Photodynamic therapy (PDT) is a non-invasive treatment of cancer with an advantage of having localized photo-activation of the drug at the targeted tumor cells leaving the healthy cells unaffected by the photo-toxicity of the PDT agent. Organic molecules and 4d/5d metal complexes have been extensively studied for their DNA cleavage activity and photo-cytotoxicity in UV and/or visible light. The photoactivity of the current PDT drugs is due to reactive singlet oxygen species. To address the hypoxic nature within neoplasia and to get a realistic scenario to build model and potent PDT agents, attempts have been made in this thesis work to design and synthesize new cobalt and copper complexes having a variety of ancillary ligands and planar phenanthroline bases showing efficient visible light-induced anaerobic plasmid DNA cleavage activity. The disulfide and thiol compounds are known to generate thyil radical in anaerobic medium in presence of some electron donating solvent. To exploit this chemistry of the sulfur anion radical as a reactive species damaging DNA under light irradiation, we have prepared copper(II) complexes of bis(2-hydroxybenzylamino-ethyl)disulfide and D-penicillaminedisulfide and characterized. The complexes are moderate binders to calf thymus DNA and exhibit plasmid DNA cleavage activity in red light. Near-IR light-induced double-strand DNA cleavage activity is observed for the complexes having 3,3' -dithiodipropionic acid and phenanthroline bases. These complexes show lethal double strand breaks in SC DNA responsible for the inhibition in DNA repair mechanism in the cells thus becoming potent candidates as transcription inhibitors. The work has been extended to achieve better visible light-induced plasmid DNA cleavage activity and UV light-induced photocytotoxicity using a more bio-compatible metal ion, viz. cobalt(II) with the same ligand system and enhancement in the photocytotoxicity is observed. To investigate the role of the disulfide ancillary ligands, complexes of salicylideneaminothiophenol bound to the copper(II) are prepared and the complexes show significant plasmid DNA cleavage activity in red light. Finally, ternary cobalt(III) phenanthroline base complexes are prepared to study their DNA cleavage activity in red light and photo-cytotoxicity in UV light. The complexes show efficient plasmid DNA cleavage activity in red light, significant cytotoxicity in UV light, low dark cytotoxicity, and protein (BSA, lysozyme) cleavage activity in UV light. The mechanistic aspects of the photo-induced DNA and protein cleavage activity of the complexes have been studied. A dual involvement of the charge transfer and d-d band is observed in the photosensitization process leading to generation of reactive oxygen species. In summary, the thesis work presents cobalt and copper complexes having thiolate and disulfide moieties that are designed and synthesized as new photodynamic therapeutic agents showing anaerobic DNA cleavage activity in red light and photocytotoxicity. The present study opens up new strategies for designing and developing cobalt and copper based photosensitizers for their potential photochemotherapeutic applications under hypoxic reaction conditions. References: Lahiri, D. et al., J Chern. Sci, 2010, 122, 321-333; Inorg. Chern., 2009, 48, 339-349; Dalton Trans. 2010,39,1807-1816; Polyhedron, 2010, 29, 2417-2425.

This thesis work deals with different aspects of the chemistry of La(III) and Gd(III) complexes, their interaction with DNA and proteins, photo-induced cleavage of double-stranded DNA, photocytotoxic effect on cancer cells, cell death mechanism and cellular localization behaviour. Chapter I gives an introduction to the metal-based anticancer agents with special emphasis on clinically used drugs and the growing field of lanthanide therapeutics. An overview of the current strategies of cancer treatment, especially photodynamic therapy (PDT), is presented. Mode of small molecule-DNA interactions and the mechanistic aspects associated with DNA photodamage reactions and PDT effect are discussed with selected examples of compounds that are known to photocleave DNA on exposure to light of different wavelengths. A brief discussion on the various therapeutic applications of the lanthanide compounds is also made. Chapter II presents the synthesis, characterization, DNA binding, BSA binding, photo-induced DNA cleavage activity and photocytotoxicity of La(III) and Gd(III) complexes of phenanthroline bases to explore the UV-A light-induced DNA cleavage activity and photocytotoxicity of the complexes. Chapter III describes the synthesis, characterization, DNA binding, photo-induced DNA cleavage activity and photocytotoxicity of La(III) and Gd(III) complexes of phenanthroline bases with an aim to improve the design of the complexes to achieve better solution stability and DNA binding of the complexes. Chapter IV presents the synthesis, characterization, DNA binding, and UV-A light-induced DNA photocleavage activity and photocytotoxicity of La(III) and Gd(III) complexes of pyridyl phenanthroline bases with an objective to improve the photoactivity of the complexes by introducing an additional pyridyl group. Cell death mechanism and confocal microscopic studies are also carried out to gain more insight into the PDT effect caused by light in the presence of the complex. Chapter V describes the synthesis and characterization of La(III) and Gd(III) complexes of terpyridine bases and acetylacetonate to study the complexes as a new class of photosensitizers to explore their DNA photocleavage activity and photocytotoxicity in HeLa cells. Effect of attaching a glucose moiety to the acetyl acetone (Hacac) ligand has been studied. The cellular uptake behaviour of the La(III) pyrenyl-terpyridine complexes has also been investigated. Finally, Chapter VI presents the synthesis and characterization of curcumin and glycosylated curcumin La(III) and Gd(III) complexes having terpyridine base with an objective to study the photoactivated anticancer activity of the complexes in visible light. This chapter describes the visible light-induced DNA cleavage activity and photocytotoxicity of the complexes by exploiting curcumin and glycosylated curcumin as the photosensitizer ligands. Study on the cellular uptake behavior of curcumin La(III) complexes having pyrenyl terpyridine ligand is also presented. The references have been assembled 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 which are characterized structurally by single crystal X-ray crystallography are provided 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 sincerely regretted.