Efficient Assemblage of Complex Biologically-Active Targets Using Donor-Acceptor

使用供体-受体有效组装复杂的生物活性靶标

基本信息

批准号：
8364688
负责人：
KEITH Thomas MEAD
金额：
$ 33.64万
依托单位：
MISSISSIPPI STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2016-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): This research will investigate a new approach to the stereoselective synthesis of complex molecular frameworks. The result will be efficient access to a number of polycyclic molecules of biological importance, allowing, in some cases, enantioselective syntheses of complex scaffolds for the first time. The strategy will involve metal-catalyzed cyclopropanations of electron-rich alkenes with ?-substituted ?-diazo esters to generate donor-acceptor cyclopropane (DAC) rings that are geminally substituted with both an electron-stabilizing group and a latent nucleophile. Activation with a Lewis acid is expected to induce ring opening to form a zwitterion, and the stabilized carbocation will be trapped by intramolecular nucleophilic addition, resulting in a net annulation of the alkene moiety. These DAC intermediates will serve as templates for the synthesis of a number of natural products that show promise as therapeutic agents. We will begin by preparing cyclopropanes that are geminally substituted with ester and diethoxyphosphoryl groups and study their rearrangement to ?-phosphono-?-lactones. Applied to a chiral 2H-chromene substrate, this method will be used to complete the first enantioselective synthesis of isochamaejasmine. This biflavonoid has been shown to alter several cell-signaling pathways, and has been found to be active against several tumor cell lines including human myeloid leukemia cells. We will then expand this strategy to the formation of carbocycles by preparing cyclopropanes that contain an ester geminally substituted with a carbon-based latent nucleophile in the form of an electron-rich alkene. Following zwitterion formation, the electron-rich alkene will act as the internal nucleophile. Among the nucleophiles studied will be alkoxy-substituted benzenes, leading to the enantioselective synthesis of a known cytotoxic benzopyran, and indoles, potentially providing an efficient route to the tetracyclic core of dragmacidin E. Dragmacidin E is an inhibitor of serine-threonine protein phosphatase, and compounds in this class have also shown antitumor activity. The ultimate goals of this research are to advance the field of synthesis and impact the field of cancer drug therapy by identifying potential lead compounds. Synthetic routes to the aforementioned targets will facilitate their comprehensive clinical analysis. PUBLIC HEALTH RELEVANCE: This project proposes to develop new synthetic strategies for preparing several medicinally-active natural products that show promise as therapeutic agents. The list includes compounds active against myeloid leukemia, diabetic neuropathy, and tuberculosis. Bio-identical laboratory syntheses of these natural products will facilitate their comprehensive clinical analysis.

描述（由申请人提供）：本研究将研究一种新方法，以实现复杂分子框架的立体选择合成。结果将有效地访问许多具有生物学重要性的多环状分子，在某些情况下，首次允许复杂支架的对映选择性合成。该策略将涉及与富含电子烯烃的金属催化的环丙烷，并取代？ - diazo酯，以产生供体 - 受体 - 受体环丙烷（DAC）环，这些环是通过电子稳定组和潜在的核寄生的，它们在geminal上替代。刘易斯酸的激活预计会诱导环的开口形成骨，并且稳定的碳定位将被分子内亲核的添加而捕获，从而导致烯烃部分的净环节。这些DAC中间体将用作综合许多天然产品的模板，这些天然产品显示出有望作为治疗剂。首先，我们将制备酯和二乙氧基磷酸基团替代的环丙烷，然后研究其重排为？-Phosphono - ？ - 内酯。应用于手性2H-奇罗烯基板，该方法将用于完成第一个对映选择性的异氨叶玛碱的合成。该双铁苷已被证明会改变几种细胞信号途径，并发现对包括人髓细胞性白血病细胞在内的几个肿瘤细胞系具有活性。然后，我们将通过制备包含含有碳基潜在潜在亲核试剂的酯的环丙烷的形式来扩展这种策略。裂开后形成后，富含电子的烯烃将充当内部亲核试剂。在研究的亲核试剂中，将是烷氧基化的苯苯甲烯，导致对映选择性合成已知的细胞毒性苯并吡喃和吲哚，可能会提供有效的龙乳糖蛋白E的四环核心。这项研究的最终目标是通过鉴定潜在的铅化合物来推进合成领域并影响癌症药物治疗领域。上述目标的合成途径将促进其全面的临床分析。公共卫生相关性：该项目提议制定新的合成策略，以准备几种具有医疗活性的天然产品，以表现出具有治疗剂的希望。该列表包括针对髓样白血病，糖尿病神经病和结核病的化合物。这些天然产品的生物相同实验室合成将有助于其全面的临床分析。