MOLECULAR PHARMACOLOGY AND BIOCHEMISTRY OF ANTITUBULINS

抗微管蛋白的分子药理学和生物化学

• 批准号: 6300629
• 负责人: BILLY W DAY
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6300629
• 关键词: antineoplastics; apoptosis; biological products; cell proliferation; chemical registry /resource; chemical structure function; chemical synthesis; colorimetry; cytotoxicity; drug design /synthesis /production; laboratory mouse; microtubules; neoplasm /cancer pharmacology; tubulin

This is Project #3 of the Program "Combinatorial Approaches for Novel Anti-cancer Agents." a multidisciplinary effort to employ chemical diversity, high throughput and smart assays to anti-tumor drug discovery. The overall goal of this Project is to evaluate the biochemical actions of a targeted library of synthetic anti-tubulin agents in order to identify new drugs with activity against solid tumors. The library consists of ca. 1500 novel derivatives of the potent and structurally unique marine natural products (+)- discodermolide and curacin A prepared in Project #1 by novel targeted-array, parallel and combinatorial methods. Thus, this Project seeks lead compound optimization by chemical diversification of potent natural products acting through a proven chemotherapeutic mechanism of action. The working hypothesis is that, since the two lead compounds show certain enhanced properties over agents with similar mechanisms of action, their chemical diversification will provide structurally unique agents with improved chemotherapeutic properties. The Specific Aims are to: (1) characterize the in vitro tubulin assembly and microtubule stabilizing activity of all novel library compounds, (2) determine the anti-proliferative and cytotoxic effects of the new agents, (3) assess the mitotic blocking and apoptosis inducing actions of highly active lead compounds and, (4) determine the in vivo anti-tumor activities of prioritized lead compounds. This Project should yield important new information on the structure-activity relationships of microtubule- stabilizing and tubulin polymerization inhibitory agents. Furthermore, there is promise that these studies may provide novel chemotherapeutic drugs.

这是“小说组合方法”计划的项目#3 抗癌剂。”利用化学物质的多学科努力 抗肿瘤药物发现的多样性、高通量和智能分析。 该项目的总体目标是评估 合成抗微管蛋白药物的目标库，以便识别 具有抗实体瘤活性的新药。该图书馆由约组成。 1500 种强效且结构独特的海洋生物的新颖衍生物 天然产物 (+)- 项目 #1 中制备的 discodermolide 和 curacin A 通过新颖的靶向阵列、并行和组合方法。因此，这个 项目通过化学多样化寻求先导化合物优化 通过经过验证的化疗机制发挥作用的有效天然产品 的行动。工作假设是，由于两种先导化合物 与具有类似机制的药物相比，显示出某些增强的特性 行动，他们的化学多样化将提供结构独特 具有改善化疗特性的药物。具体目标是 目的：(1) 表征体外微管蛋白组装和微管 所有新库化合物的稳定活性，(2) 确定 新药的抗增殖和细胞毒性作用，（3）评估 高活性铅的有丝分裂阻断和细胞凋亡诱导作用 化合物，并且，(4)测定其体内抗肿瘤活性 优先先导化合物。该项目应该产生重要的新成果 微管结构-活性关系的信息 稳定剂和微管蛋白聚合抑制剂。此外， 这些研究有望提供新的化疗药物 药物。