Discovery of Anticancer Agents of Diverse Natural Origin

总体项目摘要 在本计划项目更新申请中，申请人群体代表三个主要机构， 俄亥俄州州立大学（OSU）、伊利诺伊大学芝加哥分校（UIC）和北卡罗来纳州大学 在格林斯伯勒（UNCG）。参与者结合了他们在隔离，结构， 说明，和天然产物的生物评价，以发展一个巩固的，综合的， 发现发展为癌症的不同来源的新抗癌剂的计划 化疗剂。将在项目1（OSU）中研究的植物材料将由建立的 在NAPRALERT数据库（项目2; UIC）的帮助下，位于热带国家的植物学家，以及 地衣及其相关真菌（项目1）、蓝细菌（项目2）和丝状真菌（项目3; UNCG）也将被访问。所获得的微生物将在各种相关的电池中进行提取和评估。 目前在OSU（项目1），UIC运行的基于机制、基于细胞和肿瘤生长相关的检测 (Core 1），哥伦比亚大学（通过项目3），并通过其他外部合作者（通过核心A在俄勒冈州立大学）。 已知活性化合物的去复制将在OSU、UIC和UNCG使用计算机化技术完成。 文献调查和LC-MS结合生物测定。将在项目中采用生物测定指导的分级分离 1-3用于阐明活性成分。通过药用主导活性天然产品的开发 化学和药代动力学相关研究将在俄勒冈州立大学（核心2）进行，由俄勒冈州立大学促进 生物统计组（核心A）。因此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和一些外部合作者）。小组决定将 关于进一步开发潜在用作抗癌剂的药剂，更先进的 生物学和毒理学试验的各个阶段将通过与药物发现研究所的协商来帮助进行 OSU综合癌症中心（通过核心A）。联合会将在以下各方的参与下开展工作： 国家癌症研究所计划官员在发现过程中，并计划举行定期会议的关键科学人员 （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- 制作流程，由核心A组织。出色的隔离设施，结构确定， 化学修饰、合成、体内外生物学评价及项目总体资料 管理可用。本P01的总体目标是确定最终具有以下特性的先导化合物： 治疗癌症的治疗价值。

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.