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

• 批准号: 7609119
• 负责人: SCOTT G. NELSON
• 金额: $ 28.04万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/7609119
• 关键词: Acids; Address; Affect; Aldehydes; Alder plant; Apoptosis Regulator; Applications Grants; Biological Factors; Catalysis; Chemicals; Chemistry; Chloride Ion; Chlorides; Cinchona Alkaloids; Complex; Development; Family; Foundations; Goals; Health; Human; Imines; In Situ; Ions; Lactams; Lactones; Lead; Libraries; Methodology; Organic Synthesis; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Play; Preparation; Process; Propionates; Propionic Acids; Reaction; Relative (related person); Research; Role; Screening procedure; Stereoisomer; Sulfones; Technology; Therapeutic; Variant; apoptolidin; base; catalyst; chemotherapeutic agent; cycloaddition; design; diene; dimer; drug candidate; drug development; ketene; method development; monomer; novel; piperidine; small molecule; success; synergism

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）：基于小分子的药物继续为开发治疗大多数人类疾病的治疗策略提供基础。因此，药物化学中的药物开发工作的很大一部分致力于合成用于筛选候选药物的化合物。无论药物开发工作是针对特定的生物活性靶点还是合成选定的衍生物库，这些努力的成功关键取决于有机合成方法的同步发展，该方法允许有效和经济地制备靶向材料。认识到化学和工业药物开发之间存在的协同作用，该提案详细介绍了旨在有效和经济地获得生物活性有机化合物的新有机反应方法的开发。为了实现这一目标，我们将开发必要的反应技术，以实现聚丙酸酯衍生的天然产物的催化合成的一般策略。聚酮化合物作为重复的乙酸或丙酸单元的组成使得利用同源单体单元的迭代安装的模块化合成策略成为有吸引力的合成策略。因此，我们将开发一个模块化的战略，立体化学多样的聚丙酸酯网络的催化不对称建设。这些反应开发活动与医学研究和人类健康问题的相关性在高选择性细胞凋亡调节剂雷公藤甲素C的从头对映选择性全合成中得到了例证。杂环小分子是新药、重要先导化合物和市售药物中最普遍存在的特征之一。一个新的家庭的[4+2]和[2+2]环加成的高度取代的哌啶和2-内酰胺衍生物的不对称合成的发展，分别是受到杂环在药物开发工作中发挥的核心作用的启发。此外，开发这些环加成的催化不对称变体的努力旨在使这些反应在工业医学和工艺化学研究中的效用最大化。小分子药物继续为开发治疗大多数人类疾病的治疗策略提供基础。因此，药物化学中的药物开发工作的很大一部分致力于合成用于筛选候选药物的化合物。基于这些考虑，我们将开发新的反应技术，以加速小分子化疗药物的合成，并实现靶向和多样性导向合成的新策略。