Document Type

Dissertation

Date of Degree

Fall 2010

Degree Name

PhD (Doctor of Philosophy)

Degree In

Chemistry

First Advisor

David F. Wiemer

Abstract

Phosphonates represent an important class of organophosphorus compounds. Their use as reagents in organic synthesis is prevalent, and there is a plethora of examples of biologically active compounds possessing the phosphonate moiety. To further our exploration of phosphonates as both reagents and biologically active compounds we have developed a one-flask protocol for the direct synthesis of phosphonates from benzylic and allylic alcohols. This transformation is unprecedented and is applicable to a range of substrates. Both electron rich and electron deficient benzylic alcohols react under the conditions developed. Furthermore, good yields are achieved when converting allylic alcohols to the corresponding allylic phosphonates. In at least one case, the one-flask protocol allows for phosphonate formation that was not achievable under the standard conditions.

Bisphosphonates represent a significant subclass of phosphonates. Several nitrogenous bisphosphonates have found use in the clinic as treatments for bone-related disease including osteoporosis, and there is speculation that bisphosphonates that are enzyme-specific inhibitors may be used as cancer therapies. To develop our understanding of isoprenoid metabolism, we have prepared a range of bisphosphonates as potential inhibitors of geranylgeranyl pyrophosphate synthase. After much experimentation, an α-amino analog of a potent inhibitor of GGDPS has been synthesized and biological data is forthcoming. Furthermore, a new class of aromatic bisphosphonates, analogs of digeranyl bisphosphonic acid, has been synthesized and assayed. The bioassay results indicate that this series of compounds retains its specificity for the GGDPS enzyme, and that the dialkyl analogues retain much of their potency in the assays in spite of the increased steric bulk of the aromatic substructure.

We have also begun the design and synthesis of compounds as potential inhibitors of Rab geranylgeranyl transferase (RGGTase). The lead compound, 3-PEHPC, is documented to inhibit RGGTase selectively, albeit at less than desirable concentrations. Using 3-PEHPC as the model compound we have elected to probe the impact of modifications on the hydrophilic "head" portion of the molecule. Using the phosphonophosphinate functionality as a surrogate for the phosphonocarboxylate moiety we have successfully synthesized digeranyl phosphonophosphinate. Initial assay data indicates that this novel phosphonophosphinate does not act upon GGDPS as does the analogous bisphosphonate substructure. The bioassay data to probe this compound's impact on RGGTase is forthcoming.

Given the worldwide impact of tuberculosis infection and the emergence of drug-resistant strains of tuberculosis-causing pathogens, new and potent treatments for tuberculosis are necessary. We have engaged in the synthesis of several compounds as inhibitors of Rv2361c, an enzyme key to cell wall biosynthesis in Mycobacterium tuberculosis, the principle causative agent of tuberculosis in humans. To probe the impact of modifications at the C-9-position of the most potent of our Rv2361c inhibitors, we have made several analogues having phenyl and indole substituents. The in vitro enzyme assay data for the set of compounds has clarified understanding of the essential components of the pharmacophore, and helped to establish the direction for future efforts.

Keywords

isoprenoid, isoprenoid biosynthesis, mevalonate pathway, phosphonate, phosphonate synthesis, phosphonophosphinate

Pages

xvii, 219 pages

Bibliography

Includes bibliographical references (pages 208-219).

Copyright

Copyright 2010 Rocky James Barney

Included in

Chemistry Commons

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