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:
- 金额:$ 33.64万
- 依托单位:
- 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
- 来源:
- 关键词:AcidsAlkenesAntineoplastic AgentsBenzeneBenzopyransBiologicalBiological FactorsCarbonCellsClinicalComplexCyclopropanesDNA Sequence RearrangementDiabetic NeuropathiesElectronsEstersGoalsHumanIndolesLaboratoriesLactonesLeadMetalsMethodsModelingMolecularMyeloid LeukemiaPharmacotherapyProtein Serine/Threonine PhosphataseReagentResearchRouteSeriesSignal PathwaySignal TransductionStructureTherapeutic AgentsTimeTuberculosisTumor Cell Linebasecarbenecyclopropanecytotoxicinhibitor/antagonistinterestnovelnovel strategiesnucleophilic additionscaffold
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一些多环分子的生物学重要性,允许在某些情况下,对映选择性合成复杂的支架的第一次。该策略将涉及金属催化的富电子烯烃与?-替代品?重氮酯产生给体-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。预期用刘易斯酸活化可诱导开环以形成两性离子,并且稳定的碳阳离子将通过分子内亲核加成被捕获,导致烯烃部分的净成环。这些DAC中间体将作为模板用于合成许多天然产物,这些天然产物显示出作为治疗剂的前景。我们将开始制备被酯和二乙氧基磷酰基成对取代的环丙烷,并研究它们重排成?-膦酰基-?-内酯。应用于手性2 H-色烯底物,该方法将被用来完成第一个对映选择性合成的异Chamaejasmine。这种双黄酮类化合物已被证明可以改变几种细胞信号传导途径,并被发现对几种肿瘤细胞系(包括人类骨髓性白血病细胞)具有活性。然后,我们将扩大这一战略的碳环的形成,通过制备环丙烷,含有一个酯的偕取代的碳基潜在的亲核试剂的形式的富电子烯烃。在两性离子形成之后,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,导致已知细胞毒性苯并吡喃的对映选择性合成,以及吲哚,可能为dragmacidin E的四环核心提供有效途径。Dragmacidin E是丝氨酸-苏氨酸蛋白磷酸酶的抑制剂,并且这类化合物也显示出抗肿瘤活性。本研究的最终目标是通过鉴定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。上述目标的合成路线将有助于其全面的临床分析。
公共卫生相关性:该项目提出开发新的合成策略,用于制备几种具有药用活性的天然产物,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有效的化合物。这些天然产物的生物等同实验室合成将促进其全面的临床分析。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Acetoxy-Substituted Cyclopropane Dicarbonyls as Stable Donor-Acceptor-Acceptor Cyclopropanes.
乙酰氧基取代的环丙烷二羰基作为稳定的供体-受体-受体环丙烷。
- DOI:10.1055/s-0034-1379934
- 发表时间:2015
- 期刊:
- 影响因子:0
- 作者:Reyes,Yahaira;Mead,KeithT
- 通讯作者:Mead,KeithT
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KEITH Thomas MEAD其他文献
KEITH Thomas MEAD的其他文献
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{{ truncateString('KEITH Thomas MEAD', 18)}}的其他基金
A Synthetic Approach to Calyxins and Epicalyxins I and J
萼蛋白和表萼蛋白 I 和 J 的合成方法
- 批准号:
7126978 - 财政年份:2006
- 资助金额:
$ 33.64万 - 项目类别:
Synthetic Approaches to Blepharocalyxins D and E
眼睑萼蛋白 D 和 E 的合成方法
- 批准号:
6666077 - 财政年份:2003
- 资助金额:
$ 33.64万 - 项目类别:
SYNTHESIS OF THE SPIROKETAL SUBUNIT OF REVEROMYCIN A
瑞维霉素 A 螺酮亚基的合成
- 批准号:
6473754 - 财政年份:2000
- 资助金额:
$ 33.64万 - 项目类别:
SYNTHESIS OF THE SPIROKETAL SUBUNIT OF REVEROMYCIN A
瑞维霉素 A 螺酮亚基的合成
- 批准号:
6028231 - 财政年份:2000
- 资助金额:
$ 33.64万 - 项目类别:
APPROACH TO THE SPIROKETAL RINGS OF THE ALTOHYRTINS
阿尔托蛋白螺酮环的研究
- 批准号:
2114702 - 财政年份:1996
- 资助金额:
$ 33.64万 - 项目类别:
STEREOCONTROLLED APPROACH TO PAMAMYCIN-607
PAMAMYCIN-607 的立体控制方法
- 批准号:
2183676 - 财政年份:1991
- 资助金额:
$ 33.64万 - 项目类别:
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