A dissertation submitted in fulfillment of the requirements for the degree of Master of Science to the Faculty of Science, University of the Witwatersrand, Johannesburg, 2019 / Lung cancer is the second most common form of cancer, accounting for approximately 13% of all new cancer cases.Of these cancers about 85% are non-small cell lung car cinoma (NSCLC). The epidermal growth factor (EGF) receptor is a protein kinase, which is crucial in a cell’s life cycle, from cell growth to cell death. The over expres sion of the EGF receptor is observed in many forms of cancers including NSCLC, breast, ovarian, colorecteral and brain cancers. Although there are current kinase inhibitors on the market, they su↵er from dose limiting toxicity or drug resistance due to mutations in the kinase domain of EGFR. The focus of this body of work is on the development of more ecacious EGFR inhibitors that can overcome drug resistance issues associated with current EGFR inhibitors, as well as being less toxic to the body. This class of inhibitor should be a covalent inhibitor, requiring it to react with the solvent exposed cysteine residue that is positioned on the edge of the ATP binding pocket of EGFR. The carbonyl group of the ketoamide should undergo a 1,2 addition with this cysteine residue to form a covalent, yet reversible bond. We report herein our progress towards the synthesis and biological evaluation of a novel class of quinazoline ketoamides. The key step in this synthesis route was to form a thiol on the quinazoline core. This was to be achieved by the addition of a thiocabamoyl group to the exposed alcohol 33 to form O-4-[(3-bromophenyl)amino] 7-methoxyquinazolin-6-yldimethylcarbamothioate 49, this compound successfully un derwent the Miyazaki-Newman-Kwart rearrangement, in which the oxygen and sulfur are exchanged to form S-4-[(3-bromophenyl)amino]-7-methoxyquinazolin-6-yldimethyl carbamothioate 48 , allowing the sulfur to be on the quinazoline core. the characterisation for this compound included 1H NMR spectroscopy and 13C NMR spec troscopy to confirm it’s structure. The same rearrangement was attempted on the 3 chloro-4-fluoro analogue O-4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin 6-yldimethylcarbamothioate 66, however this rearrangement was not successfully iso lated and characterised. The next step required the carbamoyl group to be removed to expose the thiol. Although this step was attempted on both analogues, the products 4-[(3-bromo)amino]-7-methoxyquinazolin-6-thiol 47 and 4-[(3-chloro-4-fluoro)amino] 7-methoxyquinazolin-6-thiol 67 were not successfully synthesised and isolated. / TL (2020)

Thesis (Ph. D.)--Biomedical Engineering, Georgia Institute of Technology, 2007. / Committee Chair: Nie, Shuming; Committee Member: Lyon, L. Andrew; Committee Member: McIntire, Larry V.; Committee Member: Murthy, Niren; Committee Member: Prausnitz, Mark R.

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Thesis (Ph. D.)--Ohio State University, 2009. / Title from first page of PDF file. Includes bibliographical references (p. 305-320).

Thesis (Ph. D.)--University of Missouri-Columbia, 2003. / Typescript. Vita. Includes bibliographical references (leaves 186-205). Also available on the Internet.

Thesis (Ph. D.)--University of Missouri-Columbia, 2003. / Typescript. Vita. Includes bibliographical references (leaves 186-205). Also available on the Internet.

Unusual DNA secondary structures, especially G-quadruplexes and i-motifs, play important roles in gene transcriptional regulation and have been identified as novel drug targets. In this dissertation, I explored their formation in the human VEGF and RET promoters and their roles in gene transcriptional regulation. VEGF is a key regulator of angiogenesis and is up-regulated in many types of tumors. A poly-guanine/poly-cytosine (polyG/polyC) tract in its proximal promoter (-85 to -50 base pairs relative to the transcription starting site) is essential for both basal and inducible VEGF expression. I demonstrated that the guanine-rich (G-rich) and cytosine-rich (C-rich) strands in the VEGF proximal promoter are able to form G-quadruplex and i-motif structures, respectively. The major G-quadruplex formed by the VEGF G-rich sequence is an intramolecular parallel G-quadruplex containing three G-tetrads and a 1:4:1 arrangement of three double-chain-reversal loops (two single-base loops and one loop with four bases). The complementary C-rich sequence in the same region forms an intramolecular i-motif containing six semiprotonated cytosine-cytosine⁺ base pairs and a 2:3:2 loop configuration (two double-base loops and one loop with three bases). The Gquadruplexes formed by the native VEGF G-rich and its derivative sequences were also confirmed by NMR. In addition, various transcription factors including Sp1, hnRNP K, CNBP and nucleolin, which recognize different DNA structural elements including single-stranded, double-stranded or G-quadruplex/i-motif DNA in the VEGF proximal promoter, have been confirmed by EMSA, siRNA and chromatin immunoprecipitation (ChIP) assay, suggesting that the DNA in the VEGF proximal promoter region is capable of undergoing transitions between those three structures. Based on my studies, I have proposed a model to describe how various transcription factors recognize different DNA structures in the VEGF proximal promoter to regulate transcription. In the proximal promoter of another important oncogene RET, I demonstrated that the guanine-rich strand forms an intramolecular parallel G-quadruplex containing three G-tetrads and a 1:3:1 arrangement of three double-chain-reversal loops. The complementary cytosine-rich strand forms an i-motif structure containing six semiprotonated cytosine-cytosine⁺ base pairs and a 2:3:2 loop configuration. Moreover, G-quadruplex-interactive compounds TMPyP4 and telomestatin were shown to further stabilize the RET G-quadruplex structure.

published_or_final_version / Anatomy / Master / Master of Philosophy