CORE--COMBINATORIAL CHEMISTRY

描述：（申请人描述） 这项提案的总体目标是提供组合化学 支持细胞周期（项目1），空间分布（项目2）， 和抗凋亡靶点（项目3）以及体外/体内 检测（核心D）、DNA微阵列（核心B）和细胞荧光生物标志物 (Core E）方案。化学合成将在很大程度上受到相互作用的指导 在这些项目中，我们每个项目投入20%的精力，另外20%的精力用于 核心D和核心B和F（信息学）各占10%。 具体来说，我们有 三大化学目标： 1. 烯烃肽库的固相平行合成 电子等排体作为丝氨酸/苏氨酸文库开发的一部分， 其他细胞周期磷酸酶抑制剂。 2. 荧光相平行合成激酶文库 抑制剂渥曼青霉素。我们已经有509的渥曼青霉素了 用于类似物合成的起始材料。 3. 生物活性化合物聚焦类似物库的快速制备 从NCI收集的被确定为有前途的线索，在我们的 三个NCDDG项目区。该计划将适用于固体和氟 相快速合成技术。 结合起来，这三个组合化学计划的目标是 大约9个文库/y，每个文库300种化合物，用于生物学评价。 此外，一些放大的样品进入先进的动物试验 需要设置 我们将准备。0.5 g/8种化合物/y 在动物身上。在细胞培养筛选中研究的30个潜在客户中， 和小鼠中空纤维测定，我们将制备CA。100毫克每。

Description: (Applicant's Description) The overall goal of this proposal is to provide combinatorial chemistry support for the Cell Cycle (project 1 ), Spatial Distribution (Project 2), and Anti-Apoptosis Targets (project 3) as well as the in vitro/in vivo Testing (Core D), DNA Microarray (Core B) and Cell Fluorescence Biomarkers (Core E) Programs. Chemical synthesis will be heavily guided by interactions with these Projects, devoting 20% of our effort to each, as well as 20% to Core D and 10% each to Cores B and F (Informatics ). Specifically, we have three major chemistry aims: 1. The solid phase parallel synthesis of libraries of alkene peptide isosteres as part of the development of libraries of serine/threonine and other cell cycle phosphatase inhibitors. 2. The fluorous phase parallel synthesis of libraries of the kinase inhibitor wortmannin. We already have 50 9 of wortmannin available as starting material for analog syntheses. 3. The rapid preparation of focused analog libraries of bioactive compounds from the NCI collection that are being identified as promising leads in our three NCDDG project areas. This program will apply both solid and fluorous phase rapid synthesis techniques. Combined, these three combinatorial chemistry programs have a goal of approximately 9 libraries/y of 300 compounds each for biological evaluation. In addition, some scale up for samples that go into advanced animal testing will be needed. We will prepare ca. 0.5 g of 8 compounds/y that are tested in animals. Of the projected 30 leads that are studied in cell culture screen and hollow fiber assays in mice, we will prepare ca. 100 mg each.