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）：本研究将研究一种立体选择性合成复杂分子框架的新方法。其结果将是有效地获得许多具有生物学重要性的多环分子，在某些情况下，首次允许对映选择性合成复杂的支架。该策略将涉及富电子烯烃与α-取代的β-重氮酯的金属催化环丙烷化反应，生成供体-受体环丙烷（DAC）环，该环被电子稳定基团和潜在亲核试剂成对取代。预计用路易斯酸活化会引起开环形成两性离子，并且稳定的碳阳离子将通过分子内亲核加成被捕获，从而导致烯烃部分的净环化。这些 DAC 中间体将作为合成许多有望成为治疗剂的天然产物的模板。我们将首先制备被酯和二乙氧基磷酰基成对取代的环丙烷，并研究它们重排为β-膦酰基-β-内酯。应用于手性2H-色烯底物，该方法将用于完成异芍药碱的首次对映选择性合成。这种双黄酮类化合物已被证明可以改变多种细胞信号传导途径，并且被发现对包括人骨髓性白血病细胞在内的多种肿瘤细胞系具有活性。然后，我们将通过制备含有被富电子烯烃形式的碳基潜在亲核试剂成对取代的酯的环丙烷，将该策略扩展到碳环的形成。两性离子形成后，富电子烯烃将充当内部亲核试剂。研究的亲核试剂包括烷氧基取代的苯，可导致已知的细胞毒性苯并吡喃的对映选择性合成；以及吲哚，有可能提供通往 Dragmacidin E 四环核心的有效途径。 Dragmacidin E 是丝氨酸-苏氨酸蛋白磷酸酶的抑制剂，此类化合物还显示出抗肿瘤活性。这项研究的最终目标是通过识别潜在的先导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有助于其全面的临床分析。公共健康相关性：该项目提议开发新的合成策略来制备几种具有药物活性的天然产物，这些天然产物有望成为治疗剂。该列表包括对骨髓性白血病、糖尿病神经病变和结核病具有活性的化合物。这些天然产物的生物同一性实验室合成将有助于其全面的临床分析。