Novel Heterocyclic Libraries

描述（由申请人提供）：本申请获得 NIH 分子库路线图计划支持，主题为“杂环和碳环支架的加速方法”，其目的是利用 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库。我们建议生成 4 个小分子库，每个库包含 100-1,000 种不同的化合物，总共 2,100 个样本，并在 3 年内提交给 MLSMR。我们专门针对 MLSMR 中代表性远远不足的支架。所提出的3个杂环和1个桥接碳双环系统由于与天然产物或杂环药物相似，因此很可能调节生物大分子的功能，但包含新颖或极其罕见的核心结构。具体来说，我们打算实现以下目标： 1. 制备基于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。 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 和检测提供商密切合作，对 MLPCN HTS 活动中发现的任何命中的第二代文库的合成进行有效跟进。该应用的主要优点是（a）所提出的支架的药物化学相关性，其中包括杂环、碳二环和天然产物样结构，这些结构目前在 MLSMR 中表现不佳，以及（b）PI 在多毫克规模的 50-500 个特征良好的有机化合物成员库中成功平行合成的跟踪记录，包括将这些样品运送和处理到筛选社区以及与多种生物的主动相互作用合作者。

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.