Biologically active small molecules remain the foundation for the medical management of human disease. Their impacts on human health, longevity, culture, and society are difficultly overstated. In large part, medicines derived from organic compounds are the result of the tireless efforts of chemical practitioners––both past and present––who have dedicated much of their lives to the study of organic molecules and their reactivity. This working knowledge shared among chemists continues to define and expand the boundaries of what is possible. This document describes three programs to develop organic compounds for the study and betterment of human health. The first chapter details a rational approach to the development of covalent inhibitors targeting MAP2K7. The aberrant overactivity of this kinase is implicated in the molecular pathology underlying pediatric T-cell acute lymphoblastic leukemia. Work describing the design, synthesis, and evaluation of compounds that irreversibly inhibit this kinase is described. The second chapter summarizes an arduous synthetic campaign towards the synthesis of mellpaladine A, a marine natural product with selective antagonistic activity against the 5-HT5A serotonin receptor. Despite evidence that this receptor has vast implications on human physiology and disease, selective antagonists for 5-HT5A are not available. The achievement of this synthesis confers neuropharmacologists a molecular tool to better study this poorly understood receptor expressed in the brain. Finally, the third chapter describes the synthesis and in vitro evaluation of compounds inhibiting ATG4B, a cysteine protease implicated in cellular autophagy. The inhibition of autophagy may prove a fruitful means to augment the efficacy of the current standard of care for glioblastoma multiforme, a deadly cancer affecting the central nervous system.

Creator

• Kim, Dalton Robert

DOI

• https://doi.org/10.21985/n2-djye-0n14

Subject

• Organic chemistry
• Cellular biology

Language

• en

Alternate Identifier

• http://dissertations.umi.com/northwestern:16465
• etdadmin_upload_977054

Keyword

• Mellpaladine A
• Glioblastoma
• Autophagy
• MAP2K7
• T-ALL

Date created

• 2023-01-01

Resource type

• Dissertation

Rights statement

• In Copyright