Highly Diverse and Structurally Varied Heterocyclic Libraries for the MLSMR

描述(由申请人提供)：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来制备18-22个结构独特的药效团。许多拟议的战略和综合方法已经得到优化和公布，从而增加了成功的可能性。建议的药效团将使用固相法和溶液相法产生。将采取的综合办法虽然直接和富有成效，但却非常实用和可重复使用。建议的化合物将显著加强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、吲哚类、氨基三氮唑、偶氮螺、奥哌嗪和双环化合物。我们将使用溶液相化学来产生新的吲哚、哌啶、四氢喹啉和甾体库。此外，我们还将开发合成独特的有机氟化合物的方法，包括DD-二氟羰基化合物和各种二氟-四氢嘧啶衍生物。由于氟原子对生物活性的独特影响，含氟化合物在药物化学和生物医学应用中发挥着特殊的作用。为了与研究人员的研究主题保持一致，我们将以“受青睐的药效团”文库为目标，并使用“杂原子合并策略(HIS)”来利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。所有被提议的小分子文库都被设计成遵循已知的类似药物的规则，包括“利平斯基的五规则”。所有结构独特的文库将由100-200个单独的化合物(每个10-20毫克)组成，并将按照RFA的要求制备纯度等于或高于90%的化合物。这些将与详细的实验方案和溶解度信息一起传输到储存库。建议的文库是以不与PubChem数据库中当前的分子在化学空间重叠的方式选择的。大多数化学实验都是在PI和协作者的实验室中建立起来的。Torrey Pines分子研究所的PI与作为分子图书馆筛选中心网络(MLSCN)一部分的伯纳姆医学研究所之间存在并将继续存在长期的协作互动。因此，我们随时可以接触到这两个组织和MLSCN的设备和人员。

DESCRIPTION (provided by applicant): 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-investigator's laboratories. There has been, and continues to be, a long-standing 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.