1. We have successfully developed an efficient approach to 3,4-disubstituted pyridin-2-ones from Glutarimide, and proved to be applicable for the synthesis of mappicine ketone 2. Synthesis of tricyclic lactonedemonstrate the utility Norrish type 1 reaction for the formal synthesis of udotartrial

DNA photosensitizers are compounds that are capable of binding in to DNA strands through groove binding, intercalation, or electrostatic interactions. Excitation of these agents by light generates reactive oxygen species which causes extensive photo-oxidative damage to genomic DNA. Physiological concentrations of NaCl and KCl are ~ 150 mM and 260 mM within the cell nucleus where DNA is contained. Unfortunately, the ability of most photosensitizers to bind to double-helical DNA is reduced and photocleavage yields are diminished as concentrations of salt increase. The aim of this project is to observe the photocleavage of pUC19 plasmid DNA induced by N1,N1-bis(9-anthrymethyl)triethylenetetraamine tetrahydrochloride (AL-VIII 23) 1 or N,N-dimethyl-N’-(9-methylanthracenyl)ethylenediamine (NMEA) 2 in presence of salt. Spectroscopic titrations and DNA melting assays were used to study binding modes and affinities of both dyes to the helix upon the addition of salt.

Metal ions and complexes utilized as cleavage agents have influenced many synthetic approaches of scientists to assist in the cleavage and transformation of biomolecules. These metal-based synthetic cleavage agents have potential applications in biotechnology or as molecular therapeutic agents. Herein, we have examined Ce(IV) metal ion and complexes as acidic hydrolytic agents in lipid hydrolysis reactions (Chapter 2 and 3), and a copper(II) complex that photo-oxidizes DNA upon exposure to ultraviolet light (Chapter 4). In Chapter 2 we examined the hydrolysis of sphingomyelin vesicles by Ce(NH4)2(NO3)6 (Ce(IV)) and compared the results to twelve d- and f-block metal salts, hydrolysis of mixed lipid vesicles and mixed micelles of sphingomyelin by Ce(IV), and hydrolysis of phosphatidylcholine vesicles by Ce(IV), using either MALDI-TOF mass spectrometry or colorimetric assays. In Chapter 3, we described the study of a Ce(IV) complex based on 1,3-bis[tris(hydroxymethyl)methylamino]propane as a potential acidic hydrolytic agent of phospholipids using colorimetric assays and NMR spectroscopy. The hydrolytic agent provided markedly enhance hydrolysis at lysosomal pH (~ 4.8), but suppress hydrolysis when pH was raised to near-neutral pH (~ 7.2). This was due to the pKa values of the donor atoms of the ligand, in which the metal’s electrophilicity was reduced to a greater extent at ~ pH 7.2 compared to ~ pH 4.8. Chapter 4 describes the synthesis and study of a Cu(II) complex based on a hexaazatriphenylene derivative for photo-assisted cleavage of double-helical DNA. Scavenger and chemical assays suggested the formation of DNA damaging reactive oxygen species, hydroxyl and superoxide radicals, and hydrogen peroxide, in the photocleavage reactions. Thermal denaturation and UV-vis absorption studies suggested that the Cu(II) complex binds in a non-intercalative fashion to duplex DNA.

Two-photon absorption is the process in which a molecule absorbs two photons simultaneously. The two key advantages of two-photon processes over one-photon processes are the possibility of excitation of materials with high three-dimensional spatial resolution and deep light-penetration into absorbing materials. Based on bond-cleavage reactions activated by photon-induced intramolecular electron transfer, two-photon activatable acid and radical initiators and two-photon removable protecting groups have been successfully designed and synthesized for photopolymerization and three-dimensional microfabrication and for biomedical photo-triggers. The optical and chemical properties of synthesized molecules, such as quantum yield of acid generation, initiation efficiency of photopolymerization, and photolysis efficiency, have been studied by using a variety of physical and analytical techniques under one-photon conditions. The two-photon characteristics and applications of these molecules are being investigated in collaboration with other groups.

The interaction of small molecules with DNA has been extensively studied and has produced a large catalogue of molecules that non-covalently bind to DNA though groove binding, intercalation, electrostatics, or a combination of these binding modes. Anthracene, acridine, and carbocyanine-based chromophores have been examined for their DNA binding properties and photo-reactivities. Their planar aromatic structures make them ideal chromophores that can be used to probe DNA structural interactions and binding patterns. We have studied DNA binding and photocleavgage properties of a bisacridine chromophore joined by a 2,6-bis(aminomethyl)pyridine copper-binding linker (Chapter II), a series of 9-aminomethyl anthracene chromophores (Chapters III and IV), both under conditions of high and low ionic strength, as well as a series of pentamethine linked symmetrical carbocyanine dyes (Chapter V). In Chapter II we present data showing that high ionic strength efficiently increases copper(II)-dependent photocleavage of plasmid DNA by the bisacridine based chromophore (419 nm, pH 7.0). In Chapters III and IV, using an pyridine N-substituted 9-(aminomethyl)anthracene (Chapter III), a bis-9-(aminomethyl)anthracene, and its mono 9-(aminomethyl)anthracene analogue (Chapter IV), pUC19 plasmid DNA was photo-converted to highly diffuse DNA fragments (350 nm, pH 7.0) in the presence of 150 mM NaCl and 260 mM KCl. Spectroscopic analyses suggest that the combination of salts promotes a change in DNA helical structure that initiate a switch in anthracene binding mode from intercalation to an external or groove binding interactions. The alteration in DNA structure and binding mode leads to an increase in the anthracene-sensitized production of DNA damaging reactive oxygen species. Finally, in Chapter V, pUC19 plasmid DNA is converted to its nicked circular and linear forms following irradiation of a series of pentamethine linked symmetrical carbocyanines (red light, pH 7.0). The data suggest that the relative levels of photocleavage arise from the different substituents on the nitrogen alkyl side chain and the pentamethine linker.

