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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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：该研究的目标是了解如何控制立体化学上不明确但结构上简化的线性链环化反应，以合成复杂的抗癌先导物。长期目标是学习如何控制线性基序的多环化，以高选择性地访问每个可能的异构体。拟议的研究包括探索三个具有治疗癌症的有希望活性的复杂生物碱家族。第一个研究领域是开发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、循环硼化可以实现广泛适用的、区域和立体选择性的分子内氢胺化转化，从而快速合成广泛存在的氮基结构基序。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物中的应用。第二个研究领域涉及选择性细胞毒性生物碱的合成。仔细控制线性不饱和烃链的构象偏好，应该允许在烯烃的任何一个非对映面上进行正式的氢胺化，以安装一个远的立体中心。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立体化学多样化的生物碱库。研究的第三个领域探讨了抗转移性二聚体的合成。初步结果表明，a