A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the degree of Masters of Science in Medicine (Pharmacology) Johannesburg,2015 / Breast cancer, is the most frequently diagnosed cancer in women and is associated with high mortality rates in South Africa. There is a high prevalence of metastatic breast cancer and triple negative tumours, which are associated with poor prognosis. In this study, the response of two breast cancer cell lines, MCF-7 and MDA-MB-231, were evaluated when treated with novel imidazo[1 ,2-a]pyridine amines. The compounds were synthesized by the School of Chemistry of the University of the Witwatersrand using the Groebke-Blackburn-Bienayme multicomponent reaction and tested for purity by elemental analysis. The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) assay was used to determine the cytotoxic effects of test compounds on breast cancer cells and the toxic effect of compounds on non-tumorigenic unstimulated peripheral leukocytes. IC50 values of test compounds were calculated from sigmoidal dose response curves. The morphology of cells exposed to test compounds was assessed by fluorescent microscopy using Hoechst 33342, acridine orange and ethidium bromide. The ability of test compounds to induce apoptosis was measured by a colorimetric caspase-3 assay and a fluorometric Annexin-V-FITC assay. Monodansylcadaverine was used to determine if autophagic vacuoles were formed after exposure to test compounds. Three imidazo[1,2-a]pyridine amines, JD88, JD253 and JD256, were more cytotoxic to MCF-7 than to MDA-MB-231 cells. MCF-7 cells showed morphological features associated with apoptosis, and proteolysis by caspase-3/7 was observed after MCF-7 cells were exposed to JD88 for two hours. Vacuole formation induced by these compounds was not autophagic in since they did not co-localize with MDC florescent clusters. This together with the exposure of phosphatidylserine to the outer surface of MCF-7 cells suggests that apoptosis is induced in these cells. There was no evidence of cytochrome c translocation to the cytoplasm, which indicates that the intrinsic pathway of apoptosis is not activated. MDA-MB-231 cells treated with JD88, JD253 and JD256 were large with multiple nuclei and decondensed chromatin, morphological features associated with mitotic catastrophe. The cells also showed morphological features associated with necrosis and apoptosis, which include loss of cell membrane integrity and cell membrane blebbing respectively. MDA-MB-231 cells exposed to JD88 showed marked exposure of phosphatidylserine and this was observed to a minor extent in cells exposed to JD253 and JD256. Proteolysis by caspase-3/7 was activated in MDA-MB-231 cells exposed to JD88 as early as 2 hours after exposure. In conclusion three compounds; JD88, JD253 and JD256 were able to induce apoptosis in MCF-7 cells. These compounds were selectively toxic against MCF-7 cells compared to MDA-MB-231 cells and JD256 in particular was less toxic to leukocytes, which may translate to fewer serious adverse effects. Addition of a copper dioxygen complex to these compounds increases activity against both breast cancer cells. JD88 in particular has shown effective induction of apoptosis and this merits further investigation into its potential as a lead compound in breast cancer therapy. / AC2016