Phosphorus is an essential element for life, observed in all biological systems usually as inorganic phosphate and various organic phosphate esters. Phosphonates are a metabolically stable analogues of natural phosphorus containing compounds and have been used in a variety of industrial and medicinal applications. Bisphosphonates have been found to be especially good inhibitors of enzymes in the isoprenoid biosynthetic pathway. A screen of bisphosphonates against the enzyme squalene synthase (SQS) resulted in the identification of a lead target. The lead compound was resynthesized via a new method along with two other analogues. It was determined that although the lead bisphosphonate had potent and selective activity against SQS and resulted in the reduction of cholesterol, use of this drug in combination with either a statin (lovastatin) or a nitrogenous bisphosphonate (zolendronate) had an even greater impact. Furthermore co-treatment of cells with the lead compound and either lovastatin or zoledronate significantly prevented a reduction of cell viability caused by lovastatin or zoledronate alone. The combination of an SQS inhibitor with either an HMGCR or FDPS inhibitor may be beneficial for reducing cholesterol synthesis while preventing non-sterol isoprenoid depletion.
A series of stilbenoid bisphosphonates has been developed to afford potential inhibitors of enzymes in the isoprenoid biosynthetic pathway, a potential target for cancer therapies. Although the new compounds had limited activity against major enzymes in the isoprenoid biosynthetic pathway, it was determined that one of the targets had modest activity in a screen of inhibitors for decaprenyl diphosphate synthase, an enzyme vital to synthesis and maintenance of cell walls in mycobacteria. A second generation synthesis of stilbenoid bisphosphonates that contain a para-substituted electron withdrawing group was initiated, resulting in the identification of a more potent inhibitor of decaprenyl diphosphate synthase. The use of novel bisphosphonate inhibitors could have an impact on treatment of bacterial diseases such as tuberculosis. The development of novel phosphorus containing compounds could provide new inspiration for industrial and medicinal products. The รก-trisphosphonic acid esters provide a unique spatial arrangement of three phosphonate groups, and may represent an attractive motif for inhibitors of enzymes that utilize di- or triphosphate substrates. A general route to alkyl derivatives of the parent system has been developed through phosphinylation and subsequent oxidation of tetraethyl alkylbisphosphonates, and the reactivity of these new compounds has been studied in representative reactions that afford additional examples of this functionality. During the course of synthesis of the parent trisphosphonate system, an unusual oxidized bisphosphonate phosphate was discovered, and the methods to synthesize this species have been investigated.
| Identifer | oai:union.ndltd.org:uiowa.edu/oai:ir.uiowa.edu:etd-2671 |
| Date | 01 December 2011 |
| Creators | Smits, Jacqueline Patricia |
| 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 2011 Jacqueline P. Smits |
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