Isolation Chemistry of Tropical Plants and Biological Evaluation

热带植物的分离化学和生物学评价

• 批准号: 9268416
• 负责人: Alan Douglas Kinghorn
• 金额: $ 25.23万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-14 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9268416
• 关键词: Accelerometer; Acoustic Neuroma; Antineoplastic Agents; B-Lymphocytes; Back; Biological; Biological Assay; Biological Testing; Biometry; Breast; Cancer Hospital; Cell Line; Cells; Chemicals; Chemistry; Chicago; Chronic Lymphocytic Leukemia; Collaborations; Collection; Colon; Cutaneous; Development; Drug Kinetics; Evaluation; Fiber; Formulation; Fractionation; Funding; Goals; Hepatitis; Hormones; Illinois; In Vitro; Institutes; Knowledge; Laboratories; Laboratory Research; Lead; MCF7 cell; MDA MB 435; Malignant Neoplasms; Medical center; Membrane Potentials; Metabolism; Methodology; Methods; Mitochondria; Modernization; Multiple Myeloma; National Cancer Institute; Natural Killer Cells; Neurofibromatosis 2; North Carolina; Nuclear; Ohio; Patients; Pharmaceutical Chemistry; Pharmacologic Substance; Pharmacy facility; Plant Extracts; Plants; Primary Neoplasm; Procedures; Process; Research; Research Personnel; SW620; Sampling; Semaphorin-3; Semaphorins; Solubility; Solvents; Standardization; Structure; System; T-Cell Lymphoma; Techniques; Testing; Universities; Vascular Plant; Viral; Work; X-Ray Crystallography; Xenograft procedure; base; cancer cell; chemotherapeutic agent; college; experience; in vitro testing; in vivo; interest; melanoma; meningioma; multidisciplinary; novel anticancer drug; preclinical evaluation; programs; scale up; screening; solvent extraction

Project 1 at The Ohio State University (OSU) is comprised of isolation chemistry, dereplication, and biological testing components. Specific Aims 1-4 will involve: (a) preparing extracts of all primary plant materials provided mainly from Project 2 (University of Illinois at Chicago, UIC) for initial biological screening; (b) LC-MS dereplication studies on active leads following preliminary screening (in order to prioritize samples for activity-guided fractionation); (c) purification procedures using chromatographic methods (guided by both in-house bioassays and those elsewhere, in the program project); and (d) compound structure elucidation, respectively. The structures of bioactive compounds will be determined using modern spectroscopic methods, backed up by chemical transformations and X-ray crystallography [work to be performed Projects 1, 2, and the medicinal chemistry portion of Core B (OSU)], where necessary. In Specific Aim 5, plant extracts will be subjected to primary screening against a small panel of cancer cells at Core A (UIC). Extracts of interest will then be submitted for testing in Project 1 (OSU), Project 3 [Columbia University via the University of North Carolina at Greensboro (UNCG)], and a new pharmaceutical partner, Eisai Inc., Andover, MA (through Core C at OSU)}: The Project 1 bioassays will involve testing against the OSU-CLL (chronic lymphocytic leukemia) and OSU-NB (normal B-cell) cell lines, and against primary tumor samples from CLL patients at the OSU James Cancer Hospital. Testing will also occur with three in-house mechanistic assays [viz., nuclear factor-κB (NF-κB), mitochondrial transmembrane potential (MTP) inhibition, and Semaphorin-3]. Active compounds from Project 1 will also be tested in the in vitro biological test systems available at UIC (Core A), Columbia University (Project 3), and Eisai Inc. (through Core C), with promising compounds also evaluated in in vivo assays in Cores A and C. Collaborative in vitro and testing on promising lead compounds from Project 1 will be performed with colleagues at The Oho State University Wexner Medical Center (OSUWMC). In Specific Aim 6, scale-up isolations when required by programmatic needs, with compound scale up also conducted by synthesis in collaboration with Core B. Stringent efforts will be made to progress new bioactive compounds towards preclinical evaluation as potential anticancer compounds.

俄亥俄州州立大学（OSU）的项目1包括分离化学、去复制和 生物测试组件。具体目标1-4将涉及：（a）制备所有初级植物的提取物 材料主要由项目2（伊利诺伊大学芝加哥分校，UIC）提供，用于初始生物学 筛选;（B）初步筛选后对活性先导物的LC-MS去复制研究（以便 （c）使用色谱法进行纯化程序; 方法（由内部生物测定法和其他地方的生物测定法指导，在方案项目中）;以及（d） 分别进行化合物结构解析。生物活性化合物的结构将被确定 利用现代光谱学方法，并辅以化学转化和X射线晶体学， [work待执行项目1、2和核心B（OSU）的药物化学部分]，其中 必要在具体目标5中，将对植物提取物进行初步筛选， 核心A（UIC）的癌细胞。感兴趣的摘录将提交项目1（OSU）进行测试， 项目3 [哥伦比亚大学通过格林斯伯勒的北卡罗来纳州大学（UNCG）]，以及一个新的 制药合作伙伴，Pastai Inc.，Andover，MA（通过OSU的Core C）：项目1生物测定将 涉及针对OSU-CLL（慢性淋巴细胞白血病）和OSU-NB（正常B细胞）细胞系的测试， 以及针对来自OSU James癌症医院的CLL患者的原发性肿瘤样品。测试也将 用三种内部机理测定法进行[即，核因子-κB（NF-κB），线粒体跨膜 潜在（MTP）抑制和脑信号蛋白-3]。项目1的活性化合物也将在 UIC（核心A）、哥伦比亚大学（项目3）和Pakistai Inc.提供的体外生物学试验系统。 （通过核心C），其中也在核心A和C中的体内测定中评价了有前景的化合物。 将对项目1中有前途的先导化合物进行体外合作和测试， 俄亥俄州州立大学韦克斯纳医学中心（OSUWMC）的同事。在具体目标6中，扩大规模 方案需要时进行分离，也可通过合成扩大化合物规模， 与核心B的合作。将做出严格的努力，以开发新的生物活性化合物， 作为潜在抗癌化合物的临床前评价。