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Design, Synthesis, and Characterization of Porphyrin Louisiana State University LSU Digital Commons LSU Doctoral Dissertations Graduate School 2013 Design, synthesis, and characterization of porphyrin derivatives for biological applications Raja Gabadage Waruna Eranga Jinadasa Louisiana State University and Agricultural and Mechanical College, [email protected] Follow this and additional works at: https://digitalcommons.lsu.edu/gradschool_dissertations Part of the Chemistry Commons Recommended Citation Jinadasa, Raja Gabadage Waruna Eranga, "Design, synthesis, and characterization of porphyrin derivatives for biological applications" (2013). LSU Doctoral Dissertations. 1482. https://digitalcommons.lsu.edu/gradschool_dissertations/1482 This Dissertation is brought to you for free and open access by the Graduate School at LSU Digital Commons. It has been accepted for inclusion in LSU Doctoral Dissertations by an authorized graduate school editor of LSU Digital Commons. For more information, please [email protected]. DESIGN, SYNTHESIS, AND CHARACTERIZATION OF PORPHYRIN DERIVATIVES FOR BIOLOGICAL APPLICATIONS A Dissertation Submitted to the Graduate Faculty of the Louisiana State University and Agricultural and Mechanical College in partial fulfillment of the requirements for the degree of Doctor of Philosophy in The Department of Chemistry by R. G. Waruna Jinadasa B.Sc., University of Colombo, 2006 December 2013 Dedicated with love to my parents And my wife and son ii ACKNOWLEDGEMENTS First and foremost I offer my sincerest gratitude to my doctoral mentor, Professor Kevin M. Smith, who has supported me throughout my Ph.D study with his patience and unsurpassed knowledge whilst allowing me the room to work in my own way. I could not have imagined having a better advisor and mentor for my Ph.D studies. I also want give my sincere appreciations to Professor M. Graça H. Vicente for her guidance and support; she always encouraged me to do my best, and was always there for me to help me with my research. Without their guidance and persistent help, this Dissertation would not have been possible. I would like to thank my doctoral committee members: Professor Carol M. Taylor and Professor William E. Crowe, and Professor John R. White for taking time out from their busy schedules and agreeing to serve on my advisory committee. I am deeply thankful to Dr. Xiaoke Hu and Dr. Zehua Zhou for in vitro cellular investigations, to Dr. Frank R. Fronczek for the crystal structure determinations, to Connie David for the support in mass spectrometry and especially to the late Dr. W. Dale Treleaven and Dr. Thomas Weldegheorghis for all their help in the NMR facility. In my daily work I have been blessed with a friendly and cheerful group of fellow students. Heartiest thanks go to past and present fellow doctoral colleague in my group, Dr. N. V. S. Dinesh Bhupathiraju, Dr. Timsy Uppal, Dr. Alecia M. McCall, Dr. Krystal R. Fontenot, Dr. Javoris V. Hollingsworth, Dr. Benson G. Ongarora, Moses I. Ihachi, Haijun Wang, Jamie Hayes, Qianli Meng, Tyrslai Williams, Ning Zhao, Elizabeth Okoth for friendship, and for sharing their enthusiasm and suggestions on my work. I am very much grateful to my family, my wife Chamini Karunaratne and son Yevin Deemitha, who supported me in every possible way to see the completion of this work. Finally, I take this opportunity to express the profound gratitude from my deep heart to my beloved parents and my siblings for their love, encouragement and help, at every stage of my personal and academic life; they longed to see this achievement come true. iii TABLE OF CONTENTS ACKNOWLEDGEMENTS ................................................................................................................................ iii GLOSSARY OF ABBREVIATIONS ..................................................................................................................... v ABSTRACT ....................................................................................................................................................viii CHAPTER 1: INTRODUCTION ……………………………………………………………………………………………………………………1 1.1 Porphyrins ..................................................................................................................................... 1 1.2 Spectroscopic Character of Porphyrins ......................................................................................... 2 1.3 Hydroporphyrins ........................................................................................................................... 5 1.4 Naturally Occurring Porphyrins ..................................................................................................... 6 1.5 Photodynamic Therapy (PDT) ..................................................................................................... 18 1.6 References ................................................................................................................................... 29 CHAPTER 2: SYNTHESIS AND CHARACTERIZATION OF CHLORIN e6 DERIVATIVES FOR PHOTODYNAMIC THERAPY ……………………………………………………………………………………………………………………32 2.1 Introduction ................................................................................................................................ 32 2.2 Mechanistic Studies .................................................................................................................... 35 2.3 Structural Elucidation and Synthesis of Chlorin e6 Derivatives ................................................... 42 2.4 Molecular Modeling .................................................................................................................... 54 2.5 Cell Culture Studies. .................................................................................................................... 56 2.6 Conclusion. .................................................................................................................................. 61 2.7 Experimental ............................................................................................................................... 62 2.8 Supporting information ............................................................................................................... 84 2.8 References ................................................................................................................................. 123 CHAPTER 3: SYNTHESIS AND CHARACTERIZATION OF WATER SOLUBLE CHLORIN e6 DERIVATIVES FOR PHOTODYNAMIC THERAPY…………………………………………………………………………………………………………..125 3.1 Introduction .............................................................................................................................. 125 3.2 Synthesis ................................................................................................................................... 127 3.3 Cell Culture Studies. .................................................................................................................. 138 3.4 Experimental ............................................................................................................................. 142 3.5 Supporting information ............................................................................................................. 156 3.6 References ................................................................................................................................. 168 CHAPTER 4: SYNTHESIS OF ELECTRON DEFICIENT PORPHYRINS FOR A SYNTHETIC CYTOCHROME……….170 4.1 Introduction .............................................................................................................................. 170 4.2 Synthesis ................................................................................................................................... 178 4.3 Future work ............................................................................................................................... 202 4.4 Experimental ............................................................................................................................. 204 4.5 Supporting Information ............................................................................................................. 221 4.6 References ................................................................................................................................. 239 APPENDIX: LETTERS OF PERMISSION ........................................................................................................ 242 THE VITA .................................................................................................................................................... 246 iv GLOSSARY OF ABBREVIATIONS δ Chemical shift Ac Acetyl Boc N-tert-butoxycarbonyl BoDIPY Boron-dipyrromethene Bn Benzyl br broad 13C NMR Carbon 13 Nuclear Magnetic Resonance d doublet DCC N,N'-Dicyclohexylcarbodiimide DCE Dichloroethane DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DIEA N,N-Diisopropylethylamine DMAP Dimethylaminopyridine DMSO Dimethylsulfoxide ER Endoplasmic reticulum ESI Electrospray ionization EtOAc Ethyl acetate EtOH Ethyl alcohol 1H NMR Proton Nuclear Magnetic Resonance HCC Hepatocellular carcinoma HEp2 Human epithelial type 2 HOBt 1-Hydroxybenzotriazole HPLC High Performance Liquid Chromatography v HPPH 2-[1-Hexyloxyethyl]-2-devinyl-pyropheophorbide-a HRMS High Resolution Mass Spectrometry IC50 Half maximal inhibitory concentration J Coupling constant MALDI Matrix Assisted Laser Desorption Ion Ionization MeOH Methanol MS Mass Spectrometry m/z mass to charge
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