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Title: New anticancer drugs : targeting tubulin and signal transduction pathways
Author: Pireddu, Roberta
ISNI:       0000 0004 2750 230X
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2007
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The main aim of the study described in this thesis is the development of new anticancer agents. The first chapter is a general introduction to cancer, and the development of chemotherapy anticancer agents during the course of the years. The following four chapters briefly introduce the biological targets in the authors study. Chapter Two describes a general introduction to tubulin and microtubules as anticancer targets. A discussion of those compounds most relevant to this thesis is provided. Chapter Three describes Signal Transducers and Activator of Transcription 3 (STAT3) proteins, their role in cancer and the advances in the search of anticancer agent inhibitors of the STAT3 signalling pathway. Chapter Four focuses on the src homology 2 (SH2) domain containing tyrosine phosphatases SHP-2, a protein-tyrosine phosphatase implicated in pathogenesis of cancer and other human diseases. A brief discussion of the SHP-2 inhibitors is provided. Chapter Five describes the role of proteins Aurora kinases in cancer, promising targets for anticancer drug development, and the advances in the search of their inhibitors targeting the kinase activity at the ATP binding site. The following chapters (6-11) describe the authors own findings. Chapter six focuses on the design and synthesis and biological evaluation of novel styrylchromones, styrylquinazolones, and quinazolones as inhibitors of tubulin polymerization. Styrylchromones Styrylquinazolones Quinazolones Two series of isomeric styrylchromones were initially synthesized in order to establish the methoxy substitution pattern on the A ring favorable for optimal activity. The structure activity relationship on the B ring is also reported. Next, our strategy focused on identifying a chromone core replacement with improved potency. We directed our chemical efforts toward the synthesis of novel styrylquinazoline analogs. The quinazoline core would also provide easy access to the preparation of diverse sets of N-substituted derivatives (methyl and ethyl derivatives). Finally, a novel series of quinazolines were synthesized as conformationally-restricted analogs of chalcones. SAR was conducted around the quinazoline spacer between the aryl rings and systematically investigating the substituent effect in the B ring. Among the synthesized compounds we selected those analogues showing significant cytotoxicity (generally defined as IC50 value < 1.5 uM), and evaluated for activity in vitro tubulin polymerization inhibition assay. Chapter Seven focused on the identification of novel inhibitors of STAT3 dimerization. Computational analyses led us to the development of a T-shape model of molecules that can >2 occupy the pTyr-binding pocket of STAT3 SH2 domain. The rN"s' conjugate addition of nitromethane to a series of amides and the l/ J reduction of the nitro group were combined to give an easy route to onh j. the target T-shape molecules in a combinatorial fashion. The ksJJ methodology was also extended to amides activated by a nitro group. co2r observed a dramatic change in the course of the reaction, which Scaffold of T-shape molecules afforded a mixture of unexpected and unknown products, that each possessed an additional methylene group. A brief study into the mechanism was also conducted. Chapter Eight, Nine and Ten focuss on the development of Aurora kinases and SHP-2 inhibitors. Oxindole derivatives HL10581 and NSC117199 emerged as lead compounds from a high throughput screen for Aurora-A and SHP-2, respectively. f f Chapter Eight describes the synthesis of n-nfh Cl nnhN 2 several derivatives of HL10581 and H03SYYLo H03SYr>o NSC117199, directed to exploration of h h SAR around the oxindole moiety to HLiow.AAKfci-SMM nscii7,99,shp-2,,c5047 mM determine the structural features that are responsible for the activity. Chapters nine and ten report the biological evaluation of oxindole derivatives as inhibitors SHP-2 and Aurora kinases, respectively.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available