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Synthesis of Photocleavable Photosensitizer-Drug SYNTHESIS OF PHOTOCLEAVABLE PHOTOSENSITIZER-DRUG COMPLEXES by MICHAEL YANGBO JIANG B. Sc. Xiamen University, 1998 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Chemistry) THE UNIVERSITY OF BRITISH COLUMBIA May 2007 © Michael Yangbo Jiang, 2007 Abstract The objective of this work was to develop a "photodyNamic" site-specific drug delivery methodology, whereby a drug can be released by visible light at the site of irradiation. This goal was fulfilled by connecting the target drug molecule with a photosensitizer through a specially-designed double-bond linkage. Upon visible light illumination, the photosensitizer moiety of the final complex converted ground-state oxygen to the high energized singlet oxygen, which can oxidatively cleave the olefin linkage to release the drug via a tandem [2+2] cyvloaddition-dioxetane decomposition process. Our first synthetic strategy was to combine bioactive carboxylic acids with alkynylporphyrins using a ruthenium-catalyzed addition reaction. However, the preparation of the alkynylporphyrin substrate was unsuccessful. An alternative synthesis was proposed by adding the carboxylic acid to ethoxyacetylene first, but the subsequent Heck coupling of the resulting alkene to porphyrins failed as well. However, an interesting reaction intermediate 11-21-Zn was isolated and characterized by X-ray crystallography. Its formation mechanism and catalytic activity were also studied. Second Generation Linker The first generation complexes were successfully synthesized using the linker molecule 111-15. Esters as drug mimics were first attached to the linker to form an enol ether linkage by Takai alkylidenation and photosensitizers were then attached by esterification. Visible light illumination of all four complexes gave the desired [2+2] cycloaddition and dioxetane cleavage products in yields from less than 5% to as high as 60%. However, products from the "ene" reaction usually predominated in the photooxygenation. The second generation linker molecule IV-7 was synthesized to facilitate the assembly of the complexes by Takeda alkoxymethylenation and esterification. Using this strategy, drug molecules (carboxylic acid derivatives) were incorporated through an enediol ether or (8-amino enol ether linkage to give the final complexes as a mixture of Z- and E-stereomers. Despite the unimpressive photooxygenation results of most E-isomers, a complete [2+2] cycloaddition selectivity was observed in the photooxygenation of the Z-isomers, due to the cis-directing effects of the olefin hetero-substituents. Aliphatic and aromatic esters, including methyl esters of ibuprofen and naproxen, lactones, and amides have been successfully incorporated and quantitatively (or near quantitatively) released using this strategy. Table of Contents Abstract ii Table of Contents iv Listoflables x List of Figures xi List of Schemes xvi List of Abbreviations xx Nomenclature xxiv Acknowledgements xxv CHAPTER ONE Introduction 1 1.1 Porphyrinoids 2 1.2 Chemical Reactions of Singlet Oxygen 5 1.2.1 Overview 5 1.2.2 The [4+2] Cycloaddition 7 1.2.3 The "Ene" Reaction 9 1.2.4 The [2+2] Cycloaddition 11 1.3 Photodynamic Therapy (PDT) 12 1.3.1 Mechanism of Photosensitization 13 1.3.2 Photosensitizers for PDT: Past, Present and Future 15 1.3.2.1 The Historic Aspect and the First Generation PDT Drug 15 1.3.2.2 Criteria of the Ideal PDT Drug 17 1.3.2.3 Second Generation PDT Drugs 18 1.3.2.4 Third Generation PDT Photosensitizers and Current Challenges of PDT. 20 1.4 Research Obj ective 23 CHAPTER TWO Building Photosensitizer-Drug Complexes Using Palladium-Catalyzed Cross-Coupling Reactions and Ruthenium-Catalyzed Alkyne Addition Reactions 27 2.1 Design Strategy 28 2.2 Results and Discussion of the Original Design 33 2.3 Modification Using the Heck Cross-Coupling Reaction 37 2.4 Structure Characterization, Formation Mechanism and Catalytic Studies of 11-21-Zn 41 2.4.1 Structure Characterization of 11-21-Zn 41 2.4.2 Mechanism of the Formation of 11-21 -Zn 46 2.4.3 Catalytic Study of 11-21 -Zn 53 2.4.4 hisights into the Reaction Mechanism 54 2.5 Summary 56 CHAPTER THREE Building Photosensitizer-Drug Complexes with the First Generation Linker Using Takai Alkylidenation 57 3.1 Olefination of Carboxylic Acid Derivatives Utilizing Titanium Reagents 58 3.1.1 Tebbe, Grubbs, and Petasis Reagents 58 3.1.2 Takai Alkylidenation 61 3.1.3 Takeda Alkylidenation 63 3.2 Design Strategy 67 3.3 Synthesis and Structure Characterizations 71 3.4 Photooxygenation of Photosensitizer-"Drug" Complexes 92 3.4.1 Experimental Design 92 3.4.2 Results and Discussion 94 3.4.2.1 Photooxygenation of TPP-Ethyl Butyrate Complex 111-25 94 3.4.2.2 Photooxygenation of TPP-Ethyl Benzoate Complex 