Abstract

The objective of this project is to develop a new family of click chemistry reactions, termed Sulfur(VI) Fluoride Exchange (SuFEx) processes, and to utilize them in biological research. SuFEx relies on readily available materials and simple transformations to produce diverse chemical structures bearing the SVI-F motif, such as OSO2F (fluorosulfate) and SO2F (sulfonyl fluoride). New molecules originating from this chemistry will be used to develop probes functionalized with the 18FO2SO radiotracer for positron emission tomography. Small- molecule screening libraries will be constructed using this methodology to identify active compounds that perturb specific pathways in zebrafish embryogenesis.

Public Health Relevance

This project is aimed towards the development of highly useful click chemistry reactions for the production of biologically active compounds. The small molecule probes produced in this project may be used to develop improved protocols for positron emission tomography in children with neurodevelopmental disorders. New therapeutics for the treatment of developmental disorders in children may be discovered as well.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM117145-03
Application #
9387452
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2016-01-01
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost

  Institution

Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037

  Publications

Liu, Zilei; Li, Jie; Li, Suhua et al. (2018) SuFEx Click Chemistry Enabled Late-Stage Drug Functionalization. J Am Chem Soc 140:2919-2925
Mortenson, David E; Brighty, Gabriel J; Plate, Lars et al. (2018) ""Inverse Drug Discovery"" Strategy To Identify Proteins That Are Targeted by Latent Electrophiles As Exemplified by Aryl Fluorosulfates. J Am Chem Soc 140:200-210
Gao, Bing; Li, Suhua; Wu, Peng et al. (2018) SuFEx Chemistry of Thionyl Tetrafluoride (SOF4 ) with Organolithium Nucleophiles: Synthesis of Sulfonimidoyl Fluorides, Sulfoximines, Sulfonimidamides, and Sulfonimidates. Angew Chem Int Ed Engl 57:1939-1943
Gahtory, Digvijay; Sen, Rickdeb; Pujari, Sidharam et al. (2018) Quantitative and Orthogonal Formation and Reactivity of SuFEx Platforms. Chemistry 24:10550-10556
Zha, Gao-Feng; Zheng, Qinheng; Leng, Jing et al. (2017) Palladium-Catalyzed Fluorosulfonylvinylation of Organic Iodides. Angew Chem Int Ed Engl 56:4849-4852
Li, Suhua; Wu, Peng; Moses, John E et al. (2017) Multidimensional SuFEx Click Chemistry: Sequential Sulfur(VI) Fluoride Exchange Connections of Diverse Modules Launched From An SOF4 Hub. Angew Chem Int Ed Engl 56:2903-2908
Chen, Wentao; Dong, Jiajia; Plate, Lars et al. (2016) Arylfluorosulfates Inactivate Intracellular Lipid Binding Protein(s) through Chemoselective SuFEx Reaction with a Binding Site Tyr Residue. J Am Chem Soc 138:7353-64
Zheng, Qinheng; Dong, Jiajia; Sharpless, K Barry (2016) Ethenesulfonyl Fluoride (ESF): An On-Water Procedure for the Kilogram-Scale Preparation. J Org Chem 81:11360-11362
Qin, Hua-Li; Zheng, Qinheng; Bare, Grant A L et al. (2016) A Heck-Matsuda Process for the Synthesis of ?-Arylethenesulfonyl Fluorides: Selectively Addressable Bis-electrophiles for SuFEx Click Chemistry. Angew Chem Int Ed Engl 55:14155-14158
Zhang, Enxuan; Tang, Jiaze; Li, Suhua et al. (2016) Chemoselective Synthesis of Polysubstituted Pyridines from Heteroaryl Fluorosulfates. Chemistry 22:5692-7