Diversity-Oriented Synthesis of Novel Heterocyclic & Natural Product-Like Library

新型杂环的多样性导向合成

• 批准号: 7291391
• 负责人: Marvin S Yu
• 金额: $ 46.55万
• 依托单位: FLUOROUS TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-21 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7291391
• 关键词: Alkaloids; Biological Factors; Birds; Calculi; Characteristics; Chemistry; Cost Control; Coupled; Data; Development; Equilibrium; Ethers; Ethyl Ether; Future; Goals; Grant; Guidelines; Housing; Legal patent; Libraries; Nitrogen; Procedures; Production; Quality Control; Reaction; Resources; Sampling; Screening procedure; Skeletal system; System; Techniques; Technology; Time; United States National Institutes of Health; Variant; data management; design; diketopiperazine; gypsetin; innovation; instrument; interest; isaindigotone; mappicine; novel; scaffold; silochrome; size; small molecule libraries

DESCRIPTION (provided by applicant): Creative library design coupled with an established technology platform is an ideal approach for making small molecule libraries. Utilizing fluorous techniques, we aim to produce novel heterocyclic and natural product-like pilot-scale libraries in an innovative, efficient, and cost-controlled manner. This proposal has the following features: (1) More than half of the proposed library scaffolds are closely related to natural products such as mappicine, isaindigotone, sclerotigenin, and gypsetin. The remaining scaffolds are related to specific structural motifs of natural products or related to the characteristics of natural products in a more general sense, but have high structural novelty and diversity. Libraries produced by diversity-oriented synthesis have skeletal, substitution, and stereochemical variations. (2) Highly efficient and reliable fluorous tagging and separation techniques are used to produce most of the proposed libraries. The use of a "rapid synthesis system" as an integrated synthetic platform dramatically reduces time for both reaction and separation. Other cost control techniques such as "two birds with one stone"-type fluorous tagging/ cleavage, sharing common building blocks, and recovering/reusing fluorous tags and silica gel will be used to produce libraries. (3) The effort on library design/development versus library production is balanced. The design and development of pilot-scale libraries is built upon successful in-house chemistry. More effort is directed toward library production to generate compounds for submission, thus meeting NIH goals. The specific aims are: (1) Synthesis of mappicine-type natural product libraries; (2) Synthesis of isaindigotone-type natural product libraries; (3) Synthesis of sclerotigenin-type natural product libraries; (4) Synthesis of novel and diverse nitrogen-containing polycyclic libraries; (5) Synthesis of diketopiperazine-containing natural product-like libraries; (6) Synthesis of polycyclic ether and alkaloid-type libraries. Over the course of a three-year grant period, around 30 library scaffolds will be developed from 6 projects, resulting in 800-1,000 compounds being produced and submitted each year. RFA general guidelines for library production and submission including library size, quality control, sample delivery, data management, and patent issues will be closely followed. Data generated under this RFA including library synthesis procedures and compound characterization, and research resources such as synthetic technologies and instruments, will be shared willingly with future collaborators that have an interest in screening and/or studying the compounds produced in this proposal.

描述（由申请人提供）：创造性的文库设计与已建立的技术平台相结合是制作小分子文库的理想方法。 利用氟技术，我们的目标是以创新、高效和成本控制的方式生产新型杂环和类似天然产物的中试规模文库。 该提案具有以下特点：（1）超过一半的拟议文库支架与马匹碱、靛蓝酮、菌核素和石膏素等天然产物密切相关。 其余的支架与天然产物的特定结构基序相关或与更一般意义上的天然产物的特征相关，但具有较高的结构新颖性和多样性。 通过面向多样性的合成产生的文库具有骨架、取代和立体化学变异。 (2)大多数所提出的文库均采用高效可靠的荧光标记和分离技术。 使用“快速合成系统”作为集成合成平台大大减少了反应和分离的时间。 其他成本控制技术，例如“一石二鸟”型荧光标记/切割、共享通用构建模块以及回收/再利用荧光标记和硅胶将用于产生文库。 (3) 文库设计/开发与文库生产的工作是平衡的。 中试规模文库的设计和开发建立在成功的内部化学基础之上。 我们将更多精力投入到文库生产中，以生成可供提交的化合物，从而实现 NIH 的目标。 具体目标是：（1）马匹碱型天然产物库的合成； (2) 靛蓝酮型天然产物库的合成； (3) 菌​​核素型天然产物文库的合成； (4)新型多样的含氮多环文库的合成； (5) 含二酮哌嗪的天然产物类库的合成； (6)多环醚和生物碱类库的合成。 在为期三年的资助期内，将通过 6 个项目开发约 30 个库支架，每年生产并提交 800-1,000 种化合物。 将严格遵循 RFA 文库制作和提交的一般准则，包括文库规模、质量控制、样品交付、数据管理和专利问题。 根据本 RFA 生成的数据，包括文库合成程序和化合物表征，以及合成技术和仪器等研究资源，将愿意与有兴趣筛选和/或研究本提案中产生的化合物的未来合作者共享。