Defense Date

4-22-2026

Graduation Date

Summer 8-7-2026

Availability

Immediate Access

Submission Type

dissertation

Degree Name

PhD

Department

Medicinal Chemistry

School

School of Pharmacy

Committee Chair

David Lapinsky

Committee Member

Patrick Flaherty

Committee Member

Marc Harrold

Committee Member

Michael Cascio

Committee Member

Kevin Tidgewell

Keywords

Chemical biology, Chemoproteomics, Fully functionalized small-molecule probes, Clickable covalent probes, Tri-functional building blocks, Modular probe synthesis, Chemical probe library diversity, Photoaffinity labeling, Target identification, Drug discovery

Abstract

The completion of the Human Genome Project in 2003 generated expectations that genomic information would accelerate the discovery of new protein drug targets and FDA-approved therapies. However, many small-molecule drug candidates continue to fail in clinical trials, and much of the human proteome remains undercharacterized in terms of structure, function, and disease relevance. Chemical tools are therefore essential for defining protein function, mapping protein interactions, and identifying disease-associated molecular mechanisms. Among these tools, small-molecule chemical probes provide a powerful strategy for connecting biological activity with target identification, functional analysis, and the development of effective therapies.

This dissertation describes the development and application of tri-functional chemical building blocks for the synthesis of fully functionalized small-molecule probes (FFSMPs) for chemical biology-mediated drug discovery applications. FFSMPs are self-contained small molecules that integrate biological activity with handles for detection, enrichment, and analysis, thus allowing direct use in live-cell or proteomic studies. The first section describes a “double explosion” synthesis strategy centered on tri-functional 3-ethynyl-5-nitrobenzaldehyde, enabling modular access to scaffold-, appendage-, and protein-reactive functional group-diverse FFSMPs through multicomponent reactions, isosteric replacements, and lead-compound derivatizations. The second section details the production and application of minimalist aliphatic tri-functional monomers developed to address key limitations of a well-known set of minimalist aliphatic diazirine-alkynes used for FFSMP synthesis, initially disclosed by the lab of Shao Q. Yao.

Collectively, this work discloses an aromatic and aliphatic platform for synthesizing next-generation FFSMPs with synthetic versatility and biological utility. These modular building blocks expand the chemical biology toolkit and support efforts to map protein function, ligandability, and druggability within native environments.

Language

English

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