The present thesis deals with different aspects of the chemistry and photo-biology of various ferrocene-conjugated metal complexes, their interaction with double helical DNA, DNA photocleavage and photo-enhanced cytotoxicity in visible light. Phenyl analogues of the active complexes have been synthesized and used for comparison in biological assays. Chapter I provides an introduction to the potential of metal complexes as photochemotherapeutic agents with special reference to organometallic compounds. A brief overview of Photodynamic Therapy (PDT) as a new modality of cancer treatment has been given. Various modes of non-covalent interactions of small molecules with duplex DNA are mentioned. Recent reports on the metal-based photocytotoxic and DNA cleaving agents including photoactivatable organometallic compounds are discussed. The objective of the present investigation is also presented in this chapter. Chapter II presents the synthesis, characterization, structure, DNA binding, DNA photocleavage, photocytotoxicity, mechanism of cell death and cellular localization of ferrocene-conjugated L-methionine reduced Schiff base Cu(II) complexes of phenanthroline bases. To explore the role of the ferrocenyl moiety the phenyl analogues of the ferrocenyl complexes are synthesized and used as controls for comparison purpose. Chapter III deals with the photo-induced DNA cleavage and photo-enhanced cytotoxicity of ferrocene-appended L-tryptophan Cu(II) complexes of heterocyclic bases. The synthesis, characterization, structural comparisons, DNA binding, DNA photocleavage, photocytotoxic activity and cell death mechanism in visible light are discussed in detail. Chapter IV describes the synthesis, characterization and structure of ferrocenylmethyl-L-tyrosine Cu(II) complexes of phenanthroline bases. The complexes are evaluated for DNA binding, DNA photocleavage and photocytotoxic activity in visible light. The cellular localization of the complexes and the mechanism of cell death induced by the complexes are also discussed. Chapter V presents the photocytotoxic effect of ferrocene-conjugated L-amino acid reduced Schiff base Cu(II) complexes of anthracenyl/pyrenyl imidazophenanthroline. The ability of the complexes to bind to double helical DNA and cleave it under photo-illumination conditions is described. Evaluation of the complexes as photochemotherapeutic agents and comparison with currently clinically available drug Photofrin are presented. The mechanism of cancer cell death and cellular localization of the complexes are studied by fluorescence microscopy. Chapter VI describes the synthesis, characterization and photochemotherapeutic efficacy of Cu(II) complexes having ferrocene-appended L-amino acid reduced Schiff base ligands and the naturally occurring polyphenol curcumin. Stabilization of curcumin by complexation to metal for improved photodynamic effect in cancer cells is described with comparison to the parent dye and clinically used drug Photofrin. The mechanism of cell death induced by the copper complexes and their localization in cancer cells are also presented. Finally, the summary of the dissertation and conclusions drawn from the present investigations are presented. The references in the text have been indicated as superscript numbers and compiled at the end of each chapter. The complexes presented in this thesis are represented by bold-faced numbers. Crystallographic data of the structurally characterized complexes 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.

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.

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.