Generation of Stereochemically and Structurally Complex*

描述（由申请人提供）：复杂分子的快速组装作为发现新化学型和药理工具的一种手段，在面向多样性的合成（DOS）中仍然具有很大的兴趣。以这种方式合成化学文库既利用了立体化学多样性，也利用了骨架多样性。获得具有新药理特性的分子的一种独特方法是基于天然产物衍生的各种核心支架的文库合成。该提案概述了试点图书馆（P41）倡议的具体计划，以产生一些立体化学和结构复杂的化学文库，以纳入美国国立卫生研究院（NIH）分子库。五个图书馆项目计划反映了首席研究员（PI）和联合首席研究员（co -PI）对利用分子框架内的立体化学和位置变化来设计天然产物类分子的持续兴趣。共概述了16个复杂的图书馆，这些图书馆与正在进行和计划中的化学方法论和图书馆发展中心（CMLD-BU）图书馆项目不同。目标先导文库包括复合二氢嘧啶、氮唑啉衍生文库、四环生物碱型文库、外亚甲基支架和衍生螺旋环，以及大环内酰胺框架。此外，所有计划的库都被设计成包含独特的结构，这些结构在化学空间上不会与PubChem数据库中当前的分子重叠。为了促进合成和及时将文库交付给NIH知识库，重点放在利用以前在Pi和合作Pi实验室建立的化学物质上。试点图书馆倡议的数据共享中心机制包括使用基于互联网的合成协议结构可搜索数据库。将在NIH知识库中开发的目标文库包括在内，预计将有助于发现用于研究细胞过程的新药理学工具。

DESCRIPTION (provided by applicant): The rapid assembly of complex molecules continues to be of great interest in diversity-oriented synthesis (DOS) as a means to discover novel chemotypes and pharmacological tools. Synthesis of chemical libraries in this manner has employed both stereochemical and skeletal diversity. A distinct approach to obtain molecules with novel pharmacological properties involves library synthesis based on various core scaffolds derived from natural products. This proposal outlines specific plans for a Pilot Libraries (P41) initiative to generate a number of stereochemically and structurally complex chemical libraries for inclusion in the National Institutes of Health (NIH) Molecular Repository. Five library projects are planned reflecting the Principal Investigator's (PI's) and Co-Principal Investigators' (Co-PIs') continued interest in the design of natural product-like molecules using stereochemical and positional variation within the molecular framework. A total of 16 complex libraries are outlined which are distinct from ongoing and planned Center for Chemical Methodology and Library Development (CMLD-BU) library projects. Target pilot libraries include complex dihydropyrimidones, azaphilone-derived libraries, tetracyclic alkaloid-type libraries, exo-methylene scaffolds and derived spirocycles, and macrocyclic lactam frameworks. In addition, all planned libraries have been designed to include unique structures that do not overlap in chemical space with molecules currently in the PubChem database. In order to facilitate synthesis and timely delivery of libraries to the NIH repository, emphasis has been placed on utilization of chemistries previously established in the Pi's and co-PIs' laboratories. A central mechanism for data sharing for the Pilot Library initiative involves using an internet-based structure-searchable database of synthesis protocols. Inclusion of the target libraries that will be developed in this effort in the NIH repository is anticipated to facilitate discovery of new pharmacological tools for investigation of cellular processes.