COMBINATION SYNTHESIS FOR SAR OF NATURAL PRODUCTS

天然产物 SAR 的组合合成

• 批准号: 2856411
• 负责人: ROBERT W ARMSTRONG
• 金额: $ 21.98万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-03-07 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2856411
• 关键词: antineoplastic antibiotics; azo compounds; biological products; chemical structure function; chemical synthesis; cyclization; immunosuppressive; inhibitor /antagonist; multidrug resistance; oligopeptides

This proposal develops solid support methodology for the synthesis of natural products and their analogs. Multiple component condensation reactions on solid support offer a powerful strategy for compound synthesis in a single chemical reaction. Applied to solid support, these reactions afford multi-milligram quantities of thousands of compounds of high purity and in high chemical yields. These transformations are carried out in a spatially addressable fashion using a single-well single-compound format in which the chemical structure of every member of the library is known. Structure activity relationship (SAR) studies related to these compounds should provide information on establishing their minimum pharmacophore and improving their potency. Three series of natural products have been identified which test this strategy. Successful application of this approach should have wide applicability in other target areas. The solution total synthesis and solid support syntheses of each natural product and related strategies for solid support analog development are presented for the following: Part I. Carzinophilin/azinomycin B and azinomycin A are potent antitumor agents which have been extensively studied in our laboratories. Azinomycin B cross-links B-DNA in vitro in the major groove. A Passerini condensation has been successfully applied to the construction of an initial compound library and preliminary cytotoxicity data suggests a minimum pharmacophore. Described herein is the massively parallel solid support synthesis of carzinophilin analogs. Part II. Myriocin and the related mycesteracins A-E are immunosuppressive agents. In a preliminary mixed lymphocyte assay, these compounds were 10- to 100- fold more potent than the clinically useful cyclosporin A. Two routes are proposed for the synthesis of the natural product and analogs, the first involving the alkylation of serine-derived enolates, and the second using an Ugi four-component condensation. Part III. Hapalosin is a potent cancer multiple drug resistance (MDR) reversing agent. This twelve-membered ring depsipeptide represents a new structure class of MDR P-glycoprotein inhibitors. We envision as a key synthetic step an intramolecular Passerini condensation, serving the dual purpose of cyclizing the depsipeptide and introducing the butyric acid residue. A solid-phase version should provide a powerful tool for the generation of analogous structures.

该建议为合成 天然产品及其类似物。多组件凝结 坚实支持的反应为化合物提供了有力的策略 单个化学反应中的合成。应用于稳固的支持，这些 反应提供数千种化合物的多毫克 高纯度和高化学产量。这些转换是携带的 使用单孔单重合以空间寻址的方式淘汰 图书馆每个成员的化学结构的格式为 已知。结构活动关系（SAR）研究与这些研究 化合物应提供有关确定其最低限度的信息 药理并提高其效力。三个系列自然 已经确定了测试此策略的产品。成功的 这种方法的应用应在其他方面具有广泛的适用性 目标区域。溶液的总合成和固体支持合成 每种天然产品和相关的固体支持类似物的策略 发表以下介绍： 第一部分。硬蛋白/偶氮霉素B和偶氮霉素A是有效的抗肿瘤 在我们的实验室中进行了广泛研究的代理商。偶氮霉素 B在主要凹槽中在体外交叉链接B-DNA。 Passerini冷凝 已成功应用于初始化合物的构建 图书馆和初步的细胞毒性数据表明最低 药效团。本文描述的是大量平行的固体支持 黄胆蛋白类似物的合成。 第二部分。霉菌素和相关的霉菌素A-E免疫抑制作用 代理商。在初步的混合淋巴细胞测定中，这些化合物为10- 比临床上有用的环孢菌素A更有效100倍。两个 提出了用于合成天然产物和类似物的途径， 第一个涉及丝氨酸衍生烯醇的烷基化，而 第二使用UGI四组分凝结。 第三部分。 Hapalosin是一种有效的癌症多种耐药性（MDR） 反向代理。这个十二元的环型二肽代表了一个新的 MDR P-糖蛋白抑制剂的结构类别。我们设想是关键 合成步骤是分子内passerini缩合，为双重服务 循环二肽并引入丁酸丁酸的目的 残留物。固相版本应为 产生类似结构。