COMBINATORIAL SYNTHESIS OF ANTICANCER LIBRARIES

抗癌文库的组合合成

• 批准号: 6300627
• 负责人: Peter Wipf
• 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/6300627
• 关键词: analog; animal extract; antimitotics; antineoplastics; biological products; chemical registry /resource; chemical synthesis; drug design /synthesis /production; enzyme inhibitors; fluorescence; phosphoprotein phosphatase

The overall goal of the chemistry section of this Program Project grant application is the demonstration of new strategies for mechanism-based cancer drug discovery using solid-phase and novel fluorous phase combinatorial synthesis as well as phase-switching methods. Lead structure identification is derived from natural products and target-based array design. High quality, single-compound libraries will provide the broad structure-activity relationship necessary for rational lead optimization. Specifically, we have two major synthetic goals: . to optimize solid phase and fluorous phase synthesis protocols for the preparation of a library of ca. 5,000 potential phosphatase inhibitors derived from the natural products microcystin LR and calyculin A; . to apply a combined solid-phase/fluorous phase strategy for the preparation of libraries containing ca. 1,000 analogs of the anti-mitotic cyanobacterium metabolite curacin A and ca. 500 analogs of the structurally complex anti-mitotic marine natural product discodermolide. The proposed program represents a multi-dimensional effort to improve current methodologies for the combinatorial synthesis of libraries of organic molecules, establish new strategies for the use of natural products as lead structure for drug discovery, and identify novel mechanism-based anti-cancer agents.

本计划化学部分项目资助的总体目标 应用是基于机制的新策略的展示 使用固相和新型氟相进行癌症药物发现 组合合成以及相切换方法。引线结构 识别源自天然产物和基于目标的阵列 设计。高质量的单一化合物库将提供广泛的 合理先导化合物优化所必需的结构-活性关系。 具体来说，我们有两个主要的综合目标： 。优化固相和氟相合成方案 准备大约一个图书馆。 5,000 种潜在的磷酸酶抑制剂 源自天然产物微囊藻毒素LR和花萼蛋白A； 。应用固相/氟相组合策略 准备包含约的文库。 1,000 种抗有丝分裂类似物 蓝藻代谢物 curacin A 和 ca。 500 个类似物 结构复杂的抗有丝分裂海洋天然产物discodermolide。 拟议的计划代表了多方面的改进努力 当前组合合成文库的方法 有机分子，建立利用天然物质的新策略 产品作为药物发现的先导结构，并识别新的 基于机制的抗癌剂。