Synthesis and biological evaluations of novel 1,8-naphthalimide based anti-cancer agents
Citation:
Caroline Margaret Phelan, 'Synthesis and biological evaluations of novel 1,8-naphthalimide based anti-cancer agents', [thesis], Trinity College (Dublin, Ireland). School of Chemistry, 2003, pp 263Abstract:
This thesis, titled "Synthesis and Biological Evaluations of Novel 1,8-Naphthalimide based Anti-Cancer Agents" is divided into six chapters. The first chapter, the introduction includes firstly a brief examination of cancer, what causes it, how it grows and multiple and more significantly how it can be stopped with the use of chemotherapeutic agents. Following this the use of 1,8-naphthalimides as chemotherapeutic agents was explored along with an extensively investigation into their antineoplastic activities and mechanisms. This chapter also examined a series of molecules that show sequence selectivity with respect to DNA. These molecules are known as grove binders and function by mimicking proteins, naturally sequence selective molecules. By incorporating such molecules into the 1,8-naphthalimide unit the synthesis of sequence specific anti-cancer agents was envisaged. As such Chapter Two deals with the design, synthesis and successful purification of 63 novel mono, di and tribased 1,8-naphthalimide conjugates using solution phase peptide chemistry. The syntheses of these derivatives were explored using two approaches, the anchored approached were each amino acid was linked separately to the 1,8-naphthalimide moiety and the stepwise approach, in which the amino acids were linked together prior to the addition to the 1,8-nphthalimide moiety. Based on these results the synthesis of longer chained peptides via solution phase chemistry should be easily achieved in the future. Further investigations as explored in Chapter Three lead to the introduction of abasic sites such as hydrazine and dimethydiamine ethylene units into the terminus of the a-carboxylate 1,8-naphthalimide derivatives from Chapter One. In order to introduce a greater variety of functional groups into these derivatives the synthesis of a versatile and reactive a-aldehyde derivative was achieved. Following this, the introduction of oximse, a, β-unsaturated derivatives, thiazolidine and thiazole units were investigated. In Chapter Four the biological results obtained for some of the derivatives synthesised in the previous chapters were examined. These biological examinations were performed with HL-60 and K562 cancer cell lines and revealed three potentially promising derivatives; 87, a mono-1,8-naphthalimide, 120, a di-1,8-naphthalimide and 154, an abasic modified mono-1,8-naphthalimide derivative. The final discussion chapter. Chapter Five diversified these 1,8-naphthalimide derivatives further by the inclusion of a second 1,8- naphthalimide moiety into their structures to thus generate novel bis-1,8-naphthalimide derivatives. Two different types of bis-1,8-naphthalimide derivatives were synthesised, the "Top-to-Tail", 9 in total and the "Side-on-Side", 3 in total derivatives. Preliminary cytotoxicity examinations were performed on these derivatives. Results obtained showed that the "Top-to-Tail" derivatives were undoubtedly the more promising derivatives with increased cytotoxicity values being recorded in comparison to their mono-analogues. Finally fluorescent examinations with K562 cells showed unquestionable that the 1,8-naphthalimide derivatives are acting as drug molecules. The final chapter, Chapter Six is the experimental section where the procedures for the molecules discussed in Chapters Two, Three and Five are presented.
Author: Phelan, Caroline Margaret
Advisor:
Gunnlaugsson, ThorriQualification name:
Doctor of Philosophy (Ph.D.)Publisher:
Trinity College (Dublin, Ireland). School of ChemistryNote:
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Chemistry, Ph.D., Ph.D. Trinity College DublinMetadata
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