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.

该计划项目赠款的化学部分的总体目标 应用是基于机制的新策略的演示 使用固相和新型荧光期发现癌症药物 组合合成以及相距方法。铅结构 识别源自天然产品和基于目标的阵列 设计。高质量的单个复合图书馆将提供广泛的 理性铅优化所需的结构活性关系。 具体来说，我们有两个主要的合成目标： 。优化固相和荧光相综合方案 准备大约图书馆。 5,000个潜在的磷酸酶抑制剂 源自天然产物的微囊藻蛋白LR和钙化蛋白A； 。应用联合固相/易流相策略 准备包含CA的库。 1,000个抗溶质的类似物 蓝细菌代谢物素素A和Ca。 500个类似物 结构复杂的抗隔离海洋天然产物脱皮剂。 拟议的计划代表了改进的多维努力 当前的方法学用于库的组合合成 有机分子，建立使用自然使用的新策略 产品作为药物发现的铅结构，并识别新颖 基于机理的抗癌药。