Novel Heterocyclic Libraries

描述(由申请人提供)：本申请获得美国国立卫生研究院分子图书馆路线图计划的支持，主题为“加速杂环和碳环支架的方法”，目的是利用PI实验室以前发现的新方法，有效地合成用于高通量筛选的各种化学成分的中试规模文库。我们建议建立4个小分子文库，每个小分子文库包含100-1,000种不同的化合物，总共有2,100个样本，将在3年内提交给MLSMR。我们唯一的目标是 在MLSMR中远远低于代表性的脚手架。所提出的3个杂环和1个桥联碳双环系统，由于它们与天然产物或杂环药物相似，因此很有可能调节生物大分子的功能，但包含新的或极其罕见的核心结构。具体地说，我们打算追求以下目标：1.基于5，6-二氢-2H-1，2，6-噻二嗪1，1-二氧化物杂环化学型的文库的制备。2.基于4H-嘧啶并[1，2-a]嘧啶杂环化学型的文库的制备3.基于5-磺酰基嘧啶-2，4(1H，~3H)-二酮杂环化学型文库的制备4.双环[3.3.1]正碳二环化学型文库的制备。5.与MLPCN和化验提供者密切合作，对MLPCN HTS活动中确定的任何命中的第二代文库的合成采取有效后续行动。这项应用的主要优点是(A)建议支架的药物化学相关性，其中包括杂环、碳双环和天然产物类结构，这些结构目前在MLSMR中表现很差，以及(B)PI在成功地平行合成50-500个多毫克规模的特征良好的有机化合物库中的记录，包括将这些样品运送和处理到筛选社区，以及与多个生物合作者的主动互动。

DESCRIPTION (provided by applicant): The purpose of this application for support from the NIH Molecular Libraries Roadmap program on the topic of "Accelerated Approaches to Hetero- and Carbocyclic Scaffolds" is to exploit new methodologies previously discovered in the PI's laboratories for the efficient synthesis of chemically diverse Pilot-Scale Libraries for High-Throughput Screening. We propose to generate 4 small molecule libraries of 100-1,000 distinct chemical compounds each, for a total of 2,100 samples, to be submitted to the MLSMR over a period of 3 years. We exclusively target scaffolds that are far underrepresented in the MLSMR. The proposed 3 heterocyclic as well as 1 bridged carbobicyclic ring systems have a high likelihood of modulating the function of biomacro-molecules due to their similarity to natural products or heterocyclic drugs, but contain novel or exceedingly rare core structures. Specifically, we intend to pursue the following goals: 1. Preparation of libraries based on the 5,6-dihydro-2H-1,2,6-thiadiazine 1,1-dioxide heterocyclic chemotype. 2. Preparation of libraries based on the 4H-pyrimido[1,2-a]pyrimidine heterocyclic chemotype. 3. Preparation of libraries based on the 5-sulfonyl-pyrimidine-2,4(1H,3H)-dione heterocyclic chemotype. 4. Preparation of libraries based on the bicyclo[3.3.1]nonane carbobicyclic chemotype. 5. Efficient follow up on the synthesis of 2nd generation libraries for any hits identified in MLPCN HTS campaigns, in close collaboration with the MLPCN and the assay providers. The major strengths of this application are (a) the medicinal chemistry relevance of the proposed scaffolds, which include both heterocyclic, carbobicyclic, and natural product-like structures that currently are poorly if at all represented in the MLSMR, as well as, (b) the track record of the PI in the successful parallel synthesis of libraries of 50-500 members of well characterized organic compounds on multi-milligram scale, including the shipping and handling of these samples to the screening community and the proactive interactions with multiple biological collaborators.