NEW ANTITUMOR AND ANTIFUNGAL NATURAL PRODUCTS FROM FUNGI

来自真菌的新型抗肿瘤和抗真菌天然产品

• 批准号: 2084100
• 负责人: JAMES B GLOER
• 金额: $ 6.75万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-08-01 至 1995-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2084100
• 关键词: Aspergillus; Fungi; antifungal agents; antineoplastics; antiviral agents; biological products; chromatography; drug screening /evaluation; fresh water environment; immunomodulators; pharmacokinetics; saltwater environment; spectrometry

Many useful drugs have been discovered through studies of microbial natural products. However, there are a number of fungal subgroups that have not been widely studied for secondary metabolite production. Furthermore, certain aspects of the ecology and life-cycles of many of these fungi specifically suggest that they should be targeted for exploration in the search for new biologically active natural products. Antagonism between species of naturally-competing fungi has been the subject of numerous literature reports. Compounds responsible for such effects are essentially natural antifungal agents, which may also exhibit other useful bioactivities. Other fungi occupy unique nutritional environments, suggesting that they may possess metabolic adaptations that differ from more common fungi. Yet another group of fungi produce large physiological structures called sclerotia that are vital to the survival of the organism, and there is significant evidence that many of these sclerotia contain unique bioactive secondary metabolites that deter feeding by fungivorous insects. Our interests lie with three subgroups of fungi that exhibit such characteristics: coprophilous, marine/aquatic, and sclerotium-forum fungi. We propose that these three types of fungi comprise a potentially valuable source of new natural products with pharmacological activity. Therefore, we intend to undertake studies of the secondary metabolites of these three fungi subgroups in search of novel compounds with antifungal, antitumor, antiviral, and other potentially useful bioactivities. Our approach to this research is largely non-random, since it is based on the application of literature evidence, ecological rationale, and taxonomic relationships. Fungal species will be chosen for study on the basis of literature reports of antagonistic effects toward competitors, late occurrence in fungal successions, occurrence in marine environments, sclerotium-forming ability, and taxonomic relationship to fungi that have already yielded bioactive agents in our preliminary studies. Fresh isolates of fungi species and sample of fungi sclerotia will be obtained through collaborative arrangements with experts in the fields of mycology and fungal taxonomy. Prescreens of culture filtrates, extracts, chromatographic fractions, and purified metabolites for antifungal, antibiotic, and potential antitumor activities will be conducted in our laboratory, and a battery of 25 additional screens (antitumor, antiviral, antifungal, immunomodulatory, etc.) will be conducted by a cooperating pharmaceutical company. State-of-the art chromatographic and spectroscopic techniques will be used in the isolation and structure determination of active metabolites. Initial results indicate that a high percentage of the fungi we have selected thus far produce extracts that exhibit activity, and we have isolated and characterized over twenty new biologically active natural products using this approach. Through our studies in this area, we propose to explore the natural products chemistry of these fungi subgroups, while evaluating the potential of an ecologically-based approach to the discovery of novel bioactive agents.

通过对微生物的研究发现了许多有用的药物 天然产品。然而，有许多真菌亚群 对于次生代谢物的产生还没有广泛的研究。 此外，许多物种的生态和生命周期的某些方面 这些真菌特别建议它们应该成为目标 在寻找新的生物活性天然产物方面的探索。 自然竞争的真菌物种之间的对抗一直是 成为众多文学报道的主题。对此负责的化合物 效果本质上是天然的抗真菌药物，它也可能表现出 其他有用的生物活动。其他真菌具有独特的营养价值 环境，这表明它们可能具有代谢适应能力， 不同于更常见的真菌。还有一组真菌产生了大量的 被称为菌核的对生存至关重要的生理结构 而且有重要的证据表明，其中许多 菌核含有独特的生物活性次生代谢产物，可以阻止 以食真菌昆虫为食。我们的利益在于以下三个子组 表现出这些特征的真菌：共生的，海洋/水生的，和 菌核-论坛真菌。我们认为这三种真菌 包含潜在有价值的新天然产品来源，具有 药理活性。因此，我们打算进行以下研究： 寻找这三个真菌亚群的次生代谢产物 具有抗真菌、抗肿瘤、抗病毒等功能的新型化合物 潜在的有用的生物活动。 我们对这项研究的方法在很大程度上是非随机的，因为它基于 应用文献证据、生态学原理和 分类关系。将选择真菌物种进行研究 对竞争者产生对抗效应的文献报道的基础， 在真菌演替中出现较晚，在海洋环境中出现， 菌核形成能力及其与真菌的分类关系 在我们的初步研究中已经产生了生物活性物质。新鲜的 将获得真菌种类的分离和真菌菌核样本 通过与真菌学领域的专家合作安排 和真菌分类学。培养滤液、萃取物、 层析组份和抗真菌的纯化代谢物， 抗生素和潜在的抗肿瘤活性将在我们的 实验室，以及一组额外的25个筛查(抗肿瘤、抗病毒、 抗真菌、免疫调节等)将由一位合作的 一家制药公司。最先进的色谱学和 光谱技术将用于分离和结构 活性代谢物的测定。初步结果表明， 到目前为止，我们所选择的真菌中有百分比产生的提取物 展示活动，我们已经分离并鉴定了20多个新的 使用这种方法的具有生物活性的天然产品。通过我们的 在这方面的研究，我们建议探索天然产物的化学 这些真菌亚群，同时评估一个潜在的 以生态为基础的方法发现新的生物活性物质。