CHEMOPREVENTIVE AGENTS--PROVISION OF SOURCE MATERIALS

化学预防剂——原材料的提供

• 批准号: 6444602
• 负责人: NORMAN R FARNSWORTH
• 金额: $ 22.84万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-05 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6444602
• 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.

本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。这些材料将用于研究，导致癌症化学预防剂的发现和开发。同时，本项目还将为本项目的其他项目提供文献信息服务。研究的植物材料的选择将集中在（1）可食用植物，主要是非美国;（2）据报道在与癌症化学预防有关的测定中具有活性，但尚未进行化学研究的植物;（3）没有毒性史和最低水平的植物化学研究的植物;和（4）以前没有研究或研究很少的植物物种具有产生新化合物的潜力。这些候选植物将通过NAPRALERT数据库的帮助下的天然产物文献的分析来确定。候选植物材料将在田间收集、栽培和/或商业购买。它们将被干燥、研磨并提取用于生物测定（项目3和4），然后决定进行生物测定导向的分级分离，从最有希望的活性先导化合物中分离出新的癌症化学预防剂。这些材料（1-10 kg批次）将被提取并提供给项目2，用于分离有效成分。所有工厂材料都将被识别和认证。该项目还将对植物材料进行初步提取，并对已确认的活性植物化学物质进行大规模分离。根据项目2开发的方案（LC/MS/MS核心或已发表文献）分离活性化合物（0.05 - 1.0 g规模），用于评价作用机制或化学预防效率研究（项目3和4）。此外，本项目将对选择用于生物测定定向分馏的所有植物进行文献检索，并将收集每种植物的已知化学和药理学工作，并提供给主要研究者和项目负责人。将认真考虑和适用关于为拟议项目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，向合作者和植物原材料来源国提供互惠（利益分享）。GRANT-P01 CA 48112 - 08 A1 -0002在本计划项目竞争性更新申请中，建议使用生物活性分级技术继续发现植物来源的新型天然产物作为化学致癌作用的潜在抑制剂。在另一个程序中制备的所选非极性和极性植物提取物已显示在程序中的任一体外测定中或两种体外测定中具有活性，并且将根据完善的植物化学程序对另一个程序中的二级测定进行色谱分析，其中通过最初证明最大活性的短期体外生物测定来监测如此获得的级分。光谱和化学方法将用于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一致，将努力尽量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，以进行详细的生物学评价。这些天然存在的化合物本身可能具有机理甚至临床价值，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。