Bimetallic Ruthenium(Ii) Polypyridyl Complexes Bridged by a Boron

BIMETALLIC RUTHENIUM(II) POLYPYRIDYL COMPLEXES BRIDGED BY A BORON DIPYRROMETHENE (BODIPY): SYNTHESIS, SPECTROSCOPIC AND PLASMID DNA PHOTOREACTIONS AND THE IMPACT OF THE 515 NM EFFECT IN PHOTOSYNTHESIS: MODEL SYSTEM USING β-CAROTENE ACID COMPLEXES Thesis Submitted to The College of Arts and Sciences of the UNIVERSITY OF DAYTON In Partial Fulfillment of the Requirements for The Degree of Master of Science in Chemistry By Ashlee Elizabeth Wertz Dayton, Ohio May 2019 BIMETALLIC RUTHENIUM(II) POLYPYRIDYL COMPLEXES BRIDGED BY A BORON DIPYRROMETHENE (BODIPY): SYNTHESIS, SPECTROSCOPIC AND PLASMID DNA PHOTOREACTIONS AND THE IMPACT OF THE 515 NM EFFECT IN PHOTOSYNTHESIS: MODEL SYSTEM USING β-CAROTENE ACID COMPLEXES Name: Wertz, Ashlee Elizabeth APPROVED BY: Shawn M. Swavey, Ph.D., Professor Mann Chair in the Sciences Committee Chair Mark B. Masthay, Ph.D. Associate Professor. Committee Chair Jeremy M. Erb, Ph.D. Assistant Professor. Committee Member ii © Copyright by Ashlee Elizabeth Wertz All rights reserved 2019 iii ABSTRACT BIMETALLIC RUTHENIUM(II) POLYPYRIDYL COMPLEXES BRIDGED BY A BORON DIPYRROMETHENE (BODIPY): SYNTHESIS, SPECTROSCOPIC AND PLASMID DNA PHOTOREACTIONS Name: Wertz, Ashlee Elizabeth University of Dayton Advisor: Dr. Shawn M. Swavey Photodynamic therapy (PDT) is a medical technique which utilizes a photosensitizing drug, light of a certain wavelength and molecular oxygen to generate singlet oxygen, a toxic oxidizing 1 species. When present, singlet oxygen ( O2) will rapidly react with surrounding biomolecules, causing cellular damage that ultimately leads to cell death. PDT is an approved medical technique and it has been used for multiple purposes including cases of acne and psoriasis, age-related macular degeneration, and more recently, in the treatment of cancer. To the ends of creating a photosensitizer for PDT, a new pi-extended dipyrrin containing isoquinolpyrrole has been synthesized by solvent free reactions with trifluoroacetic acid (TFA) as a catalyst. The boron- dipyrrin (Bodipy) of the isoquinolpyrrole was synthesized by standard procedures followed by synthesis of the bis-ruthenium(II) Bodipy analog. The spectroscopic properties of this complex show the typical intra-ligand charge transfer transitions (ILCT) along with the Ru(π) to ligand(π*) metal to ligand charge transfer (MLCT) transitions. An intense transition at 608 nm with molar absorptivity greater than 100,000 M-1cm-1 associated with the ππ* transition of the Bodipy core is observed. In acetonitrile solutions the bis-Ru(II)-Bodipy complex generates significant singlet oxygen when irradiated with low energy light. In aqueous solutions the complex is capable of photo-nicking plasmid DNA when irradiated within the photodynamic therapy (PDT) window of 600 to 850 nm. iv ACKNOWLEDGMENTS Special thanks are in order to Dr. Shawn M. Swavey who made this thesis possible by allowing me to join his lab and by keeping the project on track to completion. I would like to thank him for the patience he showed in explaining synthesis, electrochemistry and spectroscopy and for always being around to answer my numerous questions. In addition, I am grateful for the time he spent proof reading this thesis and for his valuable feedback. I would also like to thank the University of Dayton Chemistry Department for funding this work. Finally, I would like to express my gratitude to my parents, sisters and boyfriend for providing me with support and continuous encouragement throughout my years of study. This accomplishment would not have been possible without them. Thank you. v TABLE OF CONTENTS: PART 1 ABSTRACT…………………………………………………………………………………….... iv ACKNOWLEDGMENTS…………………………………………………………………..……..v LIST OF FIGURES ………………………………………………………………….…………..vii CHAPTER 1 INTRODUCTION TO PHOTODYNAMIC THERAPY…………………...............1 Chapter 1 References …………………………………………………………………... 20 CHAPTER 2 EXPERIMENTAL …………………………………………………………..….....29 Materials ……………………………………………………………………………….. 29 Electronic Absorption Spectra ………………………………………………..................29 Luminescence Spectra ……………………………………………………….………….29 DPBF Studies …………………………………………………………………................29 DNA Photocleavage Studies………………… ………………………………………..30 Synthesis ………………………………………………………………………...............30 Chapter 2 References ……………………………………………………………………32 CHAPTER 3 RESULTS AND DISCUSSION…………………………………………………...33 Synthesis ………………………………………………………………………...............33 Spectroscopy …………………………………………………………………………….34 DNA Studies …………………………………………………………………………….37 DPBF Studies ……………………………………………………………………………39 Conclusion ………………………………………………………………………………40 Chapter 3 References ……………………………………………………………………40 vi LIST OF FIGURES Figure 1. Modified Jablonski diagram …………………………………………………………….5 Figure 2. Structure of Porfimer Sodium …………………………………………………………..7 Figure 3. Chemical Structure of Levulan® ………………………………………………………..8 Figure 4. Chemical Structure of Metvixia® ……………………………………………................8 Figure 5. Bodipy core which can be extensively modified ………………………………………10 Figure 6. Structure of common Bodipy dyes …………………………………………………….12 Figure 7. Structure of common Bodipy dyes (II) ………………………………………...............13 Figure 8. Dibromo-aza-Bodipy (ADPM06) …………………………………………...