Photochemical synthesis of bioactive molecules

生物活性分子的光化学合成

基本信息

批准号：
10389320
负责人：
Corey Stephenson
金额：
$ 8.67万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-20 至 2022-08-31
项目状态：
已结题

项目摘要

PROJECT SUMMARY The overarching theme of this proposal is the development and application of new and enabling photocatalytic methods for the preparation of compounds capable of mimicking the structure of aniline motifs commonly found in drug molecules. These approaches provide strategy-level advantages in their respective synthetic applications due to broad functional group compatibility, mild reaction conditions, scalability, and operational simplicity while simultaneously incorporating metabolism-based design criteria early in the drug discovery process. New methods using visible light, a non-toxic 'reagent' that does not generate chemical waste, are attractive strategies for chemical synthesis circumventing the reliance upon expensive and synthetically challenging starting material preparation, further enabling synthesis in an environmentally conscious fashion. The major goals of this proposal leverage strain-releasing ring-opening reactions for the preparation of previously inaccessible motifs and the demonstration of their utility as replacements of metabolically-labile aniline functionality in drug discovery. Specifically we will leverage these chemical findings to address modern challenges in therapeutic development, namely: 1) novel KCNQ agonists for unmet needs in hearing disorders (i.e. tinnitus; cyclodextrin-induced ototoxicity); and 2) metabolically-inert analogs of lapatinib which will represent new leads in cancer therapy and antimicrobial research while also serving as biological probes for studying the immunogenicity of hepatotoxic drugs.. These goals translate creativity in reaction science into immediately-impactful and multi-faceted applications in drug discovery and are intended to demonstrate the broad-reaching influence that can arise from investment in synthetic innovation.

项目摘要该提案的总体主题是开发和应用新的和启用光催化制备能够模仿苯胺基序的结构的化合物的方法在药物分子中发现。这些方法在各自的合成中提供了策略级别的优势由于功能组兼容性，轻度反应条件，可伸缩性和运行性而引起的应用简单性同时在药物发现早期同时纳入基于代谢的设计标准过程。使用可见光的新方法，一种不会产生化学废物的无毒的“试剂”，是化学合成的有吸引力的策略规避了对昂贵和合成的依赖挑战起始物质准备，以环保的方式进一步实现合成。该提案的主要目标利用了应变释放的环反应来准备以前无法访问的基序及其效用的演示作为代谢不稳的替代药物发现中的苯胺功能。具体而言，我们将利用这些化学发现来解决现代治疗性开发中的挑战，即：1）新颖的KCNQ激动剂，满足了听力障碍的需求（即耳鸣；环糊精诱导的耳毒性）； 2）Lapatinib的代谢插入类似物代表癌症治疗和抗菌研究的新铅，同时也是生物学探针研究肝毒性药物的免疫原性。这些目标将反应科学中的创造力转化为立即对药物发现中的影响和多面应用，旨在证明综合创新的投资可能会引起广泛的影响。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Advancements in Visible-Light-Enabled Radical C(sp)2-H Alkylation of (Hetero)arenes.

DOI：
10.1055/s-0037-1611658
发表时间：
2019-03
期刊：
Synthesis
影响因子：
0
作者：
通讯作者：

Aryl Transfer Strategies Mediated by Photoinduced Electron Transfer.

DOI：
10.1021/acs.chemrev.1c00388
发表时间：
2022-01-26
期刊：
CHEMICAL REVIEWS
影响因子：
62.1
作者：
Allen, Anthony R.;Noten, Efrey A.;Stephenson, Corey R. J.
通讯作者：
Stephenson, Corey R. J.

Photochemical Formal (4 + 2)-Cycloaddition of Imine-Substituted Bicyclo[1.1.1]pentanes and Alkenes.

DOI：
10.1021/jacs.1c10541
发表时间：
2021-12-22
期刊：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
影响因子：
15
作者：
Harmata, Alexander S.;Spiller, Taylor E.;Sowden, Madison J.;Stephenson, Corey R. J.
通讯作者：
Stephenson, Corey R. J.

Development of an automated screen for Kv7.2 potassium channels and discovery of a new agonist chemotype.

DOI：
10.1016/j.bmcl.2022.128841
发表时间：
2022-09-01
期刊：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
影响因子：
2.7
作者：
Hernandez, Ciria C.;Tarfa, Rahilla A.;Limcaoco, Jose Miguel I.;Liu, Ruiting;Mondal, Pravat;Hill, Clare;Duncan, R. Keith;Tzounopoulos, Thanos;Stephenson, Corey R. J.;O'Meara, Matthew J.;Wipf, Peter
通讯作者：
Wipf, Peter