Date of Award

8-2003

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Chemistry

Major Professor

George Kabalka

Abstract

Boron neutron capture therapy (BNCT) is a binary form of cancer treatment wherein 10°B nuclei, when irradiated with thermal neutrons, produce high linear energy transfer particles. These particles, because of their size and energy, are confined to a radius of approximately 9-10 μm, which is comparable to the dimensions of a single cell. The success of BNCT depends upon the development of non-toxic compounds that have the ability to accumulate in tumor cells selectively in the presence of normal cells and are able to achieve concentration levels in the range of 20-35 μg of 1°B per gram of tumor. Potential BNCT agents reported in literature include boron-containing amino acids, carbohydrates, nucleic acids, nucleosides, antibodies, and other biomolecules. This dissertation describes the strategies and methods employed in the synthesis of boronated analogues of a cylcooxygenase-2 (COX-2) enzyme inhibitor, celecoxib, and boronated unnatural cyclic amino acids as potential BNCT agents. Monosubstituted boron-containing analogues of celecoxib were synthesized. Significant progress was made towards the synthesis of the disubstituted analogues. A radiolabeled analogue of celecoxib for potential use as a Single photon emission computed tomography (SPECT) agent for imaging tumors was also achieved. The syntheses of five-membered and seven-membered boronated unnatural cyclic amino acids were accomplished. A synthetic strategy was proposed for a water soluble, carborane-containing cascade polyol derivative of the five-membered amino acid. The progress made towards the synthesis of this water-soluble derivative is also described. Previous studies reported in literature concerning COX-2 inhibitors and cyclic amino acids provide a good basis for their choice as potential BNCT agents. It is believed that the boronated analogues of celecoxib, and· the cyclic amino acids, offer good promise for potential use in cancer treatment. A study of the biodistribution and evaluation of some of these compounds is currently underway.

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