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: 8824542
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8824542
• 关键词: Alkaloids; Alkenes; Amines; Anabolism; Area; Biological Factors; Chemicals; Chemistry; Collaborations; Complex; Cyclization; Development; Dimerization; Dissection; Drug Design; Enzymes; Exhibits; Face; Family; Family member; Goals; Health; Hydrocarbons; Isomerism; Laboratories; Lead; Learning; Letters; Libraries; Methods; Nuphar; One-Step dentin bonding system; Outcome; Pathway interactions; Pharmacologic Substance; Reaction; Research; Route; Secondary to; Solutions; Stereoisomer; Structure; Testing; United States Food and Drug Administration; analog; cancer therapy; catalyst; cephalotaxine; cytotoxic; design; dimer; fascinate; fasicularin; flexibility; lepadiformine; meetings; member; monomer; preference

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）：拟议的研究的目的是了解如何对立体化学上模棱两可但结构上简化线性链的环化反应的控制，以综合复杂的抗癌引线。长期目标是学习如何控制线性基序的多环化，以访问具有高选择性的每个可能的异构体。拟议的研究包括对三个复杂生物碱家族的探索，具有有希望的癌症活性。 研究的第一个领域涉及实用的多氢化转换的发展，该变换表现出广泛的底物范围和高立体选择性。我们实验室中的初步发现表明，不饱和胺的定向环状水合构成了广泛适用的，区域和立体的分子内盐水转化，以快速合成广泛的二岛结构基序。该提案旨在研究转型的范围，并探索其在合成两个抗癌铅的合成中的应用。 第二个研究区域涉及选择性细胞毒性的阿斯玛林生物碱的合成。仔细控制线性不饱和碳氢化合物链的构象偏好应允许在烯烃的任何一个非映射面中加入正式的氢化剂，以安装远程立体中心。立体控制通过线性构象控制和环拓扑控制的组合可以导致立体化学上多样化的生物碱库。 研究的第三个领域探讨了抗转移性NUPHAR二聚体的合成。初步结果表明 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。立体选择性硫亚螺旋烷形成的辅助和催化剂对照将被研究以迅速合成四个立体异构体，以及该迷人阶级的所有16个可能的家庭成员。