Preface ........................................................ xi
Glossary for lignans ......................................... xiii
1 Introduction .................................................. 1
Nomenclature .................................................... 4
Absolute configuration ........................................ 8
Correlation of absolute configurations ........................ 9
References ................................................... 10
2 A registry of the natural lignans ............................ 12
The order of the material .................................... 12
Absolute configuration ....................................... 14
Arrangement of individual entries
(i) The Chemical Abstracts Registry number ............... 15
(ii) Literature references ............................... 16
(iii) Structural diagrams ................................ 16
References for the preamble .................................. 16
Structures and references in the registry .................... 17
3 Biological and clinical properties of podophyllotoxin and
other lignans ................................................ 85
Introduction ................................................. 85
Use of lignans in folk and modern medicine ................... 85
(i) History of podophyllotoxin ........................... 87
Biological properties and mechanism of action of
podophyllotoxin .............................................. 90
(i) Microtubules ......................................... 90
(ii) Antiviral properties ................................ 93
(iii) Nucleoside transport ............................... 94
(iv) Antitumour effects .................................. 95
Mammalian lignans ............................................ 95
(i) Structure ............................................ 95
(ii) Biological properties ............................... 97
Structure and biological activity of other lignans ........... 98
(i) Acyclic lignans ...................................... 98
(ii) Arylnaphthalenes .................................... 99
(iii) Dibenzocyclo-octadienes (bridged biphenyls) ....... 100
(iv) Lignans acting on cyclic adenosine-3',5'-
monophosphate (cAMP)......................................... 100
(v) Lignans acting on platelet activating factor (PAF) .... 102
(vi) Biological effects of lignans on plants and
insects ................................................... 103
Conclusions ................................................. 105
References .................................................. 106
4 Etoposide and Teniposide .................................... 113
Introduction ................................................ 113
Clinical applications ....................................... 114
Structure and synthesis ..................................... 116
Mechanism of action ......................................... 117
(i) Inhibition of nucleoside transport .................. 118
(ii) DNA effects ........................................ 118
(iii) Effects on oxidative phosphorylation .............. 122
Cell sensitivity and resistance towards Etoposide ........... 122
Structure/activity studies - DNA effects .................... 125
Pharmacokinetics and pharmacology ........................... 127
(i) Cellular uptake of Etoposide and Teniposide ......... 127
(ii) Pharmacokinetics ................................... 128
(iii) Metabolism ........................................ 129
(iv) Toxicity ........................................... 130
Conclusions and future studies .............................. 130
References .................................................. 132
5 Isolation, purification and initial characterisation ........ 138
Plant root sources .......................................... 138
Leaf and stem sources ....................................... 140
Seeds as sources ............................................ 140
Fruits as sources ........................................... 141
Resin and heartwood sources ................................. 142
Lignan glycosides ........................................... 144
Isolation procedures ........................................ 145
(i) Solvent extraction .................................. 145
(ii) Fractional extraction .............................. 146
(iii) Separation by precipitation ....................... 148
(iv) Extraction of polar lignans from biological
materials ............................................... 148
Chromatographic methods ..................................... 149
(i) Thin layer chromatography ........................... 149
(ii) Column chromatography .............................. 151
(iii) High-performance liquid chromatography............. 153
(iv) Gas-liquid chromatography........................... 155
Formation of artefacts ...................................... 156
(i) Changes induced by bases............................. 156
(ii) Changes induced by acids............................ 157
References .................................................. 159
6 Determination of structure .................................. 166
Ultraviolet absorption spectra .............................. 166
Dibenzocyclo-octadiene lignans .............................. 170
Arylnaphthalene lignans ..................................... 170
Infrared absorption spectra ................................. 170
(i) Lignan solvates ....................................... 171
(ii) Preparation of the sample ............................ 171
(iii) Functional group responses .......................... 171
Mass spectra ................................................ 175
Diarylbutanes and diarylbutyrolactones ...................... 177
Tetrahydrofurans (epoxylignans) ............................. 180
Furofurans (bisepoxylignans) ................................ 183
