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The design and synthesis of novel EGFR inhibitorsCarnie, Robyn Elizabeth January 2019 (has links)
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)
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Cancer nanotechnology engineering multifunctional nanostructures for targeting tumor cells and vasculatures /Kim, Gloria J. January 2007 (has links)
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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Interaction of naturally occurring and synthetic MSH peptides with peripheral and CNS melanocortin receptorsSahm, Ulrike Gisela January 1994 (has links)
No description available.
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细胞特异性核酸适配体介导的靶向葯物传输系统及其在疾病诊断与治疗中的应用兰林林, 01 January 2013 (has links)
No description available.
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Drug loading of biodegradable nanoparticles for site specific drug deliveryRedhead, Helen Margaret January 1997 (has links)
No description available.
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Biomaterials modeling of localized hyperthermia and drug delivery for breast cancerMulamba, Peter, January 2009 (has links)
Thesis (Ph. D.)--Ohio State University, 2009. / Title from first page of PDF file. Includes bibliographical references (p. 305-320).
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Synthesis of water soluble organophosphines and phospine-peptide conjugates : investigations on the biomedical utility of their transition metal complexes /Pillarsetty, Nagavarakishore, January 2003 (has links)
Thesis (Ph. D.)--University of Missouri-Columbia, 2003. / Typescript. Vita. Includes bibliographical references (leaves 186-205). Also available on the Internet.
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Synthesis of water soluble organophosphines and phospine-peptide conjugates investigations on the biomedical utility of their transition metal complexes /Pillarsetty, Nagavarakishore, January 2003 (has links)
Thesis (Ph. D.)--University of Missouri-Columbia, 2003. / Typescript. Vita. Includes bibliographical references (leaves 186-205). Also available on the Internet.
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DNA Secondary Structures in the Promoters of Human VEGF and RET Genes and Their Roles in Gene Transcriptional RegulationGuo, Kexiao January 2008 (has links)
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.
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The potential applications of AMPK activator resveratrol and PAK1 inhibitor IPA-3 in cancer therapyWong, Yuk-na, 王玉娜 January 2010 (has links)
published_or_final_version / Anatomy / Master / Master of Philosophy
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