Chemical Intermediates & Multigram Synthesis Core

化学中间体

• 批准号: 8034267
• 负责人: Harshani R Lawrence
• 金额: $ 14.08万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8034267
• 关键词: Adverse effects; Animals; Antineoplastic Agents; Biological; Chemicals; Chemistry; Combinatorial Synthesis; Generations; Goals; High Pressure Liquid Chromatography; Lead; Libraries; Metabolism; Molecular; Pharmaceutical Preparations; Play; Program Research Project Grants; Property; Reaction; Research Personnel; Role; Route; Signal Transduction; Techniques; Time; Toxic effect; chemical synthesis; combinatorial; design; flexibility; in vivo; novel; pre-clinical; research clinical testing; scaffold; small molecule libraries; tool

The primary aim of the Core C facility is synthesis of chemical building blocks (or intermediates) to facilitate the generation of Focused Chemical Libraries in Projects 1, 2, 3, 4 & 5 of the P01 program and to assist Projects 1, 2, 3, 4 and 5 with multi-gram scale re-synthesis of lead compounds for their in-vivo animal studies. The specific functions of Core C will include: ¿ The synthesis of unique chemical building blocks that are not commercially available for use by the projects for combinatorial and parallel chemistry. The chemical space explored by Projects 1, 2, 3, 4 and 5, via the synthesis of combinatorial libraries, will therefore be expanded in an efficient and exclusive manner. ¿ The multi-gram scale re-synthesis of lead and key compounds for advanced drug property studies within the projects to evaluate in-vivo activity, toxicity, selectivity, metabolism and molecular mechanism. The compounds chosen as leads from Projects 1, 2, 3, 4 and 5 need to be re-synthesized with the highest levels of purities (at least 99% pure by HPLC) possible. It is time consuming to validate the reaction conditions, purification and analytical techniques (HPLC and LCMS) necessary to provide pure materials. Researchers whose primary responsibility is lead discovery and optimization would have to devote a considerable amount of time to the re-synthesis of a particular target compound, which could have an adverse effect on their primary goal. Molecular diversity within a combinatorial library is created by attaching chemical building blocks to scaffolds or intermediates. This diversity is highly dependent upon the quality of the building block set used within the library. By providing new building blocks, novel chemical and biological space can be probed, thereby increasing the chances of discovering new highly potent anticancer agents. Flexible synthetic routes will be developed that provide novel building blocks designed to incorporate drug-like properties. Wherever possible the building blocks and their derivatives will be shared across the projects. For these reasons, chemical building block synthesis and multi-gram scale re-synthesis support will play a key role in both integrating the different projects and in achieving the goals of the P01 in identifying a number of potent and selective compounds as tools to fully investigate the biological significance of their signal transduction targets in Projects 1, 2, 3, 4 and 5 and for pre-clinical evaluation as anticancer drugs.

核心C设施的主要目的是合成化学构建块（或中间体）以促进 P01计划的项目1、2、3、4和5中的集中化学图书馆产生并协助 项目1、2、2、3、4和5，其体内动物的铅化合物的多克量表重新合成 研究。核心C的特定功能将包括： �独特的化学构建块的合成，这些块无法商业地使用 组合和平行化学的项目。项目1、2、3、4探索的化学空间 5，通过合成组合文库的合成，将以有效的和 独家方式。 �高级药物性能研究的铅和关键化合物的多克量表重新合成 在项目中评估体内活性，毒​​性，选择性，代谢和分子 机制。 这些化合物从项目1、2、3、4和5中选择作为铅，需要以最高 纯度水平（至少是HPLC纯度为99％）。验证反应很耗时 提供纯材料所需的条件，纯化和分析技术（HPLC和LCM）。 主要责任是铅发现和优化的研究人员将不得不投入 特定靶化合物的重新合成的大量时间，这可能具有 对其主要目标的不利影响。 组合库中的分子多样性是通过将化学构建块附加到脚手架上创建的 或中间体。这种多样性在很大程度上取决于在 图书馆。通过提供新的构件，可以探测新颖的化学和生物空间 增加发现新的高潜在抗癌剂的机会。灵活的合成路线将是 开发的提供了旨在结合类似毒品的特性的新型构件。无论何处 构建块及其衍生产品可能会在整个项目中共享。 由于这些原因，化学构建块合成和多克量表重新合成支持将发挥作用 在整合不同的项目和实现P01的目标方面的关键作用在识别一个数字方面 潜在和选择性化合物作为完全研究其信号生物学意义的工具 项目1、2、3、4和5中的转导靶标，以及作为抗癌药物的临床前评估。