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Synthesis and exploration of biologically important, hydrophobic, redox-active molecules: investigation of partial saturation of mycobacterial electron transport lipids

Date

2019

Authors

Koehn, Jordan T., author
Crans, Debbie C., advisor
Reynolds, Melissa M., committee member
Shi, Yian, committee member
Crick, Dean C., committee member

Journal Title

Journal ISSN

Volume Title

Abstract

There are many types of molecules that are biologically important because they either carry out crucial functions or exhibit exploitable biological activity. Some of the most interesting and challenging molecules to work with are those that are redox-active and hydrophobic or water insoluble. Herein, the synthesis and investigation of two classes of hydrophobic redox-active molecules are explored. Chapter one provides background on menaquinone (MK) and vanadium chemistry and primes the reader for the subsequent chapters. Chapter two describes the synthesis and characterization of truncated MK derivatives with varying isoprenyl side chain length and degrees of saturation. Chapter three explores the conformational flexibility of the isoprenyl side chain of MK and shows that a truncated MK analog, MK-2, can adopt folded conformations in hydrophobic environments and within a model membrane system. Chapter four isolates the conformational and chemical effect of saturation of the isoprenyl side chain on MK and shows that saturation minimally affects folded conformations of truncated MK derivatives but remarkably, a 20 mV redox potential difference was observed between unsaturated MK-1 and the saturated analog MK-1(H2). Then in chapter five, hydrophobicity and steric bulk are explored as properties to enhance membrane affinity and anti-cancer properties of Schiff base vanadium(V) catecholate complexes, where the hydrophobic [VO(Hshed)(ditertbutylcatechol)] complex was found to have enhanced hydrolytic stability and potent activity against a bone cancer cell line. Together, the findings of the studies presented herein help to further understand how the conformation and the degree of saturation in the isoprenyl side chain of MK affects the recognition, reactivity, and function of MK within the electron transport system of pathogenic bacteria. These studies are important because they begin to explain and provide a working model behind the chemical rationale as to why partially saturated MK-9 is observed in pathogenic M. tuberculosis. Furthermore, the studies with the hydrophobic vanadium(V) catecholate metallo-complexes underpin a drug design concept exploiting hydrolytic stability imparted by hydrophobicity and steric bulk of a non-innocent ligand.

Description

2019 Summer.
Includes bibliographical references.

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Subject

hydrophobic
NMR spectroscopy
vanadium
menaquinone
conformation
redox potential

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Associated Publications