Derivatives of the quinoline moiety have been shown to exert a range of biological activities, including anti-neoplastic activity. The clinical application of quinoline derivatives in the treatment of malignancies has been limited due to non-selectivity. Four novel hydroxyquinoline derivatives were synthesised as potential anticancer agents. Each of these compounds contains the characteristic quinoline nucleus: a heterocyclic moiety containing a nitrogen atom. A hydroxyl group is present on C-8 and an azo bond links the heterocyclic quinoline core to a monocyclic benzene ring with various substituents. The aim of this study was to investigate the potential anticancer properties of the four hydroxyquinolines as pertains to their in vitro cytotoxicity, ability to circumvent multidrug resistance and possible mechanism of action. The acute in vivo toxicity profile of the two most promising compounds was also investigated. The tumour specificity of a compound is an indicator of the selective cytotoxicity of a compound towards cancer cells, while maintaining minimal toxicity towards normal cells. To this end the four hydroxyquinolines were screened on a range of commercially available cancer cell lines and primary (normal) cultures. The cancer cell lines used included human cervical adenocarcinoma (HeLa), human estrogen receptor positive breast cancer (MCF-7) and several resistant cancer cell lines. Chicken embryo fibroblasts and human lymphocytes were included as primary cell cultures. From the results the cancer cell lines most sensitive to each compound were identified: breast (MCF-7) and leukaemia (Jurkat) cells were most sensitive to HQ5, a resistant colon cancer cell line (COLO 320DM) was most susceptible to HQ6 and HQ7, and HQ10 was most effective against cervical cancer (HeLa). Data indicated that HQ5 and HQ10 displayed the highest tumour specificities and these two promising hydroxyquinoline derivatives were selected for further investigation. As quinoline derivatives have been reported to modulate multidrug resistance through the inhibition of the P-glycoprotein (P-gp) efflux pump, the effect of HQ5 and HQ10 on P-gp was evaluated in two experimental models. Firstly the experimental hydroxyquinolines were used in combination with the P-gp substrates doxorubicin, vinblastine and paclitaxel on three P-gp expressing cell lines to ascertain whether a synergistic combination could be observed. Secondly the direct effect of HQ5 and HQ10 on the function of P-gp was determined through the rhodamine 123 retention assay. According to the results obtained from the combination therapy, the combinations of the experimental compounds and the known chemotherapeutic agents tested were at most additive. Data obtained from the rhodamine 123 accumulation assay revealed that HQ5 and HQ10 did not inhibit P-gp in the three P-gp expressing cell lines tested but appeared to enhance P-gp activity. The mechanism of action of the two selected hydroxyquinolines was further investigated through flow cytometric analysis. The effect of HQ5 and HQ10 on the induction of apoptosis or necrosis in MCF-7 cells was determined. Results indicated that the two experimental compounds induced apoptosis in a dose and time dependent manner. After investigating the effect of the hydroxyquinolines on the cell cycle progression of MCF-7 cells, it was observed that HQ5 and HQ10 arrested the cell cycle at the G1 checkpoint. Results suggest that at higher concentrations of HQ5 inhibition resembled a G2 inhibitor. In an acute in vivo cytotoxicity study the tolerability and safety profile of HQ5 and HQ10 were investigated. After daily intraperitoneal administration of either of the two compounds at two concentrations, no obvious histological signs of toxicity were reported. However a dose of 2 mg/kg per day of HQ10 caused a significant reduction in body weight. Haematological analysis revealed that administration of 0.1 mg/kg of HQ5 resulted in a significant decrease in white cell count. No other haematological parameters studied showed any difference between the animals in the control and experimental groups. It was thus concluded that daily dosing of HQ5 and HQ10 was well-tolerated and caused no severe toxicity. Chronic in vivo toxicity profiles were not determined in this study. The in vitro studies suggested that HQ5 and HQ10 displayed promising anticancer properties. However, further investigation revealed several unfavourable characteristics, with regards to the solubility, purity and stability of these experimental hydroxyquinolines. In addition in vivo studies added further doubt on the success of these compounds in a clinical setting and it was concluded that these compounds were unsuitable for further development. Copyright / Dissertation (MSc)--University of Pretoria, 2011. / Pharmacology / unrestricted

5 Abstract The formerly reported hydroxyamide Ph2PfcC(O)NHCH2CH2OH 1 and its respective novel congeneric analogues Ph2PfcC(O)NHCH3−n(CH2OH)n (3: n = 2; 4: n = 3) were used to prepare a series of arene-ruthenium(II) complexes [(η6 -arene)RuCl2(L-κP)] 6-8 (arene = C6H6, p-cymene, C6Me6; L = 1, 3 or 4). These complexes were studied as pre-catalysts in redox isomerization of allylic alcohols to carbonyl compounds. Among the compounds prepared, complex 6b [(η6 -p-cymene)RuCl2(1-κP)] showed best results. The solid state structure of the product of photolytic decomposition of complex [(η6 - C6Me6)RuCl2(2-κP)] (2 = Ph2PfcC(O)N(CH2CH2OH)2), viz, [(µ-Cl)3{Ru(η6 -C6Me6)}2] [FeCl4] 9, was determined by single-crystal X-ray diffraction analysis. The bis-phosphane complexes [MII Cl2(1-κP)2] (M = trans-Pd (10), cis-Pt (11) and trans- Pt (12)) together with chalcogenide derivatives Ph2P(O)fcC(O)NH(CH2)2OH (13) and Ph2P(S)fcC(O)NH(CH2)2OH (14) derived from hydroxyamide 1 were tested in vitro for their cytotoxicity against human ovarian A2780 cancer cell line. Complexes tested showed moderate cytotoxicity. Triol-amide FcC(O)NHC(CH2OH)3 15 (Fc = ferrocenyl) reacted with decavanadate (Bu4N)2[H3V10O28] at elevated temperature and prolonged reaction time yielding the hybrid hexavanadate (Bu4N)2[{FcC(O)NHC(CH2O)3}2V6O13] 16...