Oxofurofurans ............................................... 185
Aryltetralins ............................................... 186
Arylnaphthalenes ............................................ 190
Dibenzocyclo-octadienes ..................................... 191
Lignan conjugates ........................................... 192
Nuclear magnetic resonance spectra .......................... 195
(i) Introductory remarks ................................ 195
(ii) Aromatic substitution patterns ..................... 195
(iii) Dibenzylbutanes and dibenzylbutyrolactones ........ 197
(iv) 13-CNMR spectroscopy ............................... 199
Furans ...................................................... 202
(i) 9,9'-Epoxylignans ................................... 202
(ii) 7,7'-Epoxylignans .................................. 203
(iii) 7,9'-Epoxylignans ................................. 206
Furofurans .................................................. 208
Chemical correlation of furofurans and furans ............... 213
Aryltetrahydronaphthalenes .................................. 216
(i) Orientation of aromatic substituents ................ 219
(ii) Use of CM R spectra ................................ 220
(iii) Aryltetrahydronaphthalene lactones ................ 221
(iv) Absolute configuration ............................. 228
Dibenzocyclo-octadiene lignans .............................. 230
(i) Orientation of aromatic substituents ................ 235
(ii) The steganacin subgroup ............................ 237
Lignan conjugates ........................................... 242
Higher glycosides ........................................... 246
Optical rotatory dispersion and circular dichroism .......... 247
(i) Optical rotatory dispersion ......................... 247
(ii) Circular dichroism ................................. 249
(a) Dibenzylbutyrolactones .............................. 249
(b) Furans and furofurans ............................... 249
(c) Aryltetrahydronaphthalenes .......................... 253
(d) Compounds with inherent dissymmetry ................. 256
References .................................................. 257
7 Biosynthesis ................................................ 269
The chemistry of lignin ..................................... 269
Cleavage of lignin .......................................... 273
(i) Acidic cleavage ..................................... 273
(ii) Alkaline cleavage .................................. 274
(iii) Enzymic cleavage .................................. 275
Oligomers of cinnamic acid .................................. 275
Lignan biosynthesis ......................................... 278
(i) The quinone methide mechanism ....................... 279
(ii) Biomimetic synthesis ............................... 280
(iii) Experiments in vivo ............................... 287
(a) Preliminary studies and structural correlations ..... 287
(b) The tetrahydronaphthalene group ..................... 291
(c) Apolignans and arylnaphthalenes ..................... 295
(d) Biogenesis of ether groups 296 References ........... 298
Synthesis ................................................... 303
Oxidative coupling .......................................... 303
Dibenzylbutanes and dibenzylbutyrolactones .................. 306
(i) The Stobbe condensation ............................. 306
(ii) Other syntheses initiated by carbanions ............ 310
(iii) Stereoselective synthesis ......................... 313
(iv) Conjugate additions ................................ 315
Oxygenation of the side chain ............................... 318
Reactions with N-bromosuccinamide and dichlorodicyano-
1,4-benzoquinone ............................................ 322
Diels-Alder syntheses ....................................... 325
Routes to specific classes of lignins ....................... 330
Arylnaphthalenes ............................................ 330
Furans ...................................................... 333
(i) 9,9'-Epoxylignans ................................... 333
(ii) 7,7'-Epoxylignans .................................. 334
(a) The bicyclic lactone route .......................... 337
(iii) 7,9'-Epoxylignans ................................. 338
Furofurans(7,9':7',9-diepoxylignans) ........................ 339
(i) Synthesis of monolactones ........................... 340
(ii) Synthesis of dilactones ............................ 341
(a) Unsymmetrical dilactones ............................ 342
Dibenzocyclo-octadienes ..................................... 344
(i) Oxidative coupling .................................. 345
(ii) Ullmann synthesis .................................. 346
(iii) Elaboration of phenanthrenes ...................... 350
Dihydro- and tetrahydronaphthalenes ......................... 354
(i) Summary of above procedures relevant to tetralin
synthesis ................................................... 354
(a) Oxidative coupling .................................. 354
(b) Development of the Stobbe and carbanion
condensation products ................................... 355
(c) Oxidative cyclisation ............................... 355
(d) Diels-Alder synthesis ............................... 356
(ii) Modification of other lignans by Friedel-Crafts
cyclisation ............................................. 357
(iii) Synthesis of podophyllotoxins ..................... 362
(a) Bristol-Myers group syntheses ....................... 368
(iv) Derivatives of podophyllotoxins .................... 370
References .................................................. 373
Botanical index ............................................. 385
General index ............................................... 385
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