…………13 Figure 9. BF2 -chelated azadipyrromethene dibrominated analogue …………………………….14 Figure 10. Structures of Ru-porphyrin conjugates ……………………………………………….17 2+ Figure 11. [Ru(bpy)2(N–N)] complexes ………………………………………………………..18 Figure 12. Structures of the six different DNA intercalating Ru complexes 18a–f ……... ……...19 Figure 13. Synthetic route for the Bodipy -dye, complex I, and complex II. ……………...…… 34 Figure 14. Absorption spectra of the carbazole Bodipy (blue) and Ru2 carbazole Bodipy (I) (red) in acetonitrile………………………………………………………………………………..35 Figure 15. UV/vis spectra of complex I (blue) and II (red) in dry acetonitrile at 298 K using a 1 cm quartz cuvette ………………………………………………………………………36 Figure 16. Spectroelectrochemistry of complex I in dry acetonitrile (298 K) with Et4NPF6 as supporting electrolyte ………………………………………………………………..37 Figure 17. Gel electrophoresis of circular plasmid DNA ………………………………………..38 Figure 18. Gel electrophoresis of circular plasmid DNA (II) ……………………………………39 Figure 19. Time-dependent generation of singlet oxygen upon irradiation at l > 550 nm……….40 vii CHAPTER 1 INTRODUCTION TO PHOTODYNAMIC THERAPY Discovery and Background The history of using light as a therapeutic agent go back many centuries as it had long been used by the Chinese, Egyptians and Indians in the treatment of disease 1. The ancient Greeks developed heliotherapy, a restorative health treatment that involved full body exposure to sunlight. Although the origins of using light as a treatment trace back centuries, it was not until more recently that phototherapy has been widely used in medicine 2. In the eighteenth and nineteenth centuries sunlight was used for the treatment of various conditions such as tuberculosis rickets, scurvy and muscle weakness 3. Phototherapy was developed into a science and popularized by the Danish physician Nils Finsen. Finsen described the successful treatment of smallpox using red light and used ultraviolet light to treat cutaneous tuberculosis. He also initiated the use of carbon arc phototherapy for lupus vulgaris and was awarded the Nobel Prize in 1903 for his work 4,5. The concept of cell death being induced by the interaction of both light and chemicals has been recognized for over a century. The technique was first reported by medical student Oscar Raab who observed that Paramecium spp. Protozoans were killed after staining with acridine orange and subsequent exposure to bright light 6. He, along with professor von Tappeiner, demonstrated that acridine exposed to light had a greater effect on Paramecium than either acridine alone, light alone or acridine exposed to light and then added to the paramecium. They had therefore discovered that it was not the light itself, but some product of fluorescence that induced toxicity. Von Tappeiner took over Raab’s research and, with dermatologist Jesionek, published clinical data using eosin as a photosensitizer in the treatment of skin cancer and lupus of the skin. In 1904, von Tappeiner and Jodlbauer reported that the presence of oxygen was a 1 requirement for photosensitizationon 5. In 1907 these experiments were collated into a book in which von Tappeiner coined the term ‘photodynamic therapy’ to describe the phenomenon of oxygen-dependent photosensitization 7. Uses for Photodynamic Therapy The field of PDT, a medical technique using light, a photosensitizing drug and molecular oxygen, truly began to form into a practiced medical technique in the 1960’s when Dougherty 9 brought this novel therapy to the attention of a worldwide audience. Skin conditions were among the first types of diseases to be studied for use with PDT. This is due to their easy accessibility to a photosensitizer and light. The Dougherty research group at the Roswell Park Cancer Institute in Buffalo pioneered skin cancer PDT using the first photosensitizer, a water-soluble mixture of porphyrins that was named ‘haematoporphyrin derivative’ (HpD) and a xenon arc lamp. A more purified preparation of HpD later became known as Photofrin® which will be discussed in detail later. In an early study by Dougherty, 48% of transplanted mouse mammary tumors were cured 10. In 1978, Dougherty reported success in one of the first patient trials with PDT. Twenty-five patients with either primary or secondary skin tumors were treated with HpD followed by exposure to red

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