Highly Diverse and Structurally Varied Heterocyclic Libraries for the MLSMR

MLSMR 高度多样化且结构多样的杂环文库

• 批准号: 7683843
• 负责人: Richard Allen Houghten
• 金额: $ 45.9万
• 依托单位: TORREY PINES INST FOR MOLECULAR STUDIES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-05 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7683843
• 关键词: Amitrole; Biological; Chemicals; Chemistry; Collection; Databases; Equilibrium; Equipment; Fluorine; Goals; Guanidines; Heterocyclic Compounds; Human Resources; Imines; Individual; Indoles; Institutes; Laboratories; Libraries; Medical Research; Methodology; Methods; Molecular; Molecular Bank; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Piperazines; Play; Preparation; Probability; Process; Property; Protocols documentation; Publishing; Research; Research Personnel; Role; S Phase; Screening procedure; Solid; Solubility; Solutions; Steroids; United States National Institutes of Health; Urea; base; cyclic compound; design; diketopiperazine; indoline; novel; pharmacophore; piperidine; repository; small molecule; small molecule libraries; solid solution; success

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.

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。许多建议的战略和合成 已经优化并公布了各种方法，从而增加了成功的可能性。的 将使用固相和溶液相方法产生建议的药效团。合成 所采取的办法虽然直接和富有成效，但非常实用和可重复。的 所提出的化合物将显著增强MLSMR收集。 我们将采用不同的策略，以多样性为导向合成各种独特的杂环化合物， 化合物.固相合成将用于生成三嗪二酮，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 将使用液相化学生产新的吲哚，哌啶，四氢喹啉和类固醇 图书馆.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-四氢嘧啶衍生物的化合物。 含氟化合物在药物化学和生物医学中有着特殊的作用 由于氟原子对生物活性的独特影响，因此具有广泛的应用。为了与主题保持一致 在研究者的研究中，我们将以"Festival Pharmacophores"库为目标， “杂原子掺入策略（HIS）”，以使用多样性导向的合成产生新的文库。 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。所有拟定小分子 文库被设计成遵循已知的药物相似性规则，包括“Lipinski的五规则”。所有结构 独特的文库将由100 - 200种单独的化合物（每种10 - 20 mg）组成，并将制备 纯度等于或高于RFA要求的90%。这些将被传输到存储库 详细的实验方案和溶解度信息。 所提出的文库以在化学空间中不重叠的方式选择， 分子目前在PubChem数据库中。大多数化学物质在 Pi和Co-Pi的实验室一直存在并将继续存在一种长期的合作互动 托里派恩斯分子研究所和伯纳姆医学研究所的研究人员 研究，这是分子库筛选中心网络（MLSCN）的一部分。因此，我们准备好了 获得两个组织的设备和人员以及MLSCN。

项目成果

Increased diversity of libraries from libraries: chemoinformatic analysis of bis-diazacyclic libraries.

• DOI: 10.1111/j.1747-0285.2011.01100.x
• 发表时间: 2011-05
• 期刊: Chemical biology & drug design
• 影响因子: 3
• 作者: López-Vallejo F;Nefzi A;Bender A;Owen JR;Nabney IT;Houghten RA;Medina-Franco JL
• 通讯作者: Medina-Franco JL