Dissertation
Synthesis of phosphonates and bisphosphonates as potential therapeutics
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2020
DOI: 10.17077/etd.005678
Abstract
Phosphorus-based pharmaceutical agents have been explored for decades and successfully utilized to treat a variety of diseases. The phosphonate is a common scaffold used due to its increased metabolic stability compared to phosphates. Phosphonates can be designed to target the isoprenoid biosynthetic pathway. This metabolic pathway leads to the production of an immensely diverse variety of biomolecules including sterols, vitamins, hormones, and other aspects of cellular metabolism. The isoprenoid biosynthetic pathway has been connected to a wide range of cancers and disorders. To combat this, the enzymes of this pathway have been scrutinized as targets for therapeutic agents.
Phosphoantigens are small-molecule organophosphorus compounds that are recognized by a subset of immune cells that express the γδ T cell receptor. The T cell population quickly expands after detecting exogenous phosphoantigens from bacterial infections. These cells also recognize endogenous phosphoantigens, and thus play a critical role in cancer immunosurveillance. Although there are significant gaps in our understanding of the mechanism of phosphoantigen-induced T cell proliferation, it is understood that phosphoantien binding to an intracellular domain of the butyrophilin 3A1 protein is necessary for any γδ T cell response.
To probe critical protein interactions, an extensive structure-activity relationship study of phosphonates derived from the microbial phosphoantigen HMBPP have been synthesized. Recent contributions to this project include the development of a synthetic double prodrug approach, which focuses primarily on the efficacy of cell-cleavable allylic acetate moieties on the phosphoantigen payload. Another avenue of investigation is the synthesis of fluorescence quenching phosphoantigen prodrugs that can provide insight on spatiotemporal activation of the phosphoantigen payload by plasma esterases.
Details
- Title: Subtitle
- Synthesis of phosphonates and bisphosphonates as potential therapeutics
- Creators
- Nyema M. Harmon
- Contributors
- David F Wiemer (Advisor)Florence Williams (Committee Member)Tori Z Forbes (Committee Member)F. Christopher Pigge (Committee Member)Andrew J Wiemer (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Chemistry
- Date degree season
- Autumn 2020
- DOI
- 10.17077/etd.005678
- Publisher
- University of Iowa
- Number of pages
- xix, 171 pages
- Copyright
- Copyright 2020 Nyema M. Harmon
- Language
- English
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (pages 161-171).
- Public Abstract (ETD)
Phosphorus-based pharmaceutical agents have been explored for decades and successfully utilized to treat a variety of diseases. Some prominent examples are the phosphorus-based drug Remdesivir which has been one of the key contributors to the treatment of COVID-19 symptoms, and Truvada for PrEP (Pre-exposure prophylaxis), which contains the phosphorus-based drug Tenofovir for treatment or prevention of HIV/AIDS.
Our recent contribution to the synthesis of phosphorus-based pharmaceuticals is focused on a class of compounds called phosphoantigens. Phosphoantigens are phosphorus-based compounds that stimulate the human immune system to identify and destroy cells infected by diseases like malaria or tuberculosis as well as specific cancer cells. This work discusses the rational design, characterization, and evaluation of phosphoantigens as functional drugs to combat leukemia and fluorescent probes to understand how these compounds are processed in the cell.
- Academic Unit
- Chemistry
- Record Identifier
- 9984035893202771
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