Date of Award
Spring 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Chemistry
First Advisor
Ellman, Jonathan
Abstract
Nitrogen heterocycles are present in almost two-thirds of U.S. FDA approved pharmaceuticals, as well as biologically active natural products. The first two chapters discuss the application of C-H activation methodology to explore novel, nitrogen heterocycle containing molecules as potent and selective ligands towards different protein targets. The third chapter depicts the design of new N-heterocyclic covalent molecular probes that uniquely labels a serine hydrolase protein in a chemoproteomics screen. Chapter 1 details an investigation using structure-based docking with a virtual library of tetrahydropyridines (THPs) to identify unique agonists for the serotonin 5-HT2A receptor (5-HT2AR). Based around combinations of three inputs, which in a one pot C–H alkenylation, electrocyclization, and reduction sequence provide a tetrahydropyridine framework, a virtual library of 75 million tetrahydropyridines was created. Docking of this library against a model of 5-HT2AR prioritized compounds for initial synthesis. Optimization of four lead compounds using a cycle of design, synthesis, and testing for binding and function revealed two potent 5-HT2AR agonists with unusual biological activity that differs from psychedelic 5-HT2AR agonists. Chapter 2 explores structure-activity relationship studies for the inhibition of MKP5 through modifications to the scaffold and functional groups present in a previously reported lead allosteric inhibitor. MKP5 is responsible for regulating the activity of the stress-activated MAPKs and has been put forth as a potential therapeutic target for a number of diseases, including dystrophic muscle disease. A series of derivative compounds was designed, synthesized, and evaluated for inhibition of MKP5. In addition, X-ray crystal structures of six enzyme-inhibitor complexes were solved, further elucidating the necessary requirements for MKP5 inhibition. These results lay the foundation from which more potent MKP5 allosteric inhibitors can be developed for potential therapeutics towards the treatment of dystrophic muscle disease. Chapter 3 describes the synthesis and proteomic analysis of tropane sulfonyl fluorides as valuable scaffolds for the development of covalent molecular probes with new reactivity. Sulfonyl fluorides can act as warheads for covalent probe molecules capable of targeting different amino acid side chain functionalities. Using readily available inputs, tropane sulfonyl fluorides were produced in different stereo- and regio- isomeric forms. Proteomic analysis established highly specific protein labeling of probes that uniquely labeled the mitochondrial serine hydrolase ABHD10 through a rarely observed covalent functionalization of a tyrosine residue. This chapter exhibits how C(sp3)-sulfonyl fluorides displayed on rigid and densely functionalized scaffolds can provide potent and selective protein labeling.
Recommended Citation
Kweon, Oh Sang, "Discovery and Synthesis of N-Heterocyclic Drug-like Compounds by Leveraging Novel Rh(I)-Catalyzed C-H Activation Methods" (2023). Yale Graduate School of Arts and Sciences Dissertations. 1058.
https://elischolar.library.yale.edu/gsas_dissertations/1058
