New Methods and Strategies for the Synthesis of Anticancer Alkaloids

抗癌生物碱合成的新方法和新策略

• 批准号: 8420077
• 负责人: Ryan Ashok Shenvi
• 金额: $ 36.01万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8420077
• 关键词: Alkaloids; Alkenes; Alkylating Agents; Amines; Anabolism; Area; Biological Factors; Chemicals; Chemistry; Collaborations; Complex; Cyclization; DNA; Development; Dimerization; Diphosphates; Dissection; Drug Design; Enzymes; Exhibits; Face; Family; Family member; Goals; Growth; Hydrocarbons; Isomerism; Laboratories; Lead; Learning; Letters; Libraries; Malignant neoplasm of lung; Methods; Molecular; Mus; Nuphar; One-Step dentin bonding system; Outcome; Pathway interactions; Pharmacologic Substance; Publishing; Purines; Reaction; Research; Route; Secondary to; Solutions; Stereoisomer; Structure; Testing; United States Food and Drug Administration; analog; cancer therapy; catalyst; cephalotaxine; cytotoxic; cytotoxicity; design; dihydroxythiobinupharidine; dimer; fascinate; fasicularin; flexibility; lepadiformine; meetings; member; monomer; nitroxyl; novel; preference; public health relevance; purine; thiophane

DESCRIPTION (provided by applicant): The goal of the proposed research is to understand how to exert control over stereochemically ambiguous but structurally simplifying cyclization reactions of linear chains for the synthesis of complex anticancer leads. The long-term goal is to learn how to control the polycyclization of linear motifs to access each possible isomer with high selectivity. The proposed research comprises exploration of three families of complex alkaloids with promising activity for the treatment of cancer. The first area of research concerns the development of a practical polyhydroamination transform that exhibits broad substrate scope and high stereoselectivity. Preliminary findings in our lab indicate that directed, cyclic hydroboration of unsaturated amines enables a broadly applicable, regio- and stereoselective intramolecular hydroamination transform for the rapid synthesis of the widespread izidine structural motif. The proposal seeks to investigate the scope of the transformation and explore its application to the synthesis of two anticancer leads. A second research area concerns the synthesis of the selectively cytotoxic asmarine alkaloids. Careful control of the conformational preferences of a linear unsaturated hydrocarbon chain should allow for a formal hydroamination addition to either diastereotopic face of the alkene to install a remote stereocenter. Stereocontrol via a combination of linear conformational control and ring topological control can lead to a stereochemically diverse library of alkaloids. The third area of research explores the synthesis of the anti-metastatic nuphar dimers. Preliminary results indicate that dimerization of a linear surrogate of the nuphar dimers can be used to rapidly assemble these complex alkaloids. Auxiliary and catalyst-control over stereoselective thiaspirane formation will be investigated to rapidly synthesize al four stereoisomers and all sixteen possible family members of this fascinating class.

描述(申请人提供)：拟议研究的目标是了解如何对合成复杂的抗癌先导化合物的线性链的立体化学模糊但结构简化的环化反应施加控制。长期目标是学习如何控制线状基序的多环化，以高选择性地获得每一种可能的异构体。这项拟议的研究包括探索三个具有治疗癌症活性的复杂生物碱家族。第一个研究领域是开发一种具有广泛底物范围和高立体选择性的实用多氢胺化转化。我们实验室的初步研究结果表明，不饱和胺的定向环硼氢化反应能够实现广泛适用的、区域选择性和立体选择性的分子内氢胺化转变，从而快速合成广泛存在的咪啶结构基序。该提案旨在调查转化的范围，并探索其在合成两种抗癌先导化合物中的应用。第二个研究领域涉及选择性细胞毒性海藻生物碱的合成。仔细控制线性不饱和碳氢链的构象偏好，应该允许在烯烃的任一非对映面上进行正式的氢胺化反应，以安装远程立体中心。通过线性构象控制和环拓扑控制相结合的立体控制可以导致生物碱库的立体化学多样性。第三个研究领域探索了抗转移Nuphar二聚体的合成。初步结果表明，A的二聚化 Nuphar二聚体的线性替代物可用于快速组装这些复杂的生物碱。为了快速合成四个立体异构体和所有这类迷人的16个可能的家族成员，将研究立体选择性硫代阿司匹烷的辅助和催化剂控制。