Synthesis of Anti-Trypanosomal Terpenoid Oligomers

抗锥虫萜类低聚物的合成

基本信息

  • 批准号:
    8862184
  • 负责人:
  • 金额:
    $ 3.01万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-07-01 至 2017-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The goal of this proposal is synthesize a class of structurally novel oligomeric terpenoids which are presented here to have previously unreported potent and selective anti-trypanosomal activity, and to determine their biological target and structure-activity relationship (SAR.) Our long-term goal is to produce new drug leads for the treatment of chronic infections of Trypanosoma cruzi (T. cruzi,) the causative agent of Chagas disease, and demonstrate their therapeutic value through in-vitro and in-vivo testing. The proposed research comprises the development of a new class of polyene capable of rapid, highly regio- and diastereo-selective formation of fused polycyclic polyene monomers; new methods for the controlled oligomerization of these monomeric species; and application of this chemistry to short, scalable and modular syntheses of the family of terpenoids presented herein. This chemistry will be used to explore the biological impact of various moieties within the context of their terpenoid frameworks through SAR discovery, to determine how the unique chemical reactivities of these polycyclic and macrocyclic systems are related to their resulting biological activities (including the possibility of prodrug degradation into reactive intermediates within T. cruzi,) and to determine the target(s) of these compounds in collaboration with the Genomics Institute of Novartis Research Foundation (GNF.) The first phase of research concerns the streamlined development of a novel chiral dienophile, as well as a new application of the polarized dendritic polyenes - Danishefsky Dendralenes - developed in our lab which undergo highly regio- and stereoselective Diels-Alder reactions to rapidly construct the polycyclic skeleton of these monomeric terpenoids. All available literature precedent indicates that these monomeric species will have widespread utility in the rapid construction of larger complex carbocycles. The second phase of research draws inspiration from a hypothesis regarding the biogenetic origin of this complex family of terpenoids being traced back to variations on a single monomeric unit. We will explore regioselective and stereoselective strategies of controlled oligomerization of the monomeric terpenoids into the desired poly- and macrocyclic oligomers, employing a strongly substrate-directed Diels-Alder approach as well as an unprecedented formal head-to-tail macrocyclization. To achieve these cyclizations, we will investigate thermal, photochemical, and Lewis-base mediated strategies as well as solid and solution phase approaches. The third phase of research, conducted in collaboration with GNF/Novartis, involves the elucidation of the structural basis for anti-trypanosomal activity within this class of terpenoid oligomers and the determination of their mechanism of action. We present preliminary data that show the potent and selective cytotoxicity of these compounds against T. cruzi parasites.
描述(申请人提供):本方案的目标是合成一类结构新颖的低聚萜类化合物,这些化合物具有以前未见报道的有效和选择性的抗锥虫活性,并确定它们的生物靶标和构效关系(SAR)。我们的长期目标是生产治疗慢性克氏锥虫感染的新药物,克氏锥虫是恰加斯病的病原体,并通过体外和体内试验证明其治疗价值。建议的研究包括开发一类新的多烯,能够快速、高度区域和非对映选择性地形成稠合多环多烯单体;用于这些单体物种的受控齐聚的新方法;以及将这种化学应用于本文提出的短、可扩展和模块化的萜类化合物家族的合成。这一化学将被用来通过合成孔径雷达的发现来探索不同部分在其萜类框架内的生物影响,以确定这些多环和大环系统独特的化学反应与其所产生的生物活性(包括将前药降解为活性中间体的可能性)之间的关系 在T.ruzi内),并与诺华研究基金会基因组研究所合作确定这些化合物的靶标(S)。 第一阶段的研究涉及一种新型的手性双烯分子的简化开发,以及我们实验室开发的极化树枝状多烯-Danishefsky Dendralenes的新应用,它通过高度区域和立体选择性的Diels-Alder反应来快速构建这些单体萜类化合物的多环骨架。所有现有的文献先例表明,这些单体物种将在快速构建更大的复杂碳环方面具有广泛的用途。 第二阶段的研究灵感来自于一个假说,即这个复杂的萜类化合物家族的生物起源可以追溯到单个单体单位的变异。我们将探索区域选择性和立体选择性的策略,将单体萜类化合物控制齐聚成所需的多环和大环低聚物,采用强烈底物导向的Diels-Alder方法以及前所未有的从头到尾的正式大环化反应。为了实现这些环化反应,我们将研究热、光化学和Lewis碱介导的策略以及固相和溶液相方法。 与GNF/Novartis合作进行的第三阶段研究涉及阐明这类萜类低聚物中抗锥虫活性的结构基础,并确定它们的作用机制。我们提供的初步数据表明,这些化合物对克鲁兹毛滴虫具有强大的选择性细胞毒性。

项目成果

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Ruben Martin Martinez其他文献

Ruben Martin Martinez的其他文献

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{{ truncateString('Ruben Martin Martinez', 18)}}的其他基金

Synthesis of Anti-Trypanosomal Terpenoid Oligomers
抗锥虫萜类低聚物的合成
  • 批准号:
    8721181
  • 财政年份:
    2014
  • 资助金额:
    $ 3.01万
  • 项目类别:
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