Robust New Chemistries for Heterocycles

描述（由申请人提供）：NIH的分子库计划已经启动，以提供对小分子的现成公共领域访问，这些小分子可能用作生物过程的探针或潜在治疗的起点。为了维持这一计划的增长，需要新的和新颖的小分子库。该提案旨在提供与先前鉴定的“高价值”结构密切相关的分子，并且这些分子分为两类：基于小分子药物的文库和基于具有生物活性的天然产物中发现的结构基序的文库。具体而言，所提出的分子包括与激酶抑制剂密切相关的杂环，基于四氢异喹啉和同系物的结构，多环醚，简单吡喃，以及被认为是复杂多环天然产物的直向同源物的化合物。 公共卫生相关性：小分子，无论是基于天然产物还是纯合成的基础，都被广泛认为是了解和治疗人类疾病的最有价值的试剂。这项工作的重点是生产复杂的结构，这些结构可以在几个步骤中组装成分子管道的一部分，这些分子管道可能会导致新生物学的发现，并最终可能对各种疾病产生影响。

DESCRIPTION (provided by applicant): The NIH's molecular library program has been instigated to provide ready public-domain access to small molecules of potential utility as probes for biological processes or as the starting points for potential therapeutics. In order to sustain growth in this program new and novel libraries of small molecules are needed. This proposal aims to provide molecules that are closely related to previously identified 'high-value' structures and that fall into two classes: libraries that are based around small molecule drugs and libraries that are based around the structural motifs found in natural products with biological activity. Specifically, the proposed molecules include heterocycles that are close relatives to kinase inhibitors, structures based on tetrahydroisoquinolines and homologs, polycyclic ethers, simple pyrans, and compounds that are suggested to be orthologs of complex polycyclic natural products. PUBLIC HEALTH RELEVANCE: Small molecules, whether they be based on natural products or purely synthetic foundations, are widely considered to be the most valuable of agents to understand and treat human disease. This work focuses on the production of complex structures that can be assembled in a handful of steps as part of a pipeline of molecules that may lead to the discovery of new biology and that ultimately may have potential to impact on a variety of diseases.