Highly Diverse and Structurally Varied Heterocyclic Libraries for the MLSMR

我们计划利用我们在以多样性为导向的小分子化合物合成方面的专业知识 制备18-22结构独特的药效团。许多提出的策略和合成 已经对方法进行了优化和发布，从而增加了成功的可能性。这个 建议的药效团将使用固相法和溶液相法生成。合成材料 要采取的办法虽然直接和富有成效，但却非常实用和可重复使用。这个 建议的化合物将大大加强MLSMR的收集。 我们将使用不同的策略以多样性为导向合成各种独特的杂环 化合物。固相合成将被用来合成三氮杂二酮、胍基脲、 氨基四氮唑，吲哚，氨基三氮唑，偶氮阿司匹林，奥哌嗪，和双环化合物。我们 将使用溶液相化学来生产新的吲哚、哌啶、四氢喹啉和类固醇 图书馆。此外，我们还将开发合成独特的有机氟化合物的合成方法。 化合物包括DD-二氟羰基化合物和各种二氟-四氢嘧啶衍生物。 含氟化合物在药物化学和生物医学中发挥着特殊的作用 由于氟原子对生物活性的独特影响而被广泛应用。与主题保持一致 在研究人员的研究中，我们将以“受青睐的药效团”图书馆为目标，并采用 “杂原子并入策略(HIS)”，使用面向多样性的合成来生成新的文库。 这些文库的设计方式是平衡大小、多样性和复杂性，并优化纯度。 这对于避免筛查过程中的假阳性至关重要。所有提出的小分子 图书馆被设计成遵循已知的类似毒品的规则，包括利平斯基的五规则。都是结构上的 独特的文库将由100-200个单独的化合物(每个10-20毫克)组成，并将被准备好 纯度等于或高于RFA要求的90%。这些数据将被传输到存储库 有详细的实验方案和溶解度信息。 建议的文库的选择方式不与化学空间重叠 目前在PubChem数据库中的分子。大多数的化学反应都是建立在 派和联合派的实验室。一直存在并将继续存在长期的协作互动 托里·派恩斯分子研究所和伯纳姆医学研究所的PIS之间 这是分子文库筛选中心网络(MLSCN)的一部分。因此，我们已经准备好了 接触两个组织和MLSCN的设备和人员。

We plan to use our expertise in the diversity oriented synthesis of small molecule compounds for the preparation of 18-22 structurally unique pharmacophores. Many of the proposed strategies and synthetic approaches have already been optimized and published, thus increasing the probability of success. The proposed pharmacophores will be generated using solid and solution phase methods. The synthetic approaches to be pursued, while direct and productive, are highly practical and reproducible. The proposed compounds will significantly enhance the MLSMR collection. We will use different strategies for the diversity-oriented synthesis of a variety of unique heterocyclic compounds. Solid phase synthesis will be used to generate triazinediones, guanidino-ureas, aminotetrazoles, indolines, aminotriazoles, azoniaspiro, oxopiperazinium, and bis-cyclic compounds. We will use solution phase chemistry to produce novel indole, piperidine, tetrahydroquinoline, and steroid libraries. Additionally, we will develop synthetic approaches for the synthesis of unique organofluorinated compounds including DD-difluorocarbonyl compounds and varied difluoro-tetrahydropyrimidine derivatives. Fluorine-containing compounds have played a special role in medicinal chemistry and biomedical applications due to the unique influence of fluorine atoms on biological activity. In keeping with the themes of the investigator's research, we will target libraries of "Favored Pharmacophores" and employ the "Heteroatom Incorporation Strategy (HIS)" to generate novel libraries using diversity-oriented synthesis. The libraries are designed in a manner to balance size, diversity and complexity, and to optimize purity. This is essential to avoid false positives during the screening process. All proposed small molecule libraries are designed to follow known drug-likeness rules including 'Lipinski's Rule of Five'. All structurally unique libraries will consist of 100-200 individual compounds (10 to 20 mg of each) and will be prepared with purity equal or higher than 90% as required by the RFA. These will be transferred to the repository with detailed experimental protocols and solubility information. The libraries proposed were selected in a manner which does not overlap in chemical space with molecules currently in the PubChem database. The majority of the chemistries are well established in the Pi's and Co-Pi's laboratories. There has been and continues to be, a longstanding collaborative interaction between the Pis at Torrey Pines Institute for Molecular Studies and the Burnham Institute for Medical Research, which is part of the Molecular Library Screening Center Network (MLSCN). We thus have ready access to equipment and personnel at both organizations and to the MLSCN.