Syntheses and Evaluation of Phthalocyanine Derivatives For
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Louisiana State University LSU Digital Commons LSU Doctoral Dissertations Graduate School 2008 Syntheses and Evaluation of Phthalocyanine Derivatives for Applications in Photodynamic and Boron Neutron Capture Therapies for Cancer Hairong Li 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 Li, Hairong, "Syntheses and Evaluation of Phthalocyanine Derivatives for Applications in Photodynamic and Boron Neutron Capture Therapies for Cancer" (2008). LSU Doctoral Dissertations. 3294. https://digitalcommons.lsu.edu/gradschool_dissertations/3294 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]. SYNTHESES AND EVALUATION OF PHTHALOCYANINE DERIVATIVES FOR APPLICATIONS IN PHOTODYNAMIC AND BORON NEUTRON CAPTURE THERAPIES FOR CANCER A Dissertation Submitted to the Graduate Faculty of the Louisiana State University and Agricultural and Mechanical College in partial fulfillment of the requirement for the degree of Doctor of Philosophy in The Department of Chemistry By Hairong Li B.S., Nankai University, 2001 M.S., Nankai University, 2004 December, 2008 DEDICATION To my parents: Mingzhen Tang and Baiwen Li. Thank you for being wonderful parents; for giving me life, unconditional love, support, education, guidance, most importantly the freedom to make my own decisions. You have always been my source of strength and inspiration. I can never thank you enough for what you have done in my life. ii ACKNOWLEDGMENTS I would like to give my sincere gratitude to my advisor, Prof. M. Graça H. Vicente, for your mentoring, inspiration, encouragement and support for me in the past four years. You are an intelligent and knowledgeable scholar in science; a caring and considerate professor for students; an optimistic and inspiring friend to us. I would like to thank Prof. Robert Hammer, Prof. William Crowe, Prof. Jayne Garno and Prof. Gary Breitenbeck for being my committee members. Thank you for your time and patience on reading my dissertation and your valuable advice on my research. I would like to thank Prof. Kevin Smith, who has brought me a broad area of phorphyrin chemistry and set a model of what a great scientist should be. I would like to thank Prof. Steve Soper for providing me with the great fluorometer and Dr. Irina Nesterova for the assistance of photophysical study and valuable discussions. I would like to thank Mr. Tim Jensen for the cell study. The acknowledgement would also go to Dr. Frank Fronczek for the single crystal X-ray analysis. I would like to thank Dr. Dale Trelevean and Guangyu Li for the help of NMR experiments and Dr. Thomas Weldeghiorghis for running DEPT experiment for me. I need thank Dr. Azeem Hasan for obtaining the ESI data timely. I would like to thank my labmates Celinah Mwakwari and Jodie Hargus. I would like to thank all the current and past members of Dr. Vicente and Dr. Smith’s research groups: Dr. Michael Essen, Hillary Tanui, Timsy Uppal, Alecia McCall, Javoris Hollingsworth, Kiran Kumar Allam, Dr. Martha Sibrian-Vasquez, Dr. Erhong Hao, Dr. Lijuan Jiao, Dr. Celinah Mwakwari, Dr. Vijay Gottumukula, Jodie Hargus, Dr. Owendi Ongari, Dr. Caleb Clark, Dr. Jianming Lu, Dr. Wei Liu, Dr. Brahma Ghosh. Thank you iii all for your help and friendship. I enjoyed the time we shared together in LSU. Here, I would especially recognize Kiran Allam, whose sudden loss saddened all his colleagues. I would like to thank my student workers Ngan Nguyen and Dominique Williams for your industrious work in the lab. I would like to thank all my friends of LSU. Thank you all for your support and I will memorize all the fun time we are together. Finally, I need to thank my mom, Mingzhen Tang and my late dad, Baiwen Li for all your unconditional supports, sacrifice and love. I need to thank my brother Haidong Li, always caring me and instructing me. Lastly, I need to give my thanks to my beloved husband Xiangyang Xu, who is the rock behind me and always there to push me ahead without fear. Thank you for your love. Without you, this dissertation could not be simply accomplished. iv TABLE OF CONTENTS DEDICATION…………….…………………………………………………………….ii ACKNOWLEDGMENTS………………………………………………………………iii LIST OF ABBREVIATIONS…………………………………………………..………vii ABSTRACT…………………………………………………………………...…………xi CHAPTER 1 INTRODUCTION……………………………………………….………1 1.1 Overview of Phthalocyanines.………………….………………………....1 1.2 Synthetic Strategies of Phthalocyanines…………………….…...……….3 1.2.1 General Aspects of Phthalocyanine Synthesis….……………………….3 1.2.2 Mechanisms of Phthalocyanines’ Formation..……………..