Foreword ........................................................ v
Francois Diederich
Preface ........................................................ xi
Veronique Gouverneur and Klaus Midler
Section II
1 Synthesis and Properties of Fluorinated Nucleobases
in DNA and RNA ............................................... 3
Holger Gohlke, Jelena Bozilovic and Joachim W. Engels
1.1 Introduction ............................................ 3
1.2 Fluorine in Molecular Recognition ....................... 4
1.3 Synthesis of Fluoro-Substituted Benzenes,
Benzimidazoles and Indoles, and their Incorporation
into Model RNA .......................................... 6
1.3.1 Chemical syntheses of fluoro-substituted
benzenes, benzimidazoles and indoles ............. 6
1.3.2 Synthesis of 12-mer RNA duplexes that
incorporate fluoronucleosides ................... 12
1.3.3 RNA melting studies and thermodynamic data ...... 13
1.4 Origin of the Molecular Recognition Properties of
Fluorinated Nucleobases
1.4.1 Stacking and desolvation: Insights from
thermodynamic analyses
1.4.2 C-H ••• F-C interactions: Crystallographic
analysis of fluoro-substituted NNIs ............. 17
1.4.3 Molecular dynamics simulations and free
energy calculations ............................. 20
1.5 Incorporation of Fluoro-Substituted NNI into the
Hammerhead Ribozyme and siRNA Constructs and their
Acceptance by Polymerases .............................. 22
1.5.1 Hammerhead ribozyme ............................. 22
1.5.2 Fluorobenzene and benzimidazoles in RNA
interference and siRNA .......................... 24
1.5.3 Polymerase acceptance of fluorobenzimidazoles ... 26
1.6 Conclusion ............................................. 26
Acknowledgements ............................................ 27
References .................................................. 27
2 Molecular Interactions of Fluorinated Amino Acids within
the Hydrophobic Core of a Coiled Coil Peptide ............... 33
Toni Vagt, Mario Salwiczek and Beate Koksch
2.1 Introduction ........................................... 33
2.2 The a-Helical Coiled Coil as a Model System to
Investigate Fluorinated Amino Acids within a Native
Protein Environment .................................... 35
2.3 Single Fluoroamino Acid Substitutions within a
Heterodimeric Coiled Coil .............................. 39
2.3.1 The α-helical coiled coil as a model for a
natural protein environment ..................... 39
2.4 Biophysical Characterisation of the Interactions ....... 41
2.4.1 Hydrophobicity of the fluorinated amino acids ... 41
2.4.2 The impact of fluorine substitutions on coiled
coil structure .................................. 44
2.4.3 The impact of fluorine substitutions on the
thermodynamic stability of the dimer ............ 47
2.5 Screening for Native Interaction Partners .............. 52
2.6 Conclusions and Outlook ................................ 57
Acknowledgements ............................................ 58
References .................................................. 58
3 Probing the Binding Affinity and Proteolytic Stability of
Trifluoromethyl Peptide Mimics as Protease Inhibitors ....... 63
Matteo Zanda, Alessandro Volonterio, Monica Sani
and Sergio Dall'Angelo
3.1 Introduction ........................................... 63
3.2 Peptidyl Trifluoro-Ketones ............................. 64
3.3 Peptidomimetics Containing the Trifluoroethylamine
Function as Peptide Bond Replacement ................... 66
3.4 Trifluoromefhyl-Peptidomimetics as Protease
Inhibitors ............................................. 73
3.4.1 MMP inhibitors .................................. 73
3.4.2 β-Fluoroalkyl β-sulfonyl hydroxamates ........... 75
3.4.3 Dual ACE/NEP inhibitors ......................... 77
3.4.4 Crystallographic analysis of the role of the
CF3-group in the binding process to enzyme
active sites .................................... 80
References .................................................. 86
4 Trifluoromethyl-Substituted α-Amino Acids as Solid-State
19F NMR Labels for Structural Studies of Membrane-Bound
Peptides .................................................... 91
Vladimir S. Kubyshkin, Igor V. Komarov, Sergii Afonin,
Pavel K. Mykhailiuk, Stephan L. Grage and Anne S. Ulrich
4.1 Introduction ........................................... 91
4.2 Solid-State NMR for Structure Analysis of Membrane-
Associated Polypeptides ................................ 93
4.3 Choice of the CF3 Group as a Label for 19F NMR of
