Asymmetric Reaction Technologies for the Synthesis of Chemotherapeutic Agents

用于合成化疗药物的不对称反应技术

基本信息

批准号：
8080989
负责人：
SCOTT G. NELSON
金额：
$ 27.4万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-01 至 2012-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Small molecule-based drugs continue to provide the foundation for developing therapeutic strategies for treating of most human illnesses. A substantial portion of drug development efforts within medicinal chemistry is, therefore, devoted to the synthesis of compounds for screening as drug candidates. Whether drug development efforts are directed toward specific bioactive targets or the synthesis of a library of selected derivatives, success in these endeavors is critically dependent on concurrent developments in organic synthesis methodology that allows the efficient and economical preparation of the targeted materials. Recognizing the synergism existing between chemistry and industrial drug development, this proposal details the development of new organic reaction methodology designed to access biologically active organic compounds efficiently and economically. Toward this goal, we will develop the reaction technology necessary to realize a general strategy for the catalytic synthesis of polypropionate-derived natural products. The composition of polyketides as repeating acetic or propionic acid units makes a modular synthesis strategy exploiting iterative installation of homologous monomer units an attractive synthesis strategy. Thus, we will develop a modular strategy for the catalytic asymmetric construction of stereochemically diverse polypropionate networks. The relevance of these reaction development activities to medicinal research and human health issues is exemplified in a de novo enantioselective total synthesis of the highly selective apoptosis regulator apoptolidin C. Heterocyclic small molecules are among the most ubiquitous features of new drug hits, important lead compounds, and commercially available pharmaceuticals. The development of a novel family of [4+2] and [2+2] cycloadditions for the asymmetric synthesis of highly substituted piperidine and 2-lactam derivatives, respectively, is inspired by the central role heterocycles play in pharmaceutical drug development efforts. Furthermore, efforts to develop catalytic asymmetric variants of these cycloadditions are intended to maximize the utility of these reactions in industrial medicinal and process chemical research.4.4.7. PROJECT NARRATIVE Small molecule-based drugs continue to provide the foundation for developing therapeutic strategies for treating of most human illnesses. A substantial portion of drug development efforts within medicinal chemistry is, therefore, devoted to the synthesis of compounds for screening as drug candidates. Based on these considerations, we will develop new reaction technologies for accelerating the synthesis of small molecule chemotherapeutic agents and that enable new strategies for target- and diversity-oriented synthesis.

描述（由申请人提供）：小分子的药物继续为制定治疗大多数人类疾病的治疗策略提供基础。因此，药物化学中药物开发工作的很大一部分是致力于合成作为候选药物筛查的化合物的合成。是针对特定的生物活性靶标的药物开发工作还是综合选定衍生物的库，在这些努力中的成功取决于有机合成方法中的并发发展，从而有效且经济地制备了目标材料。该提案认识到化学与工业药物开发之间存在的协同作用，详细介绍了旨在有效，经济上有效地使用生物活性有机化合物的新有机反应方法的发展。为了实现这一目标，我们将开发必要的反应技术，以实现催化合成聚含量衍生的天然产品的一般策略。聚酮化合物作为重复乙酸或丙酸单元的组成使一个模块化的合成策略利用了同源单体单元的迭代安装是一种有吸引力的合成策略。因此，我们将制定一种模块化策略，用于立体化化性多样化的聚含水酸盐网络的催化不对称结构。这些反应开发活动与药物研究和人类健康问题的相关性在从头开始的对映体选择性的完全合成的高度选择性凋亡调节剂凋亡蛋白C.杂环小分子是新药物，重要的铅化合物和商业化的新药物的最普遍的特征。 [4+2]和[2+2]的新家族的发展，分别是高度替代的哌啶和2-内酰胺衍生物的不对称合成的发展，其灵感来自于杂源在药物药物开发工作中的核心作用。此外，开发这些环加成的催化不对称变体的努力旨在最大程度地提高这些反应在工业药用和过程化学研究中的效用。4.4.4.7。项目叙事基于小分子的药物继续为制定治疗大多数人类疾病的治疗策略提供基础。因此，药物化学中药物开发工作的很大一部分是致力于合成作为候选药物筛查的化合物的合成。基于这些考虑，我们将开发新的反应技术来加速小分子化学治疗剂的合成，并为目标和多样性的合成提供新的策略。