Pilot-Scale Heterocyclic and Carbocyclic Libraries for High Throughout Screening

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杂环和碳环文库，预计将展示广泛的生物活性。主要由LaRock集团开发的三种非常通用的合成方法将被使用。(1)将采用钯催化的炔烃、二烯、烯烃和芳烃的环化反应来制备吲哚、苯并呋喃、苯并并吡喃、香豆素、异香豆素、邻苯二甲酸酯、吡喃、2-喹诺酮、吡啶、异喹啉-1-酮、异吲哚-1-酮、异喹啉、卡洛林、异吲哚并[2，1-a]吲哚、咔唑、二苯并呋喃和各种其他杂环，以及吲哚、吲哚、荧烯-9-酮和9-亚烷基-9-杂荧烯。(2)利用卤素、硫、硒和有机钯亲电试剂对易得的、官能团取代的炔烃的环化作用，制备医药上有价值的吲哚、苯并呋喃、香豆素、色酮、苯并噻吩类、苯并硒、邻苯二甲酸酯、异香豆素、异色烯、异喹啉、喹啉、呋喃、异恶唑和各种螺三烯酮的文库。(3)芳烃环化反应将用于制备杂多酮、硫杂杂多酮和吖啶酮。通过众所周知的钯催化过程，含卤素的杂环和碳环将进一步细化到更不同的库中。这种方法非常有效，几乎可以容忍所有重要的有机官能团，在温和的反应条件下进行，提供非常纯的化合物的高产率，并使用容易获得的原料、试剂和催化剂。由(20-100种新颖的、小的、密集的官能化的、特别多样的化合物)组成的文库将由LaRock小组已经研究出的这种非常通用的溶液和固相化学来制备。外消旋混合物将由德克萨斯州的阿姆斯特朗小组分离，分子模拟将由堪萨斯大学的卢辛顿小组进行。所得到的文库将使用标准实验室技术和如有必要，通过堪萨斯大学化学方法学和图书馆开发卓越中心可用于PI的高通量纯化技术，提纯到一般&gt；95%的纯度。这一方法论将被广泛发表，并将得到的文库捐赠给NIH分子图书馆小分子资料库和分子图书馆筛选中心网络。

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.