Chemical Synthesis of Chiral Bioactive Molecules

手性生物活性分子的化学合成

• 批准号: 9071843
• 负责人: Sarah Elizabeth Reisman
• 金额: $ 50.31万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9071843
• 关键词: Address; Alkaloids; Area; Chemicals; Chemistry; Complex; Coupling; Development; Diterpenes; Drug Industry; Exhibits; Family; Goals; Lead; Logic; Medicine; Metals; Methods; Natural Products; Nickel; Organic Chemistry; Outcomes Research; Preparation; Process; Reaction; Reagent; Reducing Agents; Research; Research Personnel; Series; Training; catalyst; chemical reaction; chemical synthesis; design; drug candidate; drug discovery; functional group; graduate student; human disease; programs; public health relevance; research clinical testing; small molecule; success; theories; tool

 DESCRIPTION (provided by applicant): The overarching goal of this research program is to develop new chemical reactions and synthetic strategies for the preparation and study of chiral bioactive small molecules. Over the past decade, researchers in the pharmaceutical industry have begun to recognize the benefit of structural complexity in drug candidates, wherein molecules with greater complexity exhibit higher success rates as the proceed through the process of clinical testing and FDA approval. In order to enable the preparation of bioactive molecules with increased complexity, it is imperative to develop both the synthetic tools - new chemical reactions - and the synthetic logic for assembling molecules with chiral centers and polycyclic frameworks. The proposed research program will seek to address this need through chemical research in two general areas. The first research area will focus on the development of new Nickel-catalyzed enantioselective reductive cross-coupling reactions. These reactions tolerate an array of functional groups, occur under mild conditions, and employ inexpensive, earth abundant metals as catalysts and stoichiometric reductants. Most importantly, they do not require the use of pre-generated organometallic reagents. Preliminary results obtained for a series of new asymmetric reductive cross-coupling reactions provide compelling evidence for the feasibility of this research. The second research area will focus on the synthesis of complex, polycyclic natural products of the epidithiodiketopiperazine and alkaloid diterpenoid families. The expected outcomes of this research are two-fold: it will provide new reactions and strategies for preparing complex polycyclic molecules, and it will provide access to medicinally relevant natural products and their derivatives, which could serve as lead compounds in drug discovery efforts. This research will be carried out by a team composed of the PI, five chemistry graduate students and three postdoctoral researchers. As part of this project, the graduate students and postdoctoral researchers will receive rigorous training in the theory, methods, and strategies of organic chemistry. The successful execution of this research will provide new tools to enable the synthesis of small molecules for the study and treatment of human disease.

 描述（由适用提供）：该研究计划的总体目标是开发新的化学反应和合成策略，以制备和研究手性生物活性小分子。在过去的十年中，制药行业的研究人员已经开始认识到候选药物中结构复杂性的好处，随着通过临床测试和FDA批准的过程进行进展，具有更高复杂性的分子暴露了更高的成功率。为了使生物活性分子的复杂性增加，必须同时开发合成工具（新的化学反应），也必须使用手性中心和多环形框架组装分子的合成逻辑。拟议的研究计划将寻求通过在两个一般领域的化学研究来满足这一需求。第一个研究领域将着重于新的镍催化对映选择性的开发减少交叉偶联反应。这些反应可耐受一系列官能团，在轻度条件下发生，并用廉价的地球金属作为催化剂和化学计量减少。最重要的是，它们不需要使用预生成的有机试剂。一系列新的不对称交叉偶联反应获得的初步结果为这项研究的可行性提供了令人信服的证据。第二个研究领域将重点介绍杂质二甲苯吡嗪和生物碱二萜家族的复杂，多环天然产物的合成。这项研究的预期结果是两个方面：它将为准备复杂的多环分子的新反应和策略提供新的反应和策略，并将提供获得与药物相关的天然产品及其衍生物的访问，这些天然产品及其衍生物可以用作药物发现工作中的铅化合物。这项研究将由由PI，五名化学研究生和三名博士后研究人员组成的团队进行。作为该项目的一部分，研究生和博士后研究人员将在有机化学的理论，方法和策略中接受严格的培训。这项研究的成功执行将提供新的工具，以使小分子的研究和治疗人类疾病的综合。