Chapter 1: Facile entry into triazole fused tetrahydropyrazinones from amines and amino acids. In this chapter, A practical and high yielding regioselective synthesis of several new, enantiopure 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazin-6-ones is described starting from primary amines in a three step reaction sequence (alkylation, acylation, one-pot displacement with azide followed by cycloaddition) employing constrained intramolecular ‘click’ reaction as the key step. The method obviates chromatographic purification of products. This methodology was also extended to the synthesis of diverse triazole fused tetrahydropyrazinones derived from amino acids. The scope of this methodology was extended by varying the alkyl as well as acyl components which furnished other triazole fused novel heterocycles. Chapter 2: Facile entry into triazole fused heterocycles via sulfamidate derived azido-alkynes. Direct synthesis of condensed triazoles from diverse sulfamidates by ring opening of sulfamidates with sodium azide followed by one-pot propargylation and cycloaddtion furnished title compounds. The methodogy in general has been demonstrated on diverse sulfamidates derived from amino acids, amino acid derivatives to obtain a variety of triazole fused scaffolds. In one example, a condensed triazole containing amino acid has been synthesized by ring opening of a sulfamidate derivative with propargyl amine. This methodology has also been extended to the synthesis of condensed triazoles derived from D-glucose. Chapter 3: ‘Click Chemistry’ Inspired Synthesis of Novel Ferrocene-Amino acid, Peptide Conjugates. In this chapter synthesis of a wide range of ferrocene-amino acid and peptide conjugates in excellent yield is presented. Conjugation is established via copper catalyzed Huisgen 1,3-dipolar cycloaddition. Two complementary strategies were employed for conjugation, one involving cycloaddition of amino acid derived azides with ethynyl ferrocene and the other involving cycloaddition between amino acid derived alkynes with ferrocene derived azides. Labeling of amino acids at multiple sites with ferrocene is discussed. A new route to 1, 1’ unsymmetrically substituted ferrocene conjugates is reported. A novel ferrocenophane is accessed via bimolecular condensation of amino acid derived bis alkyne with azide. The electrochemical behavior of a few selected ferrocene conjugates has been studied by cyclic voltammetry. Chapter 4: Click Chemistry inspired Synthesis of Ferrocene Amino acids and other derivatives. This work reports the synthesis of a wide range of ferrocenyl-amino acids and other derivatives in excellent yield. Diverse amino acid containing azides were synthesized and ligated to ferrocene employing click reaction to access ferrocenyl amino acids. Chiral alcohols, esters, diols amines containing azido group were tagged to ferrocene via click reaction to generateferrocene derived chiral derivatives. A novel strategy for direct incorporation of ferrocene into a peptide and a new route to 1, 1’ disubstituted ferrocene amino acid derivative are reported. Synthesis of mono and disubstituted ferrocene derivatives employing ferrocene derived azides is also described. Chapter 5: Convenient synthesis of Ferrocene Conjugates mediated by Benzyltriethylammonium Tetrathiomolybdate in a multi-step tandem process. The synthesis of a wide range of ferrocene derived sulfur linked mono and disubstituted Michael adducts and conjugates mediated by benzyltriethylammonium tetrathiomolybdate in a tandem process is reported. New route to access acryloyl ferrocene and 1,1’-bis acryloyl ferrocene is discussed. Conjugation of amino acids to ferrocene is established via their Nand Ctermini and also via side chain employing conjugate addition as key step to furnish monovalent and divalent conjugates. This methodology has also been extended to access several ferrocene carbohydrate conjugates. The electrochemical behavior of a few selected ferrocene conjugates has been studied by cyclic voltammetry. Finally, 1,1’-bis acryloyl ruthenocene was synthesized and it was utilized for the preparation of ruthenocene-carbohydrate conjugate in good yield. Chapter 6: Formation of Intramolecular S-Se bond mediated by tetrathiomolybdate. In this chapter, we have disclosed our preliminary results on reactivity of tetrathiomolybdate towards compounds containing both thiocyanate and selenocyanate functionalities. Several such compounds have been synthesized from the corresponding dibromides in two steps. We have observed selective reductive dimerization of selenocyanate over thiocyanate. In all the cases we also obtained seleno-sulfides via disulfide diselenide exchange reaction upon addition of excess tetrathiomolybdate. In the case of substrates on benzene scaffold, disulfide and diselenide bridged macrocycles were obtained apart from seleno sulfides whereas in the case of ferrocene derived substrates, formation of macrocycles was not observed. A tentative mechanism for the formation of these novel seleno sulfides is also discussed.(For structural formula pl see the pdf file)

