Preface ...................................................... xiii
Acronyms ....................................................... xv
Chapter 1 Introduction ......................................... 1
1.1 Definition of Area of Study ................................ 1
1.2 Historical Aspects ......................................... 3
1.2.1 Vitamin D and Rickets ............................... 4
1.2.2 Phototherapy of Psoriasis ........................... 6
1.2.3 Neonatal Hyperbilirubinemia ......................... 7
1.2.4 Cancer .............................................. 9
Bibliography ................................................... 13
Chapter 2 Physical Matters .................................... 15
2.1 Light ..................................................... 15
2.2 Light Sources ............................................. 19
2.2.1 Sunlight ........................................... 19
2.2.2 Incandescent Lamps ................................. 19
2.2.3 Arc Lamps .......................................... 19
2.2.4 Light-emitting Diodes .............................. 20
2.2.5 Lasers ............................................. 21
2.3 Light Absorption .......................................... 23
2.3.1 The Beer-Lambert Law ............................... 23
2.3.2 Excitation ......................................... 24
2.3.2.1 Multiplicity .............................. 24
2.3.2.2 Probability ............................... 25
2.4 Emission .................................................. 27
2.5 Jablonski Diagram ......................................... 28
2.6 Quantum Efficiency ........................................ 30
2.7 Intermolecular Electronic Excitation Transfer ............. 31
2.8 Singlet Oxygen Quantum Yields ............................. 32
Bibliography ................................................... 37
Chapter 3 Singlet Oxygen ...................................... 39
3.1 General ................................................... 39
3.2 Generation of Singlet Oxygen .............................. 42
3.2.1 Chemical Methods ................................... 42
3.2.2 Physical Methods ................................... 42
3.3 Chemical Reactions ........................................ 47
3.3.1 Alkenes — the "ene" Reaction ....................... 47
3.3.2 Electron-rich Alkenes .............................. 49
3.3.3 Conjugated Dienes — Diels-Alder Addition ........... 52
3.3.4 Miscellaneous Reactions ............................ 54
Bibliography ................................................... 56
Chapter 4 Photodynamic Action ................................. 57
4.1 Definition ................................................ 57
4.2 Discovery and Development ................................. 57
4.3 Photodynamic Agents - Structural Types .................... 64
4.3.1 General Considerations ............................. 64
4.3.2 Structural Types ................................... 64
4.4 Mechanism of Photodynamic Action .......................... 70
4.4.1 The Type I Mechanism - Electron Transfer ........... 70
4.4.2 The Type II Mechanism - Energy Transfer ............ 74
4.4.3 Distinguishing between Type I and Type II
Photooxygenation Processes ......................... 76
4.4.3.1 Tests for radical intermediates (Type I
mechanism) ................................ 80
4.4.3.2 Tests for singlet oxygen (Type II
mechanism) ................................ 81
4.4.4 The Overall Mechanistic Picture .................... 83
Bibliography ................................................... 87
Chapter 5 Some Other Examples of Photomedicine ................ 89
5.1 Introduction .............................................. 89
5.2 Sunscreens ................................................ 89
5.2.1 Sunlight and the Skin .............................. 89
5.2.2 Artificial Sunscreens .............................. 92
5.3 Skin Carcinogenesis ....................................... 93
5.4 Phototherapy of Rickets (Osteomalacia) .................... 94
5.5 Psoriasis ................................................ 100
5.5.1 Photosensitisers for PUVA ......................... 100
5.5.2 Mechanism ......................................... 102
5.6 Phototherapy of Neonatal Hyperbilirubinemia .............. 103
5.6.1 Photofragmentation ................................ 104
5.6.2 Photoisomerisation/Photosolubilisation ............ 107
5.6.2.1 Photochemical configurational
isomerisation (Photobilirubins I) ........ 107
5.6.2.2 Photocyclisation (Photobilirubins II,
lumirubins) .............................. 109
Bibliography .................................................. 113
Chapter 6 The Chemistry of Haematoporphyrin Derivative
(HpD) .............................................. 115
6.1 Introduction ............................................. 115
6.2 Chemistry of HpD Stage I ................................. 117
6.3 Chemistry of HpD Stage II ................................ 118
6.4 Clinical Development ..................................... 126
Bibliography .................................................. 128
Chapter 7 Second Generation Photosensitisers ................. 129
7.1 First Generation Photosensitisers ........................ 129
7.1.1 Advantages ........................................ 129
7.1.2 Disadvantages ..................................... 129
7.2 Design Criteria for Second Generation Photosensitisers ... 130
7.2.1 Dark Toxicity ..................................... 130
7.2.2 Composition ....................................... 130
7.2.3 Synthesis ......................................... 130
7.2.4 Solution Behaviour ................................ 130
7.2.4.1 Tetraphenylporphyrin sulphonic acids ..... 131
7.2.4.2 Sulphonated metallophthalocyanines ....... 132
7.2.4.3 3-(1-Alkyloxyethyl)-3-devinylpyropheo-
phorbide α ............................... 135
7.2.4.4 Spacing of hydrophilic substituents on
the hydrophobic framework ................ 136
7.2.5 Delivery Systems .................................. 137
7.2.6 Photophysical Properties .......................... 143
7.2.7 Red Absorption .................................... 144
Bibliography .................................................. 147
Chapter 8 Porphyrin Photosensitisers ......................... 149
8.1 Introduction ............................................. 149
8.2 Porphyrin Sources ........................................ 149
8.3 Porphyrins Derived from Haemoglobin ...................... 156
8.4 Synthetic Porphyrins ..................................... 159
8.4.1 General Approaches ................................ 159