……………...4 1.2.3 Synthesis of Symmetrical Phthalocyanine…..……………..……………...6 1.2.4 Synthesis of Non-Centrosymmetric Phthalocyanine……………….……8 1.3 Applications of Phthalocyanine……...………………………….……….11 1.3.1 Applications in Photodynamic Therapy (PDT) of Cancer……………….12 1.3.2 Applications in Boron Neutron Capture Therapy (BNCT) of Cancer….16 1.4 References………………………………………………………..….…...17 CHAPTER 2 SYNTHESES AND PROPERTIES OF CATIONIC OCTAPYRIDILOXY-SUBSTITUTED PHTHALOCYANINES……....23 2.1 Background……………………………………………………………....23 2.2 Synthesis of Octapyridiloxy-Substituted Zinc Phthalocyanines................25 2.3 Synthesis of Octapyridiloxy-Substituted Silicon Phthalocyanines..…...31 2.4 Photophysical Studies of Octapyridiloxy-Substituted Zinc and Silicon Phthalocyanines…………………………………….………..……….…..36 2.5 Summary of Biological Evaluation……………………………………...42 2.6 Conclusion……………………………………………………………..43 2.7 Experimental..…………………………………..…………………..……44 2.7.1 Synthesis………………………………………..…………………..……44 2.7.2 Photophysical Study…………………………..…………………..……55 2.8 References……………………………………….………………..……56 CHAPTER 3 SYNTHESES AND PROPERTIES OF CARBORANYL CONJUGATED PHTHALOCYANINES…..……………………………………………...60 3.1 Background………...................…………………………………..…....60 3.2 Synthesis of Carboranyl Conjugated Phthalocyanines…………………62 3.3 Spectroscopic Properties of Cobaltacarboranyl-Phthalocyanines……….68 3.4 Synthesis of Carboranyl Conjugated Phthalonitriles and Future Work …72 3.5 Conclusion……………………………………………………………..77 3.6 Experimental…..……………………………………………………….77 3.7 References………………………………………………………………..93 v CHAPTER 4 SYNTHESES OF A SERIES OF HYDROXY-SUBSTITUTED ZINC PHTHALOCYANINES……………………………………………..…...96 4.1 Background……………………………………………………………….96 4.2 Synthesis of Octahydroxy-Substituted Zinc Phthalocyanines…..……….96 4.3 Synthesis of Tetrahydroxy-Substituted Zinc Phthalocyanines…………103 4.4 Synthesis of Dihydroxy-Substituted Zinc Phthalocyanines……….……106 4.5 Conclusion….………………………………………………………......110 4.6 Experimental……………………………………………………………110 4.7 References…………………………………………………………….121 CHAPTER 5 SYNTHESES OF PHOSPHONATE-SUBSTITUTED PHTHALOCYANINES……..………………………………………….124 5.1 Background………………………………………………………..……124 5.2 Synthesis of Octaphosphonate-Substituted Zinc Phthalocyanine………124 5.3 Synthesis of Precursors…………………………………………………128 5.4 Conclusion……………………………………………………………129 5.5 Experimental…………………………………………………………..130 5.6 References………………………………………………………………135 APPENDIX A: CHARACTERIZATION DATA FOR COMPOUNDS IN CHAPTER 2...137 B: CHARACTERIZATION DATA FOR COMPOUNDS IN CHAPTER 3...140 C: CHARACTERIZATION DATA FOR COMPOUNDS IN CHAPTER 4...142 D: CHARACTERIZATION DATA FOR COMPOUNDS IN CHAPTER 5...147 E: LETTERS OF PERMISSION…………………………………………......151 VITA……………………………………………………………………………………154 vi LIST OF ABBREVIATIONS δ Chemical shift λex Excitation wavelength br Broad BBr3 Boron tribromide . BBr3 SMe2 Boron tribromide dimethyl sulfide n-BuLi N-butyl lithium BF3.OEt2 Boron trifluoride etherate BOC Tert-butyl carbamate BPA L-4-dihydroxyborylphenylalanine BSH Disodium mercapto-closo-dodecaborate ºC Degrees Celsius d Doublet DPBF Diphenylisobenzofuran CHCl3 Chloroform CH3OH Methanol 13C NMR Carbon 13 nuclear magnetic resonance BNCT Boron neutron capture therapy D2O Deuterated water DBU 1, 8-Diazabicyclo[5.4.0]undec-7-ene DBN 1, 5-Diazabicyclo[4.3.0]non-5-ene DCM Dichloromethane DMAE N, N-dimethylamino-ethanol vii DMSO Dimethyl sulfoxide DMF Dimethylformamide DNA Deoxyribonucleic acid ESI Electrospray ionization FAB Fast atom bombardment FDA United States Food and Drug Administration FT-IR Ffourier transform infrared h Hours H2Pc Metal-free phthalocyanine HpD Haematoporphyrin derivatives HPLC High Performance Liquid Chromatography HRMS High resolution mass spectrometry Hz Hertz IC50 Inhibitory concentration 50% IR Infrared J/cm2 Joule per square centimeters LET Linear energy transfer MALDI Matrix assisted laser desorption/ionization MeI Methyl iodide MeOH Methanol MS Mass spectrometry m/z Mass to charge ratio nm Nanometer nM Nanomolar viii NA Not available NMP N-methylpyrrolidone NMR Nuclear magnetic resonance OH Hydroxy ppm Parts per million Pc Phthalocyanine PcH2 Free base phthalocyanine PDT Photodynamic therapy PEG Polyethylene glycol PS Photosensitizer Py.HCl Pyridine hydrochloride q Quartet rt Room temperature RES Reticulo-endothelial-system ROS Reactive oxygen species s Singlet SiPc Silicon phthalocyanine t Triplet TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran THP Tetrahydropiperine TLC Thin layer chromatography TMSBr Trimethylsilyl bromide ix TMSI Trimethylsilyl iodide µM Micromolar UV-Vis Ultraviolet visible ZnPc Zinc phthalocyanine