Dissertation
Geranylgeranyl diphosphate synthase inhibition by terpenoid bisphosphonates
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2020
DOI: 10.17077/etd.005383
Abstract
Multiple myeloma is a cancer characterized by the large-scale production and export of monoclonal antibody proteins. The exocytosis of these proteins from the trans-Golgi apparatus is contingent upon and directed by the presence of Rab proteins on the vesicle membrane. Proper membrane localization of Rab is made possible by a post-translational modification called prenylation. In this modification, a geranylgeranyl chain is added to the Rab protein bound in a complex with another protein, Rep. The geranylgeranyl chain for this modification comes from geranylgeranyl diphosphate (GGPP). By depleting the cell’s GGPP concentration, Rab prenylation is diminished, and the unmodified protein does not properly localize to vesicle membranes. Consequently, exocytosis is inhibited, resulting in a buildup of intracellular monoclonal protein in the myeloma cells. Eventually, this buildup induces the unfolded protein response and leads to apoptotic cell death.
Over the past decade, the research labs of Dr. David Wiemer and Dr. Sarah Holstein have explored a strategy to lower cellular GGPP concentrations in myeloma cells by inhibition of the enzyme responsible for its cellular synthesis - geranylgeranyl diphosphate synthase (GGDPS). The most active class of inhibitors developed to date consists of a bisphosphonate head group, a terpenoid tail, and a triazole linking the two halves of the molecule. The structure-activity relations (SAR) study through which this family has been optimized has focused primarily on modifications of the terpenoid tail. Far less work has been done on modifications at or around the bisphosphonate head, and even less work has been done looking at the linkage between the two halves of the molecule.
This work concerns itself with furthering efforts to understand GGDPS inhibition. In the first section, the attempted synthesis of a number of oxygenated terpenoid triazole bisphosphonates is discussed. The successful syntheses of biologically active vinyl and cyclopropyl terpenoid triazole bisphosphonate also is presented. During the course of this work, a new Johnson-Corey-Chaykovsky strategy for preparing unsubstituted cyclopropyl bisphosphonates from vinyl bisphosphonates was developed. In the second part, a new, amide-based linkage is developed for these inhibitors in an effort to address challenges inherent to the triazole. These challenges include the practical difficulties of large-scale azide-based syntheses, observed hepatotoxicity of the triazoles in a mouse model, and the difficult synthesis of the most-active homoneryl triazoles. The family of terpenoid amides prepared is biologically active against GGDPS, and follows – broadly – the patterns of activity found in the triazoles. The synthesis of the most active bishomogeranyl amide was comparatively straightforward and avoided the use of azides. Furthermore, this synthesis does not contain fundamental issues of scalability. Finally, future work might well show that the replacement of a triazole linkage with an amide lowers the risk of hepatotoxicity in treating myeloma with these terpenoid bisphosphonate GGDPS inhibitors.
Details
- Title: Subtitle
- Geranylgeranyl diphosphate synthase inhibition by terpenoid bisphosphonates
- Creators
- Daniel Goetz
- Contributors
- David Wiemer (Advisor)James Gloer (Committee Member)F. Christopher Pigge (Committee Member)Elizabeth Stone (Committee Member)Scott Daly (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Chemistry
- Date degree season
- Spring 2020
- DOI
- 10.17077/etd.005383
- Publisher
- University of Iowa
- Number of pages
- xxiii, 199 pages
- Copyright
- Copyright 2020 Daniel Blair Goetz
- Language
- English
- Description illustrations
- illustrations
- Description bibliographic
- Includes bibliographical references (pages 195-199).
- Public Abstract (ETD)
Multiple myeloma, a type of bone marrow and blood cancer, is the second most common blood-related cancer in the United States. Approximately half of patients die within five years. Myeloma cells produce excessive antibody proteins that are transported out of the cell using cellular shipping crates called vesicles. A specific protein, Rab, acts as a shipping label for these vesicles. It uses an anchor derived from geranylgeranyl diphosphate (GGPP) to adhere to vesicles’ surfaces.
Researchers in the labs of Dr. David Wiemer and Dr. Sarah Holstein have developed drug-candidate inhibitors of GGPP production. These inhibitors stop antibody transportation, but not creation, by preventing Rab function. The resulting buildup of unexported antibodies stresses the cell, ultimately killing it. Healthy cells are comparatively tolerant of this disruption, allowing selectivity against myeloma cells. Unfortunately, large-scale synthesis of these inhibitors is difficult, and they appear to cause liver damage in a mouse model.
These inhibitors have three parts: 1) a greasy “tail”, 2) a phosphorus-containing “head”, and 3) a linkage between them. Extensive work has examined how variations of the tail’s structure affect the inhibitors’ biological activities. The first part of this work describes attempts at incorporating an oxygen near the head and the synthesis of two new biologically-active head groups. In the second part, the linkage is replaced with one that is easier to make on scale and can be broken down in the liver. This replacement yielded biologically-active inhibitors which follow, broadly, the activity patterns observed previously.
- Academic Unit
- Chemistry
- Record Identifier
- 9983966298502771
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