The isoprenoid biosynthetic pathway (IBP) plays an important role in cellular metabolism. Currently there are drugs, including lovastatin and the nitrogenous bisphosphonates risedronate and zoledronate, that are used clinically to lower cholesterol levels and treat bone disease, respectively. These drugs work by inhibition of the upstream enzymes, HMG-CoA reductase and farnesyl diphosphate synthase (FDPS), respectively. The enzyme FDPS catalyzes the formation of farnesyl pyrophosphate (FPP), an important intermediate that represents a branch point in the pathway. The post-translational modification known as protein prenylation is mediated by the three prenyltransferase enzymes. Even though compounds like lovastatin, risedronate, and zoledronate indirectly disrupt protein prenylation, they also impair processes downstream from the point of inhibition. Therefore a direct approach would be desirable where downstream enzymes are targeted so that the rest of the cellular processes can continue to function.
One such downstream enzyme is geranylgeranyl transferase II (GGTase II). This enzyme and it catalyzes the transfer of two hydrophobic geranylgeranyl chains from geranylgeranyl pyrophosphate (GGPP) to Rab proteins, which are essential for intracellular membrane trafficking. Inhibition of GGTase II may be a good therapeutic target for diseases such as multiple myeloma characterized by an over secretion of proteins. A known GGTase II inhibitor is the carboxy phosphonate 3-PEHPC, however millimolar concentrations are necessary to observe cellular effects with this compound. In an effort to develop more potent inhibitors of this enzyme, a family of isoprenoid triazole bisphosphonates was initially prepared by click chemistry, first as a mixture of olefin isomers due to an allylic azide rearrangement. These compounds were tested by our collaborators to determine the compounds’ activity as GGTase II inhibitors.
Because some triazole bisphosphonates showed good activity as a mixture of isomers, a family of isoprenoid triazole bisphosphonates as single olefin isomers now has been prepared through the use of epoxy azides to avoid the azide rearrangement. The biological activity of these compounds has been studied and some of these triazole bisphosphonates were found to be potent and selective inhibitors of geranylgeranyl diphosphate synthase (GGDPS). While the enzyme GGDPS is upstream of the geranylgeranyltransferases, it is still downstream of the pathway’s primary branch point and provides GGPP for Rab geranylgeranylation. Two other families of triazole bisphosphonate analogues, homo- and bishomoisoprenoid triazole bisphosphonates, also have been prepared and tested by our collaborators to explore the compounds’ activity as GGDPS inhibitors, as well as the structure-activity-relationship.
Previous research has shown digeranyl bisphosphonate (DGBP) and the bisphosphonate ether C-prenyl-O-geranyl bisphosphonate to be inhibitors of GGDPS. Two C-alkyl-C-homoalkyl DGBP analogues have been synthesized in order to study further the binding of these compounds to GGDPS, and dialkylated triazole bisphosphonates have been prepared to explore the effect of a triazole moiety on the analogue’s ability to inhibit GGDPS. The activity uncovered through these studies encourages further research on inhibitors of GGDPS.
| Identifer | oai:union.ndltd.org:uiowa.edu/oai:ir.uiowa.edu:etd-5989 |
| Date | 01 July 2015 |
| Creators | Wills, Veronica Sue |
| Contributors | Wiemer, David F. |
| Publisher | University of Iowa |
| Source Sets | University of Iowa |
| Language | English |
| Detected Language | English |
| Type | dissertation |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | Copyright 2015 Veronica Sue Wills |
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