ISOLATION OF NOVEL MECHANISM-BASED ANTITUMOR AGENTS

基于新机制的抗肿瘤药物的分离

• 批准号: 6102581
• 负责人: DAVID GEORGE IAN KINGSTON
• 金额: $ 14.83万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2000-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6102581
• 关键词: DNA damage; DNA topoisomerases; Saccharomyces cerevisiae; X ray crystallography; antineoplastics; bioassay; biological products; chemical structure function; chromatography; drug screening /evaluation; enzyme inhibitors; stereochemistry

The overall objective of the proposed research is to discover new natural products with significant clinically useful anticancer activity. The specific aims of the program are: 1. To acquire 20-40 extracts per year which show good in vitro activity in topoisomerase I inhibition, topoisomerase II inhibition, or DNA damaging bioassays, The active extracts will come wither from preliminary screening carried out at the University of Virginia as part of the core activities of this Group, preliminary screening carried out at SmithKline Beecham Pharmaceuticals, or from screening carried out by us in collaboration with various colleagues around the world. 2. To fractionate each of the active extracts using a bioassay-directed fractionation scheme, and to isolate pure active compounds with selective activity in one of the bioassays indicated. 3. To determine the structures of all active compounds by whichever combination of chemical manipulation, spectroscopic techniques,a nd X-ray crystallography proves most appropriate to the specific problem. 4. To reisolate adequate amounts of all active compounds for further biological evaluation by Laboratory Program 1 (SmithKline Beecham Parmaceuticals). 5. To collaborate with Laboratory Program 4 (Dr. Sundberg, University of Virginia) in the design and synthesis of appropriate analogs of newly isolated active compounds. 6. To collaborate with other members of the Group as appropriate to assist in the development of active compounds as clinical candidates.

拟议研究的总体目标是发现新的自然 具有显着临床有用抗癌活性的产品。 这 该方案的具体目标是： 1. 每年获得20-40个在体外具有良好活性的提取物 拓扑异构酶 I 抑制、拓扑异构酶 II 抑制或 DNA 损伤 生物测定，活性提取物将通过初步筛选而枯萎 作为核心活动的一部分在弗吉尼亚大学进行 该小组在 SmithKline Beecham 进行了初步筛选 药品，或来自我们与以下机构合作进行的筛选 世界各地的各种同事。 2. 使用生物测定导向的方法分离每种活性提取物 分馏方案，并选择性地分离纯活性化合物 指示的生物测定之一中的活性。 3. 确定所有活性化合物的结构 化学操作、光谱技术和 X 射线的结合 晶体学被证明最适合具体问题。 4. 重新分离足够量的所有活性化合物以用于进一步 实验室计划 1（SmithKline Beecham 医药品）。 5. 与实验室项目4（Dr. Sundberg，University of 弗吉尼亚）在设计和合成新的适当类似物 分离出的活性化合物。 6. 酌情与小组其他成员合作，协助 开发作为临床候选的活性化合物。