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The goal of this research was to develop an understanding of the impact of component modifications on spectroscopic properties, DNA interaction, and bioactivity of tridentate, terpyridine containing ruthenium-based chromophores and chromophore coupled cisplatin analogs. The coupling of a light absorbing unit to a bioactive site offers the potential for developing supramolecules with multifunctional interactions with DNA and other biomolecules. A series of supramolecular complexes of the form [(TL)RuCl(dpp)](PF₆) and [(TL)RuCl(BL)PtCl₂](PF₆) with the BL (bridging ligand) = 2,3-bis(2-pyridyl)pyrazine (dpp) and varying TL (terminal ligand) (tpy = 2,2'':6'',2''-terpyridine, MePhtpy = 4''-(4-methylphenyl)- 2,2'':6'',2''- terpyridine, or tBu3tpy = 4,4'',4''-tri-tert-butyl-2,2'':6'',2''-terpyridine) have been designed and developed. The investigations described in this thesis were focused on the design and development of multifunctional supramolecules with improved DNA interaction and antibacterial properties. The impact of component modifications on photophysical and biological properties of the designed the supramolecular complexes was investigated. A series of supramolecular complexes of the type, [(TL)RuCl(dpp)](PF₆) and [(TL)RuCl(dpp)PtCl₂](PF₆), have been synthesized using a building block approach. Electronic absorption spectroscopy of these types of complexes displayed intense ligand-based transitions in the UV region and metal to ligand charge transfer (MLCT) transitions in the visible region. The Ru to dpp MLCT transitions in RuIIPtII bimetallic complexes were found to be red-shifted relative to the monometallic synthons. The MLCT transitions for [(TL)RuCl(dpp)](PF₆) and [(TL)RuCl(dpp)PtCl₂](PF₆) were centered at ca. 520 and 545 nm, in CH₃CN respectively. The RuIIPtII bimetallic complexes with (TL = tpy, MePhtpy, and tBu3tpy) displayed reversible RuII/III couples at 1.10, 1.10, and 1.01 V vs. Ag/AgCl, respectively. The tpy0/- reductions occurred for TL = tpy, MePhtpy, and tBu3tpy at -1.43, -1.44, and -1.59 V vs. Ag/AgCl, respectively. The RuIIPtII complexes displayed a more positive potential for the dpp0/- couples (-0.50 -0.55, -0.59 V for tpy, MePhtpy, and tBu3tpy, repectively) relative to their monometallic synthons (-1.15, -1.16, and -1.22 V), consistent with the coordination of electron deficient Pt(II) metal center. This research also presents first extensive DNA photocleavage studies of these relatively unexplored tridentate, tpy-containing chromophores. The DNA binding and photocleavage properties of a series of homoleptic and heteroleptic chromophores and RuIIPtII bimetallic complexes were investigated using agarose gel electrophoresis and equilibrium dialysis experiments. The heteroleptic complexes, [(MePhtpy)RuCl(dpp)](PF₆), [(tpy)RuCl(dpp)](PF6), and [(tBu3tpy)RuCl(dpp)](PF6), were found to photocleave DNA more efficiently than homoleptic complexes, [Ru(MePhtpy)2]2+, [Ru(tpy)2]2+, and [Ru(tBu₃tpy)2]2+, in the presence of oxygen. Coupling of [(TL)RuCl(BL)] subunit to a cis-PtIICl2 site provides for the application of typically shorter lived RuII(tpy) based chromophores in DNA photocleavage. The [(TL)RuCl(dpp)PtCl₂]+, complexes displayed covalent binding to DNA and photocleavage upon irradiation with visible light modulated by TL identity. The impact of component modifications on antibacterial properties of the designed molecules was explored for the first time. Both the RuIIPtII bimetallic complexes and their monometallic analogs displayed antibacterial properties. [(MePhtpy)RuCl(dpp)](PF₆) was found to be the most efficient antibacterial agent in the series of monometallic and RuIIPtII bimetallic complexes, displaying cell growth inhibition at 0.05 mM concentration compared to 0.1 mM concentration of [(MePhtpy)RuCl(dpp)PtCl₂](PF₆) needed to display the similar effect. A direct correlation was found to exist between the DNA interaction and bactericidal properties of the designed supramolecules. The effects of light on antibacterial properties of [(MePhtpy)RuCl(dpp)](PF₆) were also briefly examined. This complex represents the first inorganic chromophore-based photodynamic antibacterial agent. / Ph. D.