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)
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/29538 |
| Date | January 2019 |
| Creators | Carnie, Robyn Elizabeth |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | Online resource (102 leaves), application/pdf |
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