CHEMOPREVENTIVE AGENTS--PROVISION OF SOURCE MATERIALS

化学预防剂——原材料的提供

• 批准号: 6102498
• 负责人: NORMAN R FARNSWORTH
• 金额: $ 17.72万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2000-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6102498
• 关键词: Peru; alternative medicine; biomedical resource; cancer prevention; carcinogenesis inhibitor; chemoprevention; classification; data collection; drug discovery /isolation; field study; information systems; leaf; literature survey; medicinal plants; root; southeast Asia; systematic biology

The overall long term objectives and specific aims of this proposal concern the selection, procurement and extraction of plant materials having potential carcinogenesis inhibitory activity. The materials will be used for studies leading to the discovery and development of cancer chemopreventive agents. At the same time, this project will provide literature information services to the other projects in this Program Project. Selection of plant materials for study will be focused on (1) edible plants, primarily non-USA; (2) plants reported to have activity in an assay pertinent to cancer chemoprevention, but which have not been investigated chemically; (3) plants with no history of toxicity and minimal level of phytochemical studies; and (4) not previous investigated or minimally investigated plant species have the potential to yield novel chemical compounds. These candidate plants will be identified by an analysis of natural products literature with the aid of the NAPRALERT database. The candidate plant materials will be field collected, cultivated and/or commercially purchased. They will be dried, milled, and extracted for bioassay (Projects 3 and 4), and a decision will then be made to proceed with bioassay-directed fractionation for novel cancer chemopreventive agents from the most promising active leads. These materials (1-10 kg lots) will be extracted and supplied to Project 2 for the isolation of the active principles. All plant materials will be identified and authenticated. This project will also perform initial extraction of plant materials and scale-up isolation of confirmed active phytochemicals. The active compounds (0.05 - 1.0 g scale) will be isolated according to protocols developed by Project 2, the LC/MS/MS Core or from published literature, for evaluation of mechanism of action or chemopreventive efficiency studies (Projects 3 and 4). In addition, this project will conduct literature searched on all plants chosen for bioassay directed fractionation, and known chemical and pharmacological work on each of plant will be assembled and provided to the Principal Investigator and the Project Leaders. Issues on property rights and intellectual property rights for plant materials acquired and used for the proposed project will be carefully considered and applied, and appropriate measures will be taken to provide reciprocity (share of benefits) to collaborators and to source countries of the raw plant materials. GRANT-P01CA48112-08A1-0002 In this Program Project competitive renewal application, it is proposed to continue the discovery of novel natural products from plant sources as potential inhibitors of chemical carcinogenesis, using bioactivity- fractionation techniques. Selected non-polar and polar plant extracts prepared in another Program have shown to be active in either or both in vitro assays in a program and secondary assay in yet another program will be chromatographed according to well-established phytochemical procedures, with the fractions so obtained being monitored by the short- term in vitro bioassay in which the greatest activity was originally demonstrated. Spectroscopic and chemical methods will be used to determine the structures of pure bioactive compounds. In concert with literature data surveillance and studies in the LC/MS/MS Core, efforts will be made to minimize the re-isolation of compounds with known chemopreventive activity. Thus, it is expected that this project will continue to provide new chemical entities with cancer inhibitory activity for detailed biological evaluation. Such naturally occurring compounds might have mechanistic or even clinical value per se, or alternatively might serve as new lead compounds for subsequent synthetic modifications in the last project of this Program Project.

该提案的总体长期目标和具体目标涉及具有潜在致癌抑制活性的植物材料的选择、采购和提取。这些材料将用于导致癌症化学预防剂的发现和开发的研究。同时，本项目将为本计划项目中的其他项目提供文献信息服务。用于研究的植物材料的选择将集中于（1）可食用植物，主要​​是非美国植物； (2) 据报道，植物在与癌症化学预防相关的测定中具有活性，但尚未进行化学研究； (3) 无毒性历史且植物化学研究水平较低的植物； (4) 先前未研究过或最少研究过的植物物种具有产生新化合物的潜力。这些候选植物将借助 NAPRALERT 数据库对天然产物文献进行分析来确定。候选植物材料将被现场收集、栽培和/或商业购买。它们将被干燥、研磨和提取用于生物测定（项目 3 和 4），然后决定从最有希望的活性先导化合物中进行生物测定指导的新型癌症化学预防剂的分离。这些材料（1-10 公斤批次）将被提取并供应给项目 2，用于分离活性成分。所有植物材料都将被识别和验证。该项目还将进行植物材料的初步提取和已确认的活性植物化学物质的放大分离。将根据项目 2、LC/MS/MS 核心或已发表文献开发的方案分离活性化合物（0.05 - 1.0 g 规模），用于评估作用机制或化学预防效率研究（项目 3 和 4）。此外，该项目将对所有选择用于生物测定定向分馏的植物进行文献检索，并将每种植物的已知化学和药理学工作汇总并提供给首席研究员和项目负责人。将仔细考虑和应用拟议项目中获取和使用的植物材料的产权和知识产权问题，并将采取适当措施为合作者和植物原料来源国提供互惠（利益分享） 。 GRANT-P01CA48112-08A1-0002 在本计划竞争性更新申请中，建议利用生物活性分馏技术继续从植物来源发现新型天然产物作为化学致癌的潜在抑制剂。在另一个程序中制备的选定的非极性和极性植物提取物已显示在一个程序中的一个或两个体外测定中具有活性，并且另一个程序中的二次测定将根据完善的植物化学程序进行色谱分析，并获得如此获得的级分通过短期体外生物测定进行监测，其中最初证明了最大的活性。将使用光谱和化学方法来确定纯生物活性化合物的结构。与 LC/MS/MS 核心中的文献数据监测和研究相结合，将努力最大限度地减少具有已知化学预防活性的化合物的重新分离。因此，预计该项目将继续提供具有癌症抑制活性的新化学实体，用于详细的生物学评估。这些天然存在的化合物本身可能具有机械价值甚至临床价值，或者可以作为本计划项目最后一个项目中后续合成修饰的新先导化合物。