Function and Informatics Driven Assembly of New Pilot Scale Libraries

描述(申请人提供)：这个项目的目标是组装一系列中试规模的杂环库，通过访问化学多样性空间的区域来发现新的生物活性化学类型，这些区域在PubChem数据库中没有代表，在NIH分子库小分子储存库(MLSMR)中也没有。这些文库的设计将以三个主要考虑为指导，包括：(A)密切相关化学类型的有效生物活性；(B)对有利的物理化学性质进行严格的计算分析；以及(C)开发简明、并行的合成方案，以实现亲本文库的有效组装、活性化合物的再补充和重点文库的构建。该项目分为四个具体目标，包括：(A)基于二氢喹诺酮和喹啉类化合物的文库的构建；(B)支架多样化的吡咯烷酮文库的组装；(C)三环苯并二氮杂环的融合文库的合成；(D)基于多环氨基胍的文库的组装。我们将准备7个杂环库(3,600个新化合物)，旨在扩大MLSMR的收藏，使其具有复杂的天然产物样化合物，以便能够识别具有不同生物功能的新的小分子调节剂。 公共卫生相关性：这个项目的目标是组装一系列在PubChem数据库中没有代表的化学文库，在NIH分子文库小分子资源库中也没有。随后对这些化合物文库进行高通量的生物筛选将产生新的化学工具，大量可公开获取的信息，并将促进基础生物医学研究和新治疗剂的开发。

DESCRIPTION (provided by applicant): The objective of this project is to assemble a series of pilot-scale heterocyclic libraries to enable the discovery of new bioactive chemotypes by accessing the regions of chemical diversity space, which are not represented in the PubChem database and absent in the NIH Molecular Libraries Small-Molecule Repository (MLSMR). The design of such libraries will be guided by three main considerations, including (a) validated biological activity of closely related chemotypes; (b) rigorous computational analysis of favorable physicochemical properties; and (c) development of concise, parallel synthetic protocols to enable efficient assembly of parent libraries, resupply of active compounds and construction of focused libraries. The project is divided into four specific aims, including (a) construction of libraries based on dihydroquinolone and quassinoids; (b) assembly of scaffold-diversified pyrrolidinone libraries; (c) synthesis of tricyclic benzodiazepine-fused library; and (d) assembly of polycyclic amino guanidine-based libraries. We will prepare seven heterocyclic libraries (3,600 new compounds), which are designed to expand the MLSMR collection with sophisticated, natural product-like compounds in order to enable identification of new small- molecule modulators of diverse biological functions. PUBLIC HEALTH RELEVANCE: The objective of this project is to assemble a series of chemical libraries which are not represented in the PubChem database and absent in the NIH Molecular Libraries Small-Molecule Repository. Subsequent high-throughput biological screening of such compound libraries will produce new chemical tools, large amount of publicly accessible information, and will facilitate basic biomedical research and development of new therapeutic agents.