Fluoroalkyl ethers and thioethers are important for medicinal chemistry, serving as both active pharmaceutical ingredients and biological probes. Therefore, the ability to access these fluorinated substructures is critical for the development of new therapeutics. Despite recent synthetic improvements that improve access to many fluorinated substructures, the community has not generally addressed the preparation of fluoroalkyl (thio)ethers. Thus, mild, convergent, and practical procedures for accessing these substructures are still lacking, which restricts access to new biological probes and therapeutic candidates. The Altman group aims to overcome the aforementioned limitations by developing new methods and general strategies for accessing fluoroalkyl (thio)ethers directly from simple and ubiquitous alcohol- and thiol-based substrates. More specifically, the proposed work will employ base-catalyzed nucleophilic addition reactions to C?C bonds to access a variety of biomedically important fluoroalkylether substructures. Development of the proposed strategies will enable medicinal chemists to access new and unique biological probes and therapeutics. The recent surge in synthetic organofluorine chemistry has provided a plethora of new methods capable of generating many new fluorinated substructures. In many cases, the creativity of the synthetic chemists for generating these fluorinated substructures has exceeded the experimentally validated uses of these new fluorinated groups. In fact, some synthetic chemists have proposed replacing synthetically challenging fluoroalkyl ethers and metabolically instable non-fluorinated ether substructures with more readily accessible fluorinated ethermimetics. However, no in silico, in vitro and in vivo data supports these claims. The Altman group aims to experimentally characterize the physicochemical and biophysical perturbations imparted by the proposed fluorinated ethermimetics using a combination of computational, physicochemical, in vitro and in vivo methods. This experimental data will enable medicinal chemists to rationally integrate these emerging fluorinated substructures in therapeutic candidates.

Public Health Relevance

Fluoroalkyl ethers and thioethers are important for medicinal chemistry, serving as both active pharmaceutical ingredients and biological probes. The present proposal aims to develop strategies for accessing fluoroalkyl ethers and thioethers from fluorinated alkenes and simple alcohol- and thiol-based substrates. Further, the proposal aims to computationally and experimentally validate physicochemical and biophysical perturbations imparted by fluorinated ether mimetics. This work will not only enable medicinal chemists to better access fluoroalkyl ethers and thioethers, but also to predict physciochemical and biophysical properties of these substructures.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
1R35GM124661-01
Application #
9380203
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lees, Robert G
Project Start
2017-08-01
Project End
2022-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Shin, Inchul; Ambler, Brett R; Wherritt, Daniel et al. (2018) Stepwise O-Atom Transfer in Heme-Based Tryptophan Dioxygenase: Role of Substrate Ammonium in Epoxide Ring Opening. J Am Chem Soc 140:4372-4379