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 具有明显临床有用的抗癌活性的产品。 这 该计划的具体目的是： 1。每年获取20-40个提取物，显示出良好的体外活性 拓扑异构酶I抑制，拓扑异构酶II抑制或DNA损害 生物测定，主动提取物将从初步筛选中浮出水面 作为弗吉尼亚大学进行的作为核心活动的一部分 这个小组，在Smithkline Beecham进行的初步筛选 药品，或与我们合作进行的筛选 世界各地的各种同事。 2。使用以生物测定为导向的每个主动提取物分馏 分级方案，并与选择性分离纯活性化合物 指示的一个生物测定中的活动。 3。确定所有活性化合物的结构 化学操纵，光谱技术，X射线的组合 晶体学证明最适合特定问题。 4。重新分配足够的所有活性化合物以进一步 通过实验室计划1的生物学评估（Smithkline Beecham Parmaceuticals）。 5。与实验室计划合作4（Sundberg博士，大学 弗吉尼亚州）在设计和合成新的类似物中 孤立的活性化合物。 6。与小组的其他成员合作以协助协助 在开发活性化合物作为临床候选者中。