Discovery of Anticancer Agents of Diverse Natural Origin

整体项目总结 在本次计划项目续签申请中，申请者群体代表三所初级院校， 俄亥俄州立大学(OSU)、伊利诺伊大学芝加哥分校(UIC)和北卡罗来纳大学 在格林斯博罗(U.G)。参与者结合了他们在与世隔绝的结构、结构 阐明，并对天然产物进行生物评价，使之发展成一种综合、综合的 发现不同来源的新型抗癌药物以开发为癌症的计划 化疗药物。将在项目1(OSU)中研究的植物材料将由 在NAPRALERT数据库(项目2；UIC)的协助下，热带国家的植物学家，以及 地衣及其真菌(项目1)、蓝藻(项目2)和丝状真菌(项目3； 也将访问)。获得的生物体将被提取并在不同的相关电池中进行评估 目前在俄亥俄州立大学(项目1)，UIC进行的基于机制、基于细胞和与肿瘤生长相关的分析 (CORE 1)、哥伦比亚大学(通过项目3)和其他外部合作者(通过俄勒冈州立大学的CORE A)。 已知活性化合物的去复制将在OSU、UIC和UNG使用计算机化完成 文献综述和LC-MS与生物分析相结合。生物测定定向分馏将在项目中使用 1-3用于有效成分的阐明。通过医药带动活性天然产物的开发 化学和药代动力学相关研究将在俄亥俄州立大学(核心2)进行，由俄亥俄州州立大学协助 生物统计学小组(核心A)。这样发现的新的活性化合物将在我们的小组中进一步评估 体外和体内生物测定(项目1和3，核心A，以及一些外部合作者)。集体决策将 关于潜在用作抗癌剂的试剂的进一步开发。更高级的 生物和毒理学测试阶段将通过与药物发现研究所协商而得到帮助 俄亥俄州立大学综合癌症中心(通过核心A)。该财团将与以下机构合作 NCI计划官员在发现过程中，并计划定期举行关键科学人员会议 (包括我们的外部和OSU内部科学咨询委员会)，以加强沟通和决策- 制造过程，由Core A组织。用于隔离、结构确定、 化学修饰、合成、体外和体内生物学评价，以及整个项目数据 管理层是可用的。本P01的首要目标是确定最终具有 对癌症的治疗价值。

OVERALL PROJECT SUMMARY In this Program Project renewal application, the applicant group is representative of three primary institutions, The Ohio State University (OSU), the University of Illinois at Chicago (UIC), and the University of North Carolina at Greensboro (UNCG). The participants have combined their vast experience in the isolation, structure elucidation, and biological evaluation of natural products, to the development of a consolidated, integrated program for the discovery of novel anticancer agents of diverse origin for development as cancer chemotherapeutic agents. Plant materials to be studied in Project 1 (OSU) will be collected by established botanists located in tropical countries with the assistance of the NAPRALERT database (Project 2; UIC), and lichens and their fungal associates (Project 1), cyanobacteria (Project 2) and filamentous fungi (Project 3; UNCG) will also be accessed. Organisms acquired will be extracted and evaluated in a diverse battery of relevant mechanism-based, cell-based, and tumor-growth related assays currently operational at OSU (Project 1), UIC (Core 1), Columbia University (through Project 3), and via other external collaborators (through Core A at OSU). Dereplication of known active compounds will be accomplished at OSU, UIC, and UNCG using computerized literature surveys and LC-MS coupled to bioassays. Bioassay-directed fractionation will be employed in Projects 1-3 for the elucidation of the active principles. Lead development of active natural products via medicinal chemistry and pharmacokinetics-related studies will be conducted at OSU (Core 2), facilitated by the OSU Biostatistics group (Core A). Novel, active compounds thus discovered will be further evaluated in our panel of in vitro and in vivo bioassays (Projects 1 and 3, Core A, and some external collaborators). Group decisions will be made regarding the further development of agents for potential use as anticancer agents. The more advanced stages of biological and toxicological testing will be aided through consultation with the Drug Discovery Institute of the OSU Comprehensive Cancer Center (through Core A). The Consortium will work with the involvement of the NCI Program Official in the discovery process, and plans to hold regular meetings of key scientific personnel (inclusive of our External and OSU Internal Scientific Advisory Boards) to enhance communication and decision- making processes, to be organized by Core A. Excellent facilities for the isolation, structure determination, chemical modification, synthesis, and in vitro and in vivo biological evaluation, and overall project data management are available. The overarching goal of this P01 is to identify lead compounds that ultimately have therapeutic value for the treatment of cancer.