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小分子化合物的多样性导向合成方面的专业知识，制备18-22个结构独特的药效团。 许多提出的战略和合成方法已经优化和出版，从而增加了成功的可能性。 将使用固相和溶液相方法生成拟定药效团。 所要追求的合成方法虽然直接且多产，但具有高度的实用性和可重复性。 拟议的化合物将大大提高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。 固相合成将用于产生三嗪二酮、胍基脲、氨基四唑、二氢吲哚、氨基三唑、氮杂螺、氧代哌嗪和双环化合物。 我们将使用溶液相化学产生新的吲哚，哌啶，四氢喹啉和类固醇库。 此外，我们将开发合成独特的有机氟化合物的合成方法，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。 为了与研究者的研究主题保持一致，我们将以“FRENTERA药效团”的文库为目标，并采用“杂原子掺入策略（HIS）”，使用多样性导向的合成来生成新的文库。 文库以平衡大小、多样性和复杂性并优化纯度的方式设计。 这对于避免筛选过程中的假阳性至关重要。 所有提出的小分子文库都被设计为遵循已知的药物相似性规则，包括“Lipinski的五分规则”。“所有结构独特的库将由100-200个单独的化合物（每个10至20毫克）组成，并将按照RFA的要求以等于或高于90%的纯度制备。 这些将与详细的实验方案和溶解度信息一起转移到储存库。 所提出的文库以在化学空间中与PubChem数据库中的分子不重叠的方式进行选择。 大多数化学成分在PI和合作研究者的实验室中得到了很好的确立。 Torrey Pines分子研究所和Burnham医学研究所的PI之间一直存在并将继续存在长期的合作互动，该研究所是分子库筛选中心网络（MLSCN）的一部分。 因此，我们可以随时获得这两个组织的设备和人员，并可以随时进入劳动和安全合作网络。

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.