111-26 104 3.4.2.3 Photooxygenation of BPD-Ethyl Benzoate Complex 111-28 107 3.4.2.4 Photooxygenation of TPP-Methyl Pivalate Complex 111-27 112 3.5 Summary 114 CHAPTER FOUR Building Photosensitizer-Drug Complexes with the Second Generation Linker Using Takeda Alkoxymethylenation 122 vil 4.1 Design Strategy 123 4.1.1 General Consideration 123 4.1.2 Takeda Alkoxymethylenation Leading to the Enediol Ethers or Other i8-Hetero-Substituted Enol Ethers 129 4.1.3 Synthetic Approach for Photosensitizer-Drug Complexes Bearing Enediol Ether or Other /S-Hetero-Substituted Enol Ether Linkages 132 4.1.4 Synthetic Approach for Photosensitizer-Drug Complexes Bearing Enamine Linkages 134 4.2 Synthesis of Photosensitizer-Drug Complexes Bearing Enamine Linkages 135 4.3 Synthesis of Photosensitizer-Drug Complexes Bearing Enediol Ether or Other /8-Hetero-Substituted Enol Ether Linkages 137 4.4 Photooxygenation of the Second Generation Photosensitizer-Drug Complexes 143 4.4.1 Photooxygenation of Photosensitizer-Ethyl Butyrate Complexes Bearing Enediol Ether Linkages 143 4.4.2 Interpretation of Different Behaviors Observed in the photooxygenation of the First and Second Generation Complexes-—the Cis-Directing Effect 154 4.4.3 Photooxygenation of Other Second Generation Photosensitizer-Drug Complexes (Z-isomers) 159 4.4.4 Photooxygenation of Other Second Generation Photosensitizer-Drug Complexes (E-isomers) 166 4.5 Summary 169 4.6 Future Work 171 CHAPTER FIVE Experimental 181 5.1 Instrumentation and General Materials 182 5.2 Experimental Data for Chapter Two 183 5.3 Experimental Data for Chapter Three 191 5.3.1 Synthesis 191 5.3.2 Photooxygenation 204 5.3.2.1 Photooxygenation of TPP-Ethyl Butyrate Complex 111-25 206 5.3.2.2 Photooxygenation of TPP-Ethyl Benzoate Complex 111-26 209 5.3.2.3 Photooxygenation of BPD-Ethyl Benzoate Complex 111-28 210 5.3.2.4 Photooxygenation of TPP-Methyl Pivalate Complex 111-27 211 5.4 Experimental Data for Chapter Four 212 5.4.1 Synthesis 212 5.4.2 Photooxygenation 240 5.4.2.1 Photooxygenation of TPP-Ethyl Butyrate Complex IV-21-Z 241 5.4.2.2 Photooxygenation of BPD-Ethyl Butyrate Complex IV-22-Z 244 5.4.2.3 Photooxygenation of TPP-Ethyl Butyrate Complex IV-21-E 245 5.4.2.4 Photooxygenation of TPP-Ethyl Benzoate Complex IV-23-Z 247 5.4.2.5 Photooxygenation of TPP-(ô-Valerolactone) Complex IV-24-Z 248 5.4.2.6 Photooxygenation of TPP-(N-Methylbenzanilide) Complex IV-29 249 5.4.2.7 Photooxygenation of TPP-Ibuprofen (methyl ester) Complex IV-25-Z....249 5.4.2.8 Photooxygenation of BPD-Ibuprofen (methyl ester) Complex IV-26-Z...250 5.4.2.9 Photooxygenation of TPP-Naproxen (methyl ester) Complex IV-27-Z....251 5.4.2.10 Photooxygenation of BPD-Naproxen (methyl ester) Complex IV-28-Z.252 5.4.2.11 Photooxygenation of TPP-(ô-Valerolactone) Complex IV-24-E 253 5.4.2.12 Photooxygenation of TPP-Ibuprofen (methyl ester) Complex IV-25-E..254 5.4.2.13 Photooxygenation of BPD-Ibuprofen (methyl ester) Complex IV-26-E.255 5.5 Crystal Data and Details of the Structure Determination 256 References 261 List of Tables Table 2.1 Selected bond lengths and bond angles for molecule A and B of 11-21-Zn.. 43 Table 2.2 Control experiments to study the in situ reduction of Pd(PPh3)2Cl2 51 Table 3.1 Takai alkylidenation of carbonyl substrates and the desilylation 73 Table 3.2 Esterification of porphyrinoid acids 76 Table 3.3 '^C['H] NMR spectral data of 111-26 (dg-acetone, 100 MHz) 84 Table 3.4 ^H NMR spectral data of 111-28 (de-acetone, 400 MHz) 90 Table 3.5 ^^C[^H] NMR spectral data of 111-28 (de-acetone, 100 MHz) 91 Table 3.6 Photooxygenation of 111-25 95 Table 3.7 Photooxygenation of 111-28 108 Table 4.1 Reactivities of different olefin substrates towards singlet oxygenation 125 Table 4.2 Takeda alkoxymethylenation and the final esterification 139 Table 4.3 Photooxygenation of IV-21 -Z and IV-22-Z 145 Table 4.4 Photooxygenation of IV-21 -E 149 Table 4.5 Photooxygenation of IV-23-Z to IV-29-Z 161 Table 4.6 Photooxygenafion of IV-24-E, IV-25-E, and IV-26-E 167 Table 5.1 Relative GC response factors for esters in Chapter Three 205 Table 5.2 Relative GC response factors for esters and amides in Chapter Four 241 Table 5.3 Crystal data and details of the structure determination for 11-21 -Zn 257 Table 5.4 Crystal data and details of the structure determination for 111-31 259 List of Figures Figure 1.1 General structures of porphyrinoids 2 Figure 1.2 Structures of protoporphyrin IX, Heme-b, and Chlorophyll-a 4 Figure 1.3 Second generation photosensitizer candidates for PDT 18 Figure 1.4 Photosensitizer-biomolecule conjugates 21 Figure 2.1 Structure of 1-alkoxy enol ester 30 Figure 2.2 Structures of 11-17 and 11-18 36 Figure 2.3 An ORTEP drawing of 11-21 -Zn showing thermal ellipsoids at 50% probability level (top view).
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