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The concept of bioreductive prodrug chemotherapy is introduced in chapter 1. Tumour cell hypoxia is a significant factor in limiting tumour growth control with conventional radiotherapy and some chemotherapeutic agents. Following therapy these cells can repopulate and cause a relapse of the cancer. On the other hand, hypoxia is unique to tumours, and is therefore potentially exploitable. Bioreductive prodrugs are compounds in which a oxygen inhibited redox-based bioactivation step triggers a reaction leading to a lethal intermediate. The concept of bioreductive DNA alkylators and DNA topoisomerase 11 inhibitors is discussed. The synthesis of model thiazolylindole compounds based on the natural product BE \0988 are discussed in chapter 2. Two strategies were employed for the construction of the thiazolylindoles: the Hantzsch reaction; and nucleophilic substitution on 2-bromothiazole by an indolyl anion. The synthesis of thiazolylindolequinone compounds are discussed in chapter 3. The quinone C(5) position of the thiazolylindolequinone analogues was elaborated to provide a series of cyclic and acyclic C(5)-amino derivatives. Synthetic strategies towards the synthesis of indole-2-carboxylates are discussed in chapter 4. The Moody-Rees and Cadogan-Sundberg reactions were employed to provide a synthesis of the useful highly substituted indole [154]. The Brederek imidazole reaction (i.e., the reaction of a amidine and a-halo ketone) is discussed in chapter 5. Application of the Brederek reaction was employed towards the construction of the bisindole imidazole natural compounds, the nortopsentins. The biological properties of the compounds of the compounds synthesised are discussed in chapter 6. The compounds were tested for DNA topoisomerase 11 inhibitory activity and cytotoxicity under a hypoxic environment.

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Class of 2012 Abstract / Specific Aims: This study was aimed to evaluate inpatient clinical treatment characteristics associated with the use of intracranial implantation of chemotherapeutic wafers for malignant brain neoplasms within United States, and assess inpatient mortality and total charges regarding treatment with wafer versus without. Methods: A retrospective cohort investigation was conducted utilizing inpatient discharge records from the Agency for Healthcare Research and Quality (AHRQ) Healthcare Cost and Utilization Project (HCUP) Nationwide Inpatient Sample from 2005 to 2009. From this nationally- representative sample, 9,455 adults aged 18 years or older were identified with malignant neoplasms of the brain treated with implantable chemotherapeutic wafers. Outcomes of inpatient mortality and charges were assessed via multivariate regression analysis, controlling for patient characteristics, hospital structure, comorbidities, and clinical complications. Main Results: The average age of patients with brain neoplasms was 56.6 (±16.5) years, and of those patients, 42.9% were female. The odds ratio for inpatient mortality of patients treated with implantable chemotherapeutic wafers was OR=0.380 (P<0.001), and patients that received wafer treatment had increased charges exp(b)=2.147 (P<0.001). Conclusions: Multiple factors were associated with inpatient mortality and charges among the 247,829 patients that were diagnosed with malignant brain neoplasms from 2005-2009. With regards to these patients, implantable chemotherapeutic wafers were associated with increased inpatient survival and increased charges.