Peptides in Membranes .................................. 96
4.4 Suitable CF3-Labelled Amino Acids for 19F NMR
Analysis ............................................... 98
4.5 α-CF3-Substituted Amino Acids: TfmAla ................. 99
4.5.1 Synthesis ....................................... 99
4.5.2 Separation of the TfmAla enantiomers ........... 106
4.5.3 Incorporation of TfmAla into peptides .......... 107
4.5.4 19F NMR structure analysis of peptides
with TfmAla .................................... 109
4.6 Amino Acids with a Rigid Spacer Between Ca and the
CF3 Group: 4-TfmPhg and TfmBpg ........................ 111
4.6.1 Synthesis of 4-TfmPhg .......................... 111
4.6.2 Separation of the 4-TfmPhg enantiomers ......... 117
4.6.3 Incorporation of 4-TfmPhg into peptides ........ 118
4.6.4 Synthesis of TfmBpg ............................ 120
4.6.5 Synthesis of peptides containing TfmBpg ........ 121
4.6.6 19F NMR structure analysis of peptides with
4-TfmPhg and TfmBpg ............................ 122
4.7 Conclusions and Perspectives .......................... 124
Acknowledgements ........................................... 128
References ................................................. 128
Section 2 ..................................................... 139
5 Fluorine-Containing Pharmaceuticals ........................ 141
Steve Swallow
5.1 Introduction .......................................... 141
5.1.1 Survey of fluorine-containing pharmaceuticals .. 142
5.2 Case Studies .......................................... 144
5.2.1 Ezetimibe (Zetia) .............................. 144
5.2.2 Celecoxib (Celebrex) ........................... 147
5.2.3 Sitagliptin (Januvia) .......................... 147
5.2.4 Fluconazole (Diflucan) and Voriconazole
(Vfend) ........................................ 154
5.2.5 Fluoroquinolones ............................... 158
5.2.6 Fluticasone propionate (Flovent, Flixotide) .... 160
5.2.7 Aprepitant (Emend) ............................. 165
5.3 Summary and Future Outlook ............................ 169
References ................................................. 170
6 Applications of Pentafluorosulfanyl Substitution in Life
Sciences Research .......................................... 175
John T. Welch
6.1 Introduction .......................................... 175
6.2 General Preparative Information ....................... 177
6.2.1 Synthesis of 1-fluoro-4-nitro-2-
(pentafluorosulfanyl)benzene and derivatives ... 178
6.2.2 Synthesis of 4,5-dihydroisoxazoles with
allylic pentafluorosulfanyl substituents ....... 178
6.2.3 Pentafluorosulfanyl (SF5) pyrrole carboxylic
acid esters .................................... 179
6.3 Agrochemical Applications ............................. 180
6.3.1 3-(2-Chloro-4-(pentafluorosulfanyl)phenoxy)
benzoic acid ................................... 180
6.3.2 Pentafluorosulfanylphenyl and
benzoylisoxazoles .............................. 181
6.3.3 Trifluralin analogue ........................... 182
6.3.4 Insecticidal derivatives of substituted
phosphorylated phenylalkyl iminooxazolines
and iminothiazolines ........................... 183
6.3.5 Fungicidal (E)-methyl 2-(2-(3-
(pentafluorosulfanyl)phenoxymethyl) phenyl)-
3-methoxyacrylate, 44 .......................... 183
6.3.6 N-(3-Phenylpropyl) and (3-phenylethyl)
benzamides ..................................... 184
6.4 Medicinal Chemistry ................................... 184
6.4.1 l-(Pentafluorosulfanylphenyl)-3-( 1,2,4-
triazol-3-ylthioalkyl)-3-azabicyclo[3.1.0]hexanes,
dopamine D3 receptor modulators ....................... 185
6.4.2 Pentafluorosulfur piperazinylpiperidines ....... 186
6.4.3 Pentafluorosulfanyl arene containing
pyrazoles ...................................... 187
6.4.4 N-(phenoxycyanomethylethyl)
(pentafluorosulfanyl) benzamide ................ 187
6.4.5 Preparation of pentafluorosulfanyl-
substituted compounds for use as vanilloid
receptor VR1 ligands ........................... 188
6.4.6 4-Fluoro-N-(4-pentafluorosulfanylphenyl)
-4-(3-fluoropyridin-2-yl)
cyclohexanecarboxamide 84 ...................... 189
6.4.7 Pentafluorosulfanylarene aminoimidazoles ....... 190
6.4.8 3-Phenylhydantoins ............................. 191
6.4.7 Pentafluorosulfanyl benzoylguanidines .......... 192
6.4.10 Pentafluorosulfanylphenoxy-substituted
benzoylguanidines .............................. 193
6.4.11 Functionalization of
pentafluorosulfanylphenoxy-substituted
