NATURAL PRODUCT LIKE LIBRARIES FOR CANCER DRUG SCREENS

用于癌症药物筛查的天然产品如文库

• 批准号: 6563928
• 负责人: STUART L SCHREIBER
• 金额: $ 19.71万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6563928
• 关键词: alkaloids; antineoplastics; biological products; chemical registry /resource; chemical structure; chemical synthesis; drug design /synthesis /production; drug screening /evaluation; enzyme inhibitors; method development; nanotechnology; protein binding; protein kinase; shikimate; tubulin

The overall goal of this Program Project is to find a general method for discovering small-molecule ligands that modulate the function of proteins relevant to cancer. In Project 1, we will build million-member libraries of small molecules that mimic natural products in their size, rigidity, complexity in stereochemistry and functional diversity. These molecules will be designed so that the functionalities displayed on the skeleton of molecule are presented in a well-defined way over a large area (>50 A/2). These design principles are derived from a study of natural products known to bind to proteins. The libraries will be constructed on solid phase beads using the split- pool synthesis technique. This approach allows the synthesis of large libraries of molecules (> 10/6 members) in a small number of chemical steps. To use split-pool synthesis to prepared libraries with significant structural and functional diversity, we will develop new synthetic methods, applicable to immobilized substrates, to allow enantioselective reactions in this format. We propose the development of several libraries, including a library based on 1,3-diol derivatives to yield polyketide-related molecules. We will also use the Diels-Alder reactions of N-acylpyridinium salts to yield polycyclic alkaloid-like molecules. Shikimic acid derivatives will be employed as a template in another library, using cycloaddition and ring opening reactions to produce a library of very high structural complexity. Palladium-catalyzed cyclocarbometallation reactions will be used to construct a library of spirocyclic molecules. We will also synthesize "dumbbell" libraries, in which each member of a library is linked to a ligand of FKBP. To identify new ligands for know classes of proteins, we will construct several libraries based on know ligands. Protein kinase inhibitors will be developed by incorporating purine monomers, and by using enantioselective catalytic ring-opening reactions to produce small molecules similar to the natural product balanol. A library of dolastatin- like compounds will be synthesized to identify gamma-tubulin inhibitors. These libraries will be used in the screens developed in Projects 2 and 3 to discover novel small molecules that affect processes involved in cancer. As we identify new ligands that modulate protein-protein interactions in the screens for cancer drugs described in Projects 2 and 3, we will use this information to guide the design for new libraries.

该计划项目的总体目标是找到一种通用方法 发现调节蛋白质功能的小分子配体 与癌症有关。项目一，我们将建设百万会员图书馆 模仿天然产物的大小、刚性的小分子， 立体化学的复杂性和功能多样性。这些分子 将被设计为使功能显示在骨架上 分子以明确的方式呈现在大面积（>50 A/2）上。 这些设计原则源自对已知天然产品的研究 与蛋白质结合。 文库将使用分流器构建在固相珠上 池合成技术。这种方法允许合成大 少数化学物质中的分子库（> 10/6 成员） 步骤。使用分池合成来制备具有显着性的文库 结构和功能多样性，我们将开发新的合成 适用于固定化底物的方法，可实现对映选择性 这种格式的反应。 我们建议开发几个库，包括基于库的库 1,3-二醇衍生物产生聚酮化合物相关分子。我们将 还利用 N-酰基吡啶鎓盐的 Diels-Alder 反应得到 多环生物碱样分子。莽草酸衍生物将 在另一个库中用作模板，使用环加成和环 打开反应以产生结构复杂性非常高的库。 钯催化的环碳金属化反应将用于 构建螺环分子库。我们还将综合 “哑铃”库，其中库的每个成员都链接到 FKBP的配体。为了识别已知蛋白质类别的新配体，我们 将根据已知配体构建多个库。蛋白激酶 抑制剂将通过结合嘌呤单体来开发，并通过 利用对映选择性催化开环反应生成小分子 分子类似于天然产物balanol。多拉司他汀库- 将合成类似的化合物来鉴定γ-微管蛋白抑制剂。 这些库将用于项目 2 和 3 中开发的屏幕 发现影响相关过程的新型小分子 癌症。当我们发现调节蛋白质-蛋白质的新配体时 项目 2 中描述的抗癌药物筛选中的相互作用 3、我们将使用这些信息来指导新库的设计。