This study evaluated comparative genomic hybridisation (CGH) as a tool to detect candidate regions of the genome associated with chemoresistance. Using a variation on conventional CGH, DNA from three cell lines that were resistant to thymidylate synthase (TS) inhibitors (tomudex [TDX] or 5-fluorouracil [5-FU]) and their sensitive parent cells were evaluated. In MCF-7 and H630, cells that were resistant to TDX, a specific TS inhibitor with no other known cytotoxic potential, only a single region of change (18p gain) was apparent. The third cell line H630R10, which was resistant to 5-FU, had changes in several genomic regions following the acquisition of resistance, including 18p. Gain in the chromosomal region containing the TS gene (18pll.32) was detected by CGH in all three resistant cell lines. However, additional novel regions of interest were identified in the cells that were resistant to 5-FU, a cytotoxic agent known to have several other modes of cytotoxicity besides TS inhibition. These results suggested that CGH is of potential use in the detection of regions of the genome involved in chemoresistance. Having shown the potential of CGH as a tool for assessing chemoresistance at the genomic level, steps toward clinical application of this technique were evaluated. A prerequisite for study in archival pathology samples was successful DNA extraction and universal amplification of tumour DNA from paraffin-embedded tumour sections for CGH analysis. Degenerate oligonucleotide primed - polymerase chain reaction (DOP-PCR) was performed on minute quantities (50ngs) of fresh cell line DNA (H630R10) and tumour DNA (osteosarcoma), as well as paraffin-embedded DNA from the same case. The results of these DOP-PCR CGH reactions were compared with conventional CGH using l|0.g quantities of fresh DNA from both H630R10 cell line and osteosarcoma. The CGH profiles of the conventional CGH and DOP-PCR CGH did not show a high level of concordance, only 55% of the gains and 83.3% of losses detected by conventional CGH were detected by DOP-PCR CGH The use of universal amplification by DOP-PCR in paraffin-embedded sections was not taken forward into clinical evaluation. A study of colorectal cancer (CRC) was initiated which involved the microdissection of 29 Dukes' C CRC tumours from fresh frozen material for CGH analysis. This conventional CGH analysis of CRC tumours involved assessing each tumour twice by reversal of fluorochromes. Only genomic regions that were detected as changed in both forward and reverse profiles were accepted. This approach detected several regions of genome as changed across the 29 tumours. In all, 108 gains (a mean number of 3.7 aberrations per tumour, range 1-12) and 85 losses (a mean number of 2.9 aberrations per tumour, range 0-11) were detected in the 29 tumours. CGH analyses identified certain chromosomal regions as more likely to be changed than others. The most frequent aberrations detected across the 29 tumours was a loss of chromosomal arm 18q, seen in 31% of the tumours assessed. Gain was also common at some sites throughout the genome, for example, gain of chromosomal arms, 13q and 20q was seen in 27.6% of cases. Mann-Whitney U tests investigating the association between specific chromosomal aberrations such as gain of 20q or loss of 18q and known markers of CRC tumourigenesis (p53, p27, p21, Rb, cyclin Dl, PCNA, P-catenin, e-cadherin, c-erbB-2, bcl2, EGFR and c-erbB-2) assessed by immunohistochemistry (IHC) in 29 tumours found no association. Testing of the total number of genomic aberrations detected (loss + gain = genetic grade) rather than the frequency of aberration at specific chromosomal loci also found no association with the CRC tumour markers. Finally, the association between the chromosomal aberrations detected by CGH was investigated in relation to patient survival. This thesis has demonstrated the value of a global approach to the study of chemoresistance and tumourigenesis through the application of powerful technology such as CGH.

Solid tumors are commonly subject to hypoxia. Hypoxic cancer cells have undesirable properties such as a high tendency to metastasize and resistance to chemotherapy and radiotherapy. Hypoxia-inducible factors (HIFs) respond to the changes in oxygen levels, orchestrating the transcription of many proteins that are vital for the survival of hypoxic cancer cells. With their parent drug SN-38 as an inhibitor of both topoisomerase 1 and HIF-1, hypoxia-activated SN-38s may have a dual inhibitory effect on hypoxic tumor cells due to hypoxia-targeting and HIF-1 inhibition. To develop hypoxia-activated prodrugs of SN-38; 2-, 3-, and 4-nitrobenzyl SN-38s have been synthesized with good yields (78%, 67% and 68%, respectively). Topoisomerase 1 inhibitory assay on 2- and 4-nitrobenzyl SN-38s and cell viability assay on 2-, 3- and 4-nitrobenzyl SN-38s have been performed. All three derivatives showed less toxicity on K562 cells, which meets the principle of prodrug design. Cyclic voltammetry results suggest that the reduction potentials of these three derivatives may be not high enough for these compounds to be activated. The manner of reduction of three nitrobenzyl SN-38s is quasi-reversible under the testing condition, not against the proposed mechanism of activation. Two new derivatives of SN-38 have been designed to elevate reduction potential and further reduce toxicity. They are to be synthesized and tested for future work. / October 2016