Photoelectrocyclizations to Virulence Inhibiting Natural Product

光电环化作用抑制天然产物的毒力

• 批准号: 10393381
• 负责人: JON Douglas RAINIER
• 金额: $ 0.84万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10393381
• 关键词: Alkenes; Amides; Bacterial Infections; Biological; Cell Adhesion; Chemistry; Communication; DNA; Development; Disease; Event; Family; Flagellin; Funding; Goals; Gram-Positive Bacteria; Growth; Human; Immune Targeting; Immune response; Immunology; Indolequinones; Infection; Interruption; Lead; Ligands; Lipids; Microbial Biofilms; Naphthoquinones; Natural Products; Peptidyltransferase; Play; Prevalence; Proteins; Pyrazoles; RNA; Reaction; Reporting; Research; Role; Structure; System; Testing; Thalidomide; Toll-like receptors; Torque; Variant; Virulence; Wages; Work; analog; antimicrobial; coronavirus disease; drug resistant bacteria; improved; inhibitor/antagonist; microbial; pathogen; programs; quinone methide; response; response to injury; small molecule; small molecule therapeutics; sortase; therapeutic target; ubiquitin-protein ligase

Supplemental Funding Request for Photochemical Electrocyclizations to Virulence Inhibiting Natural Products Project Summary Abstract of R01 GM132531. Reports of the increasing prevalence of drug resistant bacteria has resulted in a vital need for new strategies for the development of antimicrobials. This application offers such an approach. We plan to take advantage of the enhanced understanding of the role that communication plays in bacterial virulence to develop small molecules that interrupt this phenomenon. Specifically, this work is focused on developing structurally and biologically interesting small molecule natural products from the discorhabdin and abietane families as virulence inhibitors. As part of our effort to generate these families we are developing new chemistry centered around photochemical electrocyclization reactions including enantioselective transformations. Request: We are requesting funds for salary support for Ms. Drue Domagala to carry out research in the Rainier group for the summer of 2021. Ms. Domagala will be carrying out research on the development of selective TLR-PROTAC systems as a means of targeting the immune response to diseases including COVID and bacterial infections. Summary: There are 10 structurally related Toll-Like Receptors (TLR’s) that are known in humans. The TLR’s are involved in the immune response to injury and insult through their ability to recognize pathogens (lipopeptides and proteins, RNA, lipids, flagellin, DNA, small molecules, etc.). The immune response to these pathogens, while necessary, can become uncontrolled. These unfortunate events happen across nearly all diseases and when it does it can problematic. We propose that the development of selective inhibitors of TLR’s may lead to the improved response to disease including bacterial infections and COVID. We propose to synthesize and develop PROTAC inhibitors that consist of known pyrazole ligands that have shown selectivity for various TLR’s with the E3 ligase inhibitor thalidomide.

光化学电环化的补充资金申请

项目成果

A Biaryl-Cyclohexenone Photoelectrocyclization/Dearomatization Sequence to Substituted Terpenes.

• DOI: 10.1016/j.tet.2022.133180
• 发表时间: 2022-12
• 期刊: Tetrahedron
• 影响因子: 2.1
• 作者: K.S. Satyanarayana Tummalapalli;Xuchen Zhao;J. Rainier

Biphenyl Cyclobutenone Photoelectrocyclizations.

• DOI: 10.1021/acs.joc.1c01809
• 发表时间: 2021-11-05
• 期刊: The Journal of organic chemistry
• 作者: Dai C;Zhao X;Song C;Schwartz Z;Rainier JD
• 通讯作者: Rainier JD

Stereodivergent Photoelectrocyclization Reactions of Bis-aryl Cycloalkenones: Intercepting Photoelectrocyclization Intermediates with Acid.

双芳基环烯酮的立体发散光电环化反应：用酸拦截光电环化中间体。

• DOI: 10.1021/acs.orglett.9b03214
• 发表时间: 2019
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: Zhao,Xuchen;Song,Changqing;Rainier,JonD
• 通讯作者: Rainier,JonD

The Synthesis of Conjugated Bis-Aryl Vinyl Substrates and Their Photoelectrocyclization Reactions towards Phenanthrene Derivatives.

• DOI: 10.1055/s-0040-1706001
• 发表时间: 2021
• 期刊: Synthesis
• 作者: Zhao X;Rainier JD
• 通讯作者: Rainier JD

Photoelectrocyclization Reactions of Amidonaphthoquinones.

氨基萘醌的光电环化反应。

• DOI: 10.1021/acs.joc.9b03417
• 发表时间: 2020
• 期刊: The Journal of organic chemistry
• 作者: Yin,Jinya;Landward,MichaelB;Rainier,JonD
• 通讯作者: Rainier,JonD