The present thesis deals with different aspects of the chemistry and photo-biology of various ferrocene-conjugates, their interaction with double helical DNA, DNA photocleavage and photo-enhanced cytotoxicity in visible light, localization and cellular uptake to study the mechanism of cell death. Phenyl analogues of the active complexes have been synthesized and used for comparison in biological assays. Chapter I presents an overview of cancer and its types, various treatments for cancer. A general overview on the Photodynamic Therapy, a new modality of light activated cancer treatment and its various possible mechanism of action, has been made. The promise of photoactivated chemotherapy is discussed with recently developed metal based antitumor agents. Biological applications of few ferrocene conjugates as anticancer and anti-malarial agents 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 and cellular localization of ferrocene-conjugated dipicolylamine oxovanadium(IV) complexes of curcumin. To explore the role of the ferrocenyl moiety the phenyl analogue of the ferrocenyl complexes is synthesized and used as a control for comparison purpose. Chapter III deals with the photo-induced DNA cleavage and photo-enhanced cytotoxicity of ferrocene-conjugated oxovanadium(IV) complexes of heterocyclic bases. The synthesis, characterization, structural comparisons, DNA binding, DNA photocleavage and photocytotoxic activity in visible light are discussed in detail. Chapter IV describes the synthesis, characterization and structure of ferrocene-conjugated oxovanadium(IV) complexes of acetylacetonate derivatives. The complexes are evaluated for DNA binding, DNA photocleavage and photocytotoxic activity in HeLa, MCF-7, 3T3 cells in visible light. The fluorescent nature of the complexes is used to study the cellular localization of the complexes and the mechanism of cell death induced by the complexes is also discussed. Chapter V presents the photocytotoxic effect of ferrocene-conjugated oxovanadium(IV) complexes of different curcuminoids in HeLa , HepG2 and 3T3 cells. Curcumin based fluorescence has been successfully used to study the cellular uptake and localization behavior of the complexes. The positive role of the ferrocenyl complex is evident from the ~4 fold increase in its photocytotoxicity compared to the phenyl analogue. The apoptotic mode of cell death is evident from nuclear co-staining using Hoechst dye. Chapter VI describes the synthesis, characterization and photochemotherapeutic efficacy of ferrocene conjugates of N-alkyl pyridinium salts. Mitochondria targeting property of ferrocene compound having n-butyltriphenylphosphonium group has been studied by JC-1 assay. FACS analysis showed significant sub G1/G0 phase cell-cycle arrest in cancer cells on visible light treatment. 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. INDEX WORDS: Ferrocene conjugates Crystal structure DNA binding DNA photocleavage Photocytotoxicity Vanadium Cellular Imaging

Ferrocene is an important molecule in the field of chemical biology due to its stability, unique redox property and significant lipophilicity for better cellular delivery. The medicinal importance of ferrocene is well recognized after its successful incorporation into breast cancer drug tamoxifen and antimalarial drug chloroquin. Designing ferrocene conjugated transition metal complexes is an interesting area of research in the field of photodynamic therapy, a new modality of light activated cancer treatment. The objective of the present thesis work is to develop photoactive ferrocene conjugates showing DNA photocleavage and photocytotoxic activity. We have synthesized the ferrocene conjugated imidazophenanthroline derivative which exhibits visible light induced DNA photocleavage activity and photocytotoxicity in HeLa cell line. The corresponding phenyl analogue is found to be inactive. Polypyridyl platinum(II) complexes of ferrocenyl as well as phenyl moiety are prepared and studied their interactions with calf thymus DNA. The cytotoxicity of the complexes enhance significantly upon irradiation of UV-A light of 365 nm. To enhance the photodynamic potential and to understand the role of organometallic ferrocenyl moiety, ferrocene conjugated terpyridyl copper(II) complexes having planar phenanthroline bases are prepared. The interaction of these complexes with duplex DNA and their photo-induced DNA cleavage and anticancer activity in HeLa cancer cells are studied. The complexes are able to generate ROS in the presence of visible light which causes DNA damage as well as cell death. The importance of ferrocenyl moiety is evidenced from the less activity of the corresponding phenyl analogues complex. We have prepared copper(II) complexes of ferrocenyl methyl dipicolylamine ligand to understand the role of terpyridyl moiety. These complexes lacking any conjugation between the copper(II) and the ferrocenyl moiety are found to be less active compared to the terpyridyl conjugated system. The copper(II) complexes are found to show undesirable dark cytotoxicity in the presence of cellular thiols like GSH. To overcome the dark toxicity problem and to understand the mechanistic aspects of DNA photocleavage and photocytotoxicity, a series of binary ferrocene conjugated terpyridyl complexes of Fe(II), Co(II), Cu(II) and Zn(II) are prepared and their DNA photocleavage and anticancer activity studied. The zinc(II) complex having redox-active ferrocenyl moiety and redox-inactive zinc(II) center exhibits significant PDT effect with low dark toxicity compared to its copper(II) analogue. The ferrocenyl moiety plays an important role towards showing photocytotoxic activity since its phenyl analogue is inactive in nature. Finally, the present thesis work opens up a new strategy for designing and developing new ferrocene based metal complexes as novel photosensitizers for PDT applications.

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.