Heterocyclic /Carbocyclic Libraries for High Throughput

高通量杂环/碳环文库

• 批准号: 7193848
• 负责人: RICHARD C. LAROCK
• 金额: $ 34.31万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7193848
• 关键词: NIH Roadmap Initiative tag; biomedical resource; chemical models; chemical registry /resource; chemical structure; chemical structure function; chemical synthesis; combinatorial chemistry; computer simulation; heterocyclic compounds; high throughput technology; molecular dynamics; physical separation; racemization; small molecule

DESCRIPTION (provided by applicant): The Larock group at Iowa State University will prepare for high throughput screening a large number of libraries of heterocycles and carbocycles expected to exhibit a wide range of biological activity. Three very general synthetic methods primarily developed in the Larock group will be employed. (1) The Pd-catalyzed annulation of alkynes, dienes, alkenes and arynes will be employed to prepare specially diverse libraries of indoles, benzofurans, benzopyrans, coumarins, isocoumarins, phthalides, pyrones, 2-quinolones, pyridines, isoquinolin-1-ones, isoindolin-1-ones, isoquinolines, carbolines, isoindolo[2,1-a]indoles, carbazoles, dibenzofurans and various other heterocycles, plus indenones, indenes, fluoren-9-ones and 9-alkylidene-9Hfluorenes. (2) The cyclization of readily available, functionally-substituted alkynes by halogen, sulfur, selenium and organopalladium electrophiles will be utilized to prepare libraries of medicinally interesting indoles, benzofurans, coumestans, chromones, benzothiophenes, benzoselenophenes, phthalides, isocoumarins, isochromenes, isoquinolines, quinolines, furans, isoxazoles and various spirotrienones. (3) Aryne annulations will be used to prepare xanthones, thioxanthones and acridones. Halogen-containing heterocycles and carbocycles will be further elaborated to more diverse libraries by well known, Pd-catalyzed processes. This methodology is very efficient, tolerates virtually all important organic functional groups, proceeds under mild reaction conditions, affords high yields of very pure compounds, and uses readily available starting materials, reagents and catalysts. Libraries consisting of (20-100 novel, small, densely functionalized, specially diverse compounds will be prepared by this very versatile solution and solid phase chemistry already worked out in the Larock group. Racemic mixtures will be separated by the Armstrong group in Texas and molecular modeling will be carried out by the Lushington group at Kansas University. The resulting libraries will be purified to generally >95% purity using standard laboratory techniques and, if necessary, the high throughput purification techniques available to the PI through the Kansas University Center of Excellence in Chemical Methodologies and Library Development. This methodology will be widely published and the resulting libraries donated to the NIH Molecular Libraries Small-Molecule Repository and the Molecular Libraries Screening Center Network.

描述（由申请人提供）：爱荷华州立大学的 Larock 小组将准备高通量筛选大量预计表现出广泛生物活性的杂环和碳环文库。将采用主要由 Larock 小组开发的三种非常通用的合成方法。 (1) Pd催化的炔、二烯、烯烃和芳炔的环化将用于制备特殊多样的吲哚、苯并呋喃、苯并吡喃、香豆素、异香豆素、苯酞、吡喃酮、2-喹诺酮、吡啶、异喹啉-1-酮文库、异吲哚啉-1-酮、异喹啉、咔啉、异吲哚并[2,1-a]吲哚、咔唑、二苯并呋喃和各种其他杂环，以及茚酮、茚、芴-9-酮和9-亚烷基-9H芴。 (2) 通过卤素、硫、硒和有机钯亲电子试剂环化容易获得的功能取代的炔烃，将用于制备药用吲哚、苯并呋喃、香豆素、色酮、苯并噻吩、苯并硒吩、苯酞、异香豆素、异色烯、异喹啉的文库、喹啉类、呋喃类、异恶唑类以及各种螺三烯酮。 (3)芳炔环化将用于制备氧杂蒽酮、噻吨酮和吖啶酮。含卤素杂环和碳环将通过众所周知的 Pd 催化过程进一步精制为更多样化的文库。该方法非常有效，能够耐受几乎所有重要的有机官能团，在温和的反应条件下进行，提供高产率的非常纯的化合物，并且使用容易获得的起始材料、试剂和催化剂。由（20-100种新型、小型、密集功能化、特殊多样化的化合物组成的文库将通过这种非常通用的解决方案和已在Larock小组中研究出来的固相化学来制备。外消旋混合物将由德克萨斯州的阿姆斯特朗小组和分子建模将由堪萨斯大学 Lushington 小组进行，所得文库将使用标准实验室技术纯化至一般 >95% 的纯度，如有必要，还可通过堪萨斯大学中心向 PI 提供高通量纯化技术。该方法将被广泛出版，并将所得的图书馆捐赠给 NIH 分子图书馆小分子存储库和分子图书馆筛选中心网络。