The current thesis addresses the various facets of the chemistry of photocytotoxic iron complexes including their syntheses, characterization, evaluation of the anti-proliferative activities in various cancer cell lines upon photo-exposure, mechanism of cell death, the cellular uptake, localization inside cells, the interaction with double stranded DNA and their ability to induce DNA photocleavage. Chapter I presents a general introduction to cancer and the anticancer agents. It covers various procedures available for cancer treatment and different aspects of chemotherapy are discussed in details. The mechanism of action of several chemotherapeutic agents, the DNA cleavage pathways and the anticancer activity of bleomycins are delineated. Photo-chemotherapy or photodynamic therapy which has emerged as an alternative treatment modality is described. It also contains a brief description of ideal photosensitizers and the ones that are currently approved. The potential of transition metal complexes as photo-chemotherapeutic agents is discussed based on the recent literature reports on the prospective photocytotoxic metal complexes, the photo-release of cytotoxic molecules from metal complexes, the DNA cleavage activities and their cytotoxicities. The biochemistry of iron and its medical utility which prompted the development of iron based cytotoxins has been presented. The objective of the present investigation is also defined in this chapter. Chapter II describes the syntheses, characterization, evaluation of visible light induced cytotoxicity and interaction with DNA of a series of iron(II) bis-terpyridine complexes. Some interesting redox behaviour observed for two of the complexes has been described in details and rationalized from theoretical calculations. The DNA binding affinities of the complexes and their ability to induce DNA photocleavage in green light are discussed. The importance of this work lies in the remarkable photocytotoxic behaviour of the iron(II) complexes with visible light which was not reported earlier. Chapter III addresses the syntheses of a series of iron(III) catecholate complexes which upon irradiation with red light can initiate photoreactions to generate cytotoxic species and induce death in HeLa, HaCaT, MCF-7 and A549 cells. The mechanisms of cell death, effect of the complexes on the cell cycle under various conditions, the uptake inside cells and the cellular localization of the complexes are studied. The DNA binding affinities of the five complexes and their ability to induce DNA photocleavage in red light are also presented here. These are the first iron based complexes to show red light induced photocytotoxicity. Chapter IV addresses the drawbacks associated with the aforementioned iron(III) catecholates and their modification with a mitochondria targeting triphenylphosphonium unit. The synthesis, characterization, photocytotoxicities in HeLa, HaCaT, MCF-7 and A549, cell death mechanisms and cellular uptake and localization of four iron(III) complexes are discussed. Chapter V describes the syntheses, characterization and the biological activities of carbohydrate appended iron(III) complexes and their non-glucose analogues. The selective and faster internalization of the glyco-conjugated complexes in HeLa cells has been studied using various spectroscopic and microscopic techniques. The red light induced cytotoxicities of the complexes, their effect on the progression of the cell cycle with and without irradiation and the mechanisms of cell death are explored. DNA binding abilities and photocleavage of DNA are also discussed. Chapter VI presents the syntheses, characterization of a series of iron(III) complexes of a pyridoxal derivative and their salicyldehyde analogues for exploring their differential photocytotoxicity and cellular uptake in cancer cells compared to normal cells. The visible light induced cytotoxicities of the complexes in HeLa, HaCaT, MCF-7 A549 cells and HPL1D cells, their effect on the progression of the cell cycle in dark and light, the mechanisms of cell death and the localization of the complexes inside the cells are explored. The references have been compiled at the end of each chapter and given as superscripts in the text. The complexes presented in this thesis are indicated 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 have been made wherever the work described is based on the findings of other investigators. Any unintentional omission that might have happened due to oversight is regretted. INDEX WORDS: Iron complexes • Crystal structure • Red light induced cytotoxicity • Cellular imaging • DNA binding • DNA photocleavage.

The present thesis deals with different aspects of the chemistry of oxovanadium(IV) complexes, their interaction with double stranded DNA, photo-induced DNA cleavage, photo-enhanced cytotoxicity in visible light and red light and localisation and cellular uptake to understand the mechanism of cell death. Chapter I presents a general introduction on potential of transition metal complexes as photochemotherapeutic agents. A brief introduction about Photodynamic Therapy (PDT) as a new alternative to chemotherapy for treating cancer has been made. Various modes of interaction of small molecules with duplex DNA are described. Recent reports on metal-based photocytotoxicity, photo-induced DNA cleavage activity and cellular localization are presented in detail. Objective of the present investigation is also dealt in this Chapter. Chapter II of the thesis deals with the synthesis, characterization, DNA binding and photo-induced DNA cleavage activity of ternary oxovanadium(IV) complexes of ONO-donor 2-(2-hydroxybenzylideneamino)phenol (salamp) and phenanthroline bases to explore the photo-induced DNA cleavage activity in UV-A light of 365 nm and photocytotoxicity in visible light. Chapter III deals with the photo-induced DNA cleavage and photocytotoxicity of ternary oxovanadium(IV) complexes containing ONN-donor N-2-pyridylmethylidine-2-hydroxyphenylamine (Hpyamp) Schiff bases and phenanthroline bases. The objective of this work is to investigate the photo-induced DNA cleavage activity in near-IR light. Photocytotoxicity and cell cycle arrest have been studied in HeLa cancer cells. Chapter IV deals serendipitous discovery of planar triazinuim cationic species by vanadyl-assisted novel ring cyclization reaction. The compounds are synthesised, characterized and their DNA binding and anaerobic photoinduced DNA cleavage activity are presented. The importance of the thiazole moiety in the triazinuim species in cellular uptake has been investigated. Photocytotoxicity, localization and cell death mechanism have been studied in HeLa and MCF-7 cells. Chapter V describes the synthesis, characterization, DNA binding, photo-induced DNA cleavage activity and photocytotoxicity of oxovanadium(IV) complexes containing 2-(1H-benzimidazol-2-yl)-N-(pyridin-2-ylmethylene)ethaneamine (Hpy-aebmz) and curcumin as photosensitizer. The effect of conjugating naphthalimide on Hpy-aebmz on photoinduced DNA cleavage and photocytotoxicity has been studied. Cellular uptake, localization and mechanism of cell death induced by complexes have been investigated. Chapter VI presents ternary oxovanadium(IV) complexes having, 2-((1H-benzimidazol-2-yl)methylimino-methyl)phenol (Hsal-ambmz) and phenanthroline bases. The complexes were synthesized, characterized and their DNA binding property studied. Photo-induced DNA cleavage activity and photocytotoxicity in red light has been discussed. Anthracene has been conjugated to a tridentate ligand to investigate cellular uptake, localization and cell death mechanism. Mitochondria targeting property of the complexes having dipeptide has been studied and compared with clinically used drug Photofrin®. The references have been compiled at the end of each chapter and indicated as superscript numbers in the text. The complexes presented in this thesis are represented by bold-faced numbers. Crystallographic data of the complexes, characterized structurally by single crystal X-ray crystallography, are given in CIF format in the enclosed CD (Appendix-I). Due acknowledgements have been made wherever the work described is based on the findings of other investigators. Any unintentional omission that might have happened due to oversight or mistake is regretted.