Graduation Semester and Year

2010

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Chemistry

Department

Chemistry and Biochemistry

First Advisor

Kevin A Schug

Abstract

Chirality of molecules is a major topic in the design, discovery and development of new drugs. Currently, analytical chemistry research divisions are challenged to find new methods to screen enantiospecific molecular recognition properties of potential chiral drug candidates with targeted biological molecules in a time-sensitive environment. Recently, mass spectrometry (MS) has received significant attention for its use in studying molecular recognition systems. Electrospray ionization mass spectrometry (ESI-MS) has received the most attention for the investigation of stereochemical association phenomena, due to its capacity to transfer solution phase chiral interactions into the gas phase for analysis in single-stage mass spectra. ESI-MS based chiral molecular recognition studies on cinchona alkaloid-carbamate model systems had been initiated by our group in order to test the viability of mass spectrometric techniques to trace solution phase enantiomeric interactions in their respective mass spectra. Importantly, these studies have returned results in good correlation with those found previously by in liquid phase separation techniques. It was realized that mass spectrometry is an invaluable tool to pre-screen such recognition systems. In order to further corroborate this argument, our group had been in search of novel, less well understood chiral molecular recognition systems to be analyzed using ESI-MS, where other frequently used analytical techniques have failed to clarify their underlying mechanistic details. Antimony(III) tartrate also known as "tartar emetic", the bis-potassium salt of dianionic antimony(III)-L-tartarate, has a long history which traces back to medieval times and is filled with intrigue and peril. It has also been used as a therapeutic indication for diseases like typhoid, bronchitis, pneumonia and schistosomiasis. To date, mechanistic details of its actions, especially its biomolecular recognition properties, are not very well understood. While trying to indicate ESI-MS as an invaluable tool to study molecular recognition phenomena, we also hypothesized that ESI-MS based noncovalent binding studies of antimony(III)-D/L-tartrate complexes may provide useful information about its molecular recognition capacity. Since tartar emetic has also shown antibacterial properties, ESI-MS studies were carried out to visualize tartar emetic's selective binding towards biologically relevant amino acid enantiomers. Consequently, a previously unprecedented proton-assisted enantioselective character of "tartar emetic" towards neutral D-amino acid enantiomers was revealed. A serendipitous observation resulted from these studies was its ability to capture unusual solvent reaction products generated during negative ionization mode ESI, which in fact provided a new understanding for the overall electrospray ionization mechanism. Additionally, theoretical studies, accompanied by multinuclear magnetic resonance experiments revealed that tartar emetic can assume a previously unknown structural isomer which is proven to co-exist with its crystallographically-determined structure. These findings and many ongoing research efforts suggest that this phenomenon may be responsible for many of tartar emetic's inexplicable observations. This dissertation discusses our ongoing efforts to indicate ESI-MS for studying interesting molecular recognition phenomena of antimony(III)-tartrate binding to amino acids as well as providing useful molecular information of an inexpensive organo-metallic complex which could potentially be structurally altered to be used in many applications.

Disciplines

Chemistry | Physical Sciences and Mathematics

Comments

Degree granted by The University of Texas at Arlington

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