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

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。利用含氟技术，我们旨在以创新，高效和成本控制的方式生产新型杂环和天然产品样的中试规模库。本方案具有以下特点：(1)半数以上的文库支架与天然产物密切相关，如mappicine、isaindiotone、sclerotigenin、gypsetin等。其余支架与天然产物的特定结构基序或更一般意义上的天然产物特性有关，但具有较高的结构新颖性和多样性。由多样性导向合成产生的文库具有骨架、取代和立体化学变化。(2)高效可靠的氟标记和分离技术被用于生成大多数所提出的库。使用“快速合成系统”作为综合合成平台，大大减少了反应和分离的时间。其他成本控制技术，如“一石二鸟”式氟标签/裂解，共享共同的构建模块，回收/再利用氟标签和硅胶将被用于制作库。(3)图书馆设计/开发与图书馆生产的努力是平衡的。中试规模图书馆的设计和开发建立在成功的内部化学基础上。更多的努力是针对图书馆生产产生化合物提交，从而满足NIH的目标。具体目标是：(1)合成mappicine型天然产物库；(2) isaindigotone型天然产物库的合成；(3)硬化剂型天然产物文库的合成；(4)合成新颖多样的含氮多环化合物库；(5)含二酮哌嗪类天然产物文库的合成；(6)多环醚和生物碱类文库的合成。在为期三年的资助期内，将从6个项目中开发约30个图书馆支架，每年生产并提交800-1,000个化合物。RFA关于图书馆制作和提交的一般指导方针，包括图书馆规模、质量控制、样品交付、数据管理和专利问题，将密切遵循。根据该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，将自愿与对筛选和/或研究本提案中产生的化合物感兴趣的未来合作者共享。

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.