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（由申请人提供）：拟议研究的目标是了解如何控制立体化学上模糊但结构上简化的线性链环化反应，以合成复杂的抗癌先导化合物。长期目标是学习如何控制线性基序的多环化，以高选择性地获得每种可能的异构体。拟议的研究包括探索三个家族的复杂生物碱，具有治疗癌症的前景。 研究的第一个领域涉及一个实用的polyhydroamination转化，表现出广泛的底物范围和高立体选择性的发展。在我们的实验室的初步研究结果表明，定向，环状硼氢化不饱和胺，使一个广泛适用的，区域和立体选择性的分子内氢胺化转化为广泛的izidine结构基序的快速合成。该提案旨在研究转化的范围，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的海鞘生物碱的合成。仔细控制线性不饱和烃链的构象偏好应允许对烯烃的任一非对映异构面进行正式的氢胺化加成，以安装远程立体中心。通过线性构象控制和环拓扑控制的组合进行立体控制可以产生立体化学多样的生物碱库。 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， 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。辅助和催化剂控制立体选择性噻螺烷的形成将被研究，以快速合成所有四个立体异构体和所有十六个可能的家庭成员这一迷人的类。