8.4.2 Specific Examples ................................. 166
8.5 Endogenous Porphyrin: δ-ALA as a Pro-drug ................ 173
Bibliography .................................................. 174
Chapter 9 Chlorins and Bacteriochlorins ...................... 177
9.1 Structural Definition .................................... 177
9.2 Absorption Spectra ....................................... 178
9.3 Naturally Derived Chlorins and Bacteriochlorins .......... 183
9.4 Chlorins Derived from Protohaem .......................... 186
9.4.1 From Deụteroporphyrin (88) ........................ 187
9.4.2 From Protoporphyrin (61) .......................... 188
9.4.3 From Photoprotoporphyrin (132) .................... 189
9.5 Chlorins and Bacteriochlorins by Total Synthesis ......... 190
9.5.1 By Reduction ...................................... 190
9.5.2 By Other β, β'-Addition Reactions ................. 193
9.5.3 By Meso-β Cyclisation ............................. 193
Bibliography .................................................. 198
Chapter 10 Phthalocyanines and Naphthalocyanines .............. 199
10.1 Structural Considerations ................................ 199
10.2 Spectra .................................................. 201
10.3 5-Azaporphyrins .......................................... 203
10.4 Benzoporphyrins .......................................... 203
10.5 Phthalocyanines .......................................... 203
10.5.1 General ........................................... 203
10.5.2 Synthesis ......................................... 211
10.5.3 PDT Photosensitisers .............................. 219
10.5.3.1 Zinc(11) phthalocyanine .................. 219
10.5.3.2 Su I phonic acids ........................ 220
10.5.3.3 Hydroxyphthalocyanines ................... 220
10.5.3.4 Axial ligand variation ................... 221
10.6 Naphthalocyanines ........................................ 222
Bibliography .................................................. 223
Chapter 11 Other Photosensitisers ............................. 225
11.1 Cyanine Dyes ............................................. 225
11.1.1 Merocyanine 540 ................................... 225
11.1.2 Indocyanine Green ................................. 226
11.2 Hypericin ................................................ 226
11.3 Phenothiazines ........................................... 226
11.4 Porphycenes .............................................. 227
11.5 Squaraines ............................................... 229
11.6 Texaphyrins .............................................. 229
11.7 Xanthenes ................................................ 231
11.8 Conjugated Photosensitisers .............................. 233
Bibliography .................................................. 235
Chapter 12 Photobleaching ..................................... 237
12.1 Definitions .............................................. 237
12.2 Potential Value of Photobleaching in PDT ................. 238
12.3 Kinetic Studies .......................................... 238
12.4 Product Studies .......................................... 241
12.4.1 Photomodification ................................. 241
12.4.1.1 Protoporphyrin ........................... 241
12.4.1.2 m-THPP ................................... 243
12.4.1.3 m-THPC ................................... 244
12.4.1.4 Purpurins ................................ 244
12.4.1.5 Haematoporphyrin ......................... 245
12.4.2 Photobleaching .................................... 246
12.4.2.1 m-THPC and m-THPBC ....................... 246
12.4.2.2 Other photosensitisers related to
porphyrins ............................... 246
12.5 Biological Systems ....................................... 248
12.5.1 In vitro Studies .................................. 248
12.5.2 In vivo Studies ................................... 248
Bibliography .................................................. 256
Chapter 13 Biological Aspects ................................. 257
13.1 Biological Assay ......................................... 257
13.1.1 Preliminary Physical Tests ........................ 257
13.1.2 In vitro Bioassays ................................ 258
13.1.3 Intermediate Bioassays ............................ 259
13.1.4 In vivo Bioassays ................................. 260
13.1.4.1 Tumour photonecrotic activity ........... 260
13.1.4.2 Tumour selectivity ...................... 261
13.2 Localisation ............................................. 262
13.2.1 Protein Binding ................................... 264
13.2.2 Intracellular Localisation ........................ 264
13.2.3 Localisation in vivo .............................. 265
13.3 Photosensitiser Excretion ................................ 268
13.4 Mechanisms of Tumour Destruction ......................... 269
Bibliography .................................................. 270
Chapter 14 Clinical and Commercial Developments: Prospects
for the Future ..................................... 271
14.1 Introduction ............................................. 271
14.2 PhotofrinR (also referred to as porfimer sodium) ......... 272
14.3 Second Generation Drugs at the Clinical Stage ............ 273
14.3.1 δ-ALA (104) ....................................... 273
14.3.2 m-THPC (77) ....................................... 274
14.3.3 Tin Etiopurpurin — SnEt2 .......................... 275
14.3.4 Mono-L-aspartylchlorin ℮6 — MACE (125) ............ 275
14.3.5 3-(1-Hexyloxyethyl)-3-devinylpyropheophorbide a
(75) .............................................. 275
14.3.6 Sulphonated Aluminium Phthalocyanine .............. 275
14.3.7 Benzoporphyrin Derivative (131) ................... 275
14.3.8 Lutetium Texaphyrin (187) ......................... 276
14.3.9 Porphycenes ....................................... 276
14.4 Comparative Data ......................................... 276
14.5 Future Prospects ......................................... 277
14.5.1 Synthesis of New Sensitisers ...................... 277
14.5.2 Light Sources ..................................... 277
14.5.3 New Clinical Directions in PDT ................... 278
14.5.3.1 Psoriasis ............................... 278
14.5.3.2 Arthritis ............................... 278
14.5.3.3 Age-related Macular Degeneration
(AMD) ................................... 278
14.5.3.4 Other Conditions and Treatments ......... 278
14.5.3.5 Microbicidal Activity ................... 278
Bibliography .................................................. 289
Index ......................................................... 291
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