Dissertation
Synthesis of modulators of the isoprenoid biosynthetic pathway
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2020
DOI: 10.17077/etd.005330
Abstract
The isoprenoid biosynthetic pathway (IBP) plays a critical role in the metabolism of many biomolecules. Modulators of this pathway, including the schweinfurthin family of natural products and bisphosphonates designed to be enzyme inhibitors, have been found to have activity that may provide effective cancer treatments.
The schweinfurthins are a family of meroterpenoid compounds that show potent and selective activity against a glioblastoma multiforme cell line, SF-295, in the National Cancer Institute’s 60-cell line panel. Their site of action is currently unknown, but it previously has been found that 3-deoxy schweinfurthin B (3dSB) decreases total cholesterol, intracellular farnesyl diphosphate, and geranylgeranyl diphosphate levels and that schweinfurthin A impairs the activity of Rho proteins. These previous findings indicate that the schweinfurthins modulate the isoprenoid biosynthetic pathway at some key point or points.
Because the location of action within the cell is still unknown, synthesis of a fluorescent schweinfurthin to pinpoint the site of activity now has been achieved. Two new schweinfurthin analogues were synthesized through these efforts and sent to the National Cancer Institute for biological testing. Both show some activity in a schweinfurthin-like pattern and the synthesis and current bioassay results are reported herein.
Steps towards the synthesis of an enol functionalized schweinfurthin analogue are also outlined herein. This substitution of the stilbene linkage by an enol was proposed to combat the poor water solubility of the stilbenes, and thus poor blood plasma solubility of the schweinfurthins. The increase in polar functionality would provide an additional hydrogen bond acceptor as the ketone form, or a hydrogen bond donor and acceptor as the enol form. This effort should lead to an analogue that is potentially more soluble in water, and several key intermediates have been prepared as a first proof of concept.
Nitrogenous bisphosphonates are also known to inhibit the key enzyme FDPS in the isoprenoid biosynthetic pathway and are used clinically for the treatment of bone disease. However, inhibition of FDPS depletes downstream intermediates leading to cholesterol and other steroids, and this inhibition turns off other pathways that require FDP. To circumvent this limitation, the Wiemer group has synthesized terpenoid bisphosphonates to target the more downstream enzymes GGDPS and GGTase II. Synthesis of three new α-hydroxy bisphosphonate isoprenoids is described within. The biological activity of one, a triazole α-hydroxy bisphosphonate, shows promise as an inhibitor of GGDPS and is currently driving the synthesis of further α-hydroxy bisphosphonates with potential for increased potency.
Details
- Title: Subtitle
- Synthesis of modulators of the isoprenoid biosynthetic pathway
- Creators
- Chloe Morton Schroeder
- Contributors
- David F Wiemer (Advisor)Christopher M Cheatum (Committee Member)F Christopher Pigge (Committee Member)Daniel M Quinn (Committee Member)Elizabeth A Stone (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.005330
- Publisher
- University of Iowa
- Number of pages
- xxiii, 228 pages
- Copyright
- Copyright 2020 Chloe Morton Schroeder
- Language
- English
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (pages 220-228).
- Public Abstract (ETD)
On average, it takes about 10 years to advance a new drug from discovery to market in the United States and of the compounds that first begin this course, only ~0.02% make it to market. The process begins with an idea for a new drug candidate which is developed into a material suitable for laboratory and animal testing. The research contained herein reports the very early synthetic work, in the discovery stage, of compounds that could be used to treat specific cancers.
The schweinfurthins are a family of compounds that were discovered in the late nineties at the National Cancer Institute that show specific activity against highly malignant brain tumors. However, it is currently unclear exactly how this family of compounds works to kill or stunt the growth of these cancerous cells. Therefore, we have synthesized a fluorescent schweinfurthin analogue that could, quite literally, illuminate how the schweinfurthin family targets brain tumors.
In addition, the schweinfurthins do not dissolve very well in water, and therefore, they may not be very soluble in the bloodstream. To combat this, progress towards a schweinfurthin analogue with the potential for greater water solubility is outlined herein.
Finally, nitrogenous bisphosphonates have been used to treat bone disease for many years. However, these drugs still have side effects that could be minimized by developing a compound that targets a more specific enzyme of the isoprenoid biosynthetic pathway. Several compounds have been synthesized to target this enzyme, and one shows sufficient biological activity to be a promising treatment for multiple myeloma.
- Academic Unit
- Chemistry
- Record Identifier
- 9983956196902771
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