisms. Selected genera from other sponge orders, which may possess photosynthetic symbionts such as cyanobacteria, are targeted for investigation because they should yield new secondary metabolites. Compounds with novel structures will be completely defined by exhaustive NMR study, computer molecular modeling, and X-ray examination when suitable crystals can be grown. A part of this project will be the continuation of studies on sponge products possessing desirable cytotoxicities. This will involve cytotoxic alkaloids from as many as eleven structural classes discovered during the investigator's prior research. Corresponding attention will be given to isolating analogs and preparing semisynthetic derivatives of these active lead compounds.

描述（调查员的摘要）：项目的目的是为 寻找新的癌症化疗剂。 这项研究会发现 并研究具有体外的新型海绵衍生的化合物 针对缓慢生长的肿瘤细胞的效力。 癌症测定模型是 由两个合作者提供，雅培实验室的杰克·克莱门特博士， 由Ven博士协调的国家癌症治疗（NCI-DCT）组 纳拉亚南。 长期目标是：（a）发现新的结构 细胞毒性活性天然产品的概念，（b）采用简洁 涉及快速体外测定作为筛选提取物的工具的方法 从经过少量探索的海洋海绵家族（C）到分离细胞毒性 海绵类群的原则被预测为自然的来源 由Symobionts（包括光合作用）生物合成的产品 微型植物或异养细菌，（d）有效阐明 活性化合物的结构，（e）追求和修饰有效的细胞毒性 在调查人员之前发现的生物碱事先研究，（f） 转发最有选择性的体外活性天然产品或 与合作者进行体内测定后续过程的半合成衍生物。 制定了一个创新的实验计划来指导该项目。 特别的 重点是从两个海绵命令（Choristida）和 Poecilesclerida。 调查员迄今为止的工作表明 以前的顺序可以被视为新型细胞毒性的主要来源 生物碱。 文献为信念提供了理由 后一种海绵是多种杂环的来源 源自共生的异养微生物。 选择的属 其他海绵订单，可能具有光合物共生体，例如 蓝细菌是针对调查的，因为它们应该产生新的 次生代谢产物。 具有新颖结构的化合物将完全 由详尽的NMR研究，计算机分子建模和X射线定义 检查合适的晶体可以种植。这个项目的一部分 将继续对拥有海绵产品的研究 理想的细胞毒性。 这将涉及来自AS的细胞毒性生物碱 许多是在研究者的中发现的11个结构类别 先前的研究。 将给予相应的注意力隔离类似物 并制备这些活性铅化合物的半合成衍生物。