The thesis work delineates the rational design and successful syntheses of platinum (II) complexes for achieving light promoted dual action anticancer properties. The research work focuses on the syntheses, elaborate characterization including crystallization and mechanistic aspects of photodegradation processes. Theoretical studies were done to elucidate the properties of the excited states. The interaction of active Pt (II) species with DNA is also explored. The cellular studies include evaluation of the photo-induced cytotoxicities, mode of cell death, nature of reactive oxygen species (ROS), quantification of cellular Pt content and cellular and sub-cellular localization of the complexes. Chapter I provides an overview of the hallmarks of cancer and the current anticancer treatment modalities. It outlines the evolution of platinum based chemotherapeutic drugs, their mechanism of action and associated disadvantages. It also depicts the resurgence of metal complexes as photosensitizers for photoactivated chemotherapy, a selective tripartite strategy which permits light induced tumor destruction. Detailed literature reports of potential transition metal complexes showing light induced generation of ROS and controlled delivery of multiple drugs in tumor microenvironment are presented. The key challenges are the delivery and controlled activation of the clinically approved platinum (II) drugs. These prime objectives of the present investigation are depicted as a concluding segment of this introductory chapter. Chapter II includes the syntheses, characterization, evaluation of visible light induced cytotoxicity and interaction with DNA of novel ferrocenyl terpyridine appended platinum (II) complexes. Detailed mechanistic investigations revealed the important role of ferrocene in light triggered generation of reactive oxygen species. The effect of extensive conjugation on the photophysical properties of the complexes were also rationalized from theoretical calculations. The alteration in DNA binding affinities of the complexes on incorporation of a ferrocene unit in the platinum (II)terpyridines is also reflected. The work is the first report of the remarkable photocytotoxicity of platinum(II) complexes in visible light with nominal dark toxicity. Chapter III deals with novel ferrocenyl terpyridyl platinum(II) complexes having tumor targeting biotinylated acetylides which were synthesized for achieving selective photocytotoxicity only in cancer cells. An interesting observation was the red light promoted release of biotinylated acetylide ligands from platinum centre thereby generating mono-functional Pt(II) species. The possible covalent interactions of these platinum(II) species with DNA were also explored. These biotin complexes exhibit preferential cellular uptake in BT474 breast cancer cells over HBL-100 breast normal cells resulting in targeted photocytotoxicity in visible light. Chapter IV rationalizes design, syntheses and extensive characterization of 2-(phenylazo)pyridine based platinum(II) catecholates containing photosensitizers. The O^O donor ligand was chosen to release the more cytotoxic bi-functional platinum(II) species based on the prior knowledge of the labile Pt-O bonds. Interestingly, we observed glutathione triggered release of the catecholates imparting dual action anticancer properties to the molecules. Detailed mechanistic aspects indicated a possible reduction of the metal coordinated azo bond by cellular glutathione. The excellent photocytotoxicity in HaCaT and MCF-7 cells, cellular ROS generation and apoptosis, cellular Pt content and localization of these complexes are discussed. Chapter V addresses the advantages of navigating the platinum(II) complexes to mitochondrial DNA instead of genomic DNA. BODIPY appended platinum(II) catecholates were synthesized and the BODIPY core was modified to fine-tune the photophysical properties. The visible light induced growth inhibitory effects of the complexes and the mechanism of cell death in light exposed cells are explored. The novelty of this work is the mitochondria targeted remarkable photocytotoxicity as well as cellular imaging properties of the complexes making them ideal candidates for developing platinum based theranostic agents. Chapter VI presents the syntheses, characterization of unprecedented platinum(II) complexes of curcumin for dual action DNA crosslinking and photochemotherapeutic activities. The important feature of these Pt(II) prodrugs is the photorelease of curcumin from Pt(II) centre which results in controlled delivery of two potential anticancer agents. The visible light induced cytotoxicities of the complexes in HaCaT, BT474, T47D, Hep3B and HPL1D cells, their effect on the various cellular events, the interaction of the complexes with DNA and their cellular distribution in light and dark are explored. The appropriate references are provided at the end of each chapter and allocated as superscripts in the main text. The synthesized complexes are denoted by bold-faced numbers. Crystallography data of the complexes that are structurally characterized by single crystal X-ray crystallography are given in CIF format in the enclosed CD (Appendix-I). Due acknowledgements are provided for mentioned literature reports. Any omission is purely unintentional and is deeply regretted. INDEX WORDS: Platinum(II) complexes • Crystal structure • Visible light induced cytotoxicity • Cellular imaging • Photochemotherapeutic agents • DNA crosslink.