Novel Heterocyclic Libraries

描述（由申请人提供）：本申请旨在获得NIH分子库路线图项目关于“肝素和碳环支架的加速方法”的支持，目的是利用PI实验室先前发现的新方法，有效合成用于高通量筛选的化学多样性中试规模文库。我们建议生成4个小分子文库，每个文库包含100- 1，000种不同的化合物，总共2，100个样品，在3年内提交给MLSMR。我们专门针对 这些支架在MLSMR中的代表性远远不足。所提出的3个杂环以及1个桥连碳双环系统由于其与天然产物或杂环药物的相似性而具有很高的调节生物大分子功能的可能性，但包含新颖或极其罕见的核心结构。具体而言，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4 H-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，3 H）-二酮杂环化学型的文库的制备。4.基于双环[3.3.1]壬烷碳双环化学型的文库的制备。5.与MLPCN和检测供应商密切合作，有效跟踪MLPCN HTS活动中识别的任何命中的第二代文库的合成。本申请的主要优势在于：（a）所提出的支架的药物化学相关性，其包括杂环、碳双环和天然产物样结构，这些结构目前在MLSMR中的代表性很差，以及（B）PI在成功平行合成50-500个成员的多毫克规模的充分表征的有机化合物库中的跟踪记录，包括将这些样本运送和处理到筛查社区以及与多个生物学合作者的积极互动。

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.