1,2,4-Triazine-Accelerated Azide-Alkyne Cycloaddition and Synthesis of Metalloenzyme Inhibitors

Author

Belinda Shea LadyFollow

Date of Award

5-2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Chemistry

Major Professor

Shane Foister

Committee Members

Michael D. Best, Jimmy W. Mays, Thomas A. Zawodzinski

Abstract

The work of this dissertation describes the design and synthesis of 1,2,4-triazine ligands and other N-containing heterocycles and their use in the copper-catalyzed azide-alkyne cycloaddition (CuAAC). A variety of ligands were synthesized to probe the steric and electronic demands required for use in the CuAAC reaction. Substituents on the 1,2,4-triazine were systematically altered and the core 1,2,4-triazine modified to determine the most active ligand. Additional experiments explored the variability in the reaction conditions, such as solvent choice, use of reducing agents, and optimal stoichiometry. Under optimum conditions 5,6-diphenyl-3-(2-pyridyl)-1,2,4-triazine and copper (II) tetrafluoroborate in the presence of triethylamine was found to be an effective accelerant producing 97% of the desired 1,2,3-triaozle in 1 hour. A broad substrate scope was conducted with an assortment of azides and alkynes.

The use of 1,2,4-triazine-accelerated CuAAC was applied to the synthesis of solid-supported catalysts on both polystyrene and silica. Immobilized catalysts provide advantages over their soluble counterparts in that they can be recycled and can prevent metal contamination of 1,2,3-triazole products. Results indicated that 1,2,4-triazines appended to solid supports were more effective when compared to 1,2,3-triazole control catalysts. In addition, less metal leaching occurred with triazine supports as compared to triazole controls.

The optimal ligand from the homogeneous screening was then used in the synthesis of a library of small molecules containing 1,2,3-triazoles and/or 1,2,4-triazoles. Upon synthesis, compounds were screened for activity against various histone deacetylase (HDAC) enzymes for both activity and selectivity. Although successfully synthesized, the molecules did not prove to be active against the selected metalloenzyme.

Recommended Citation

Lady, Belinda Shea, "1,2,4-Triazine-Accelerated Azide-Alkyne Cycloaddition and Synthesis of Metalloenzyme Inhibitors. " PhD diss., University of Tennessee, 2013.
https://trace.tennessee.edu/utk_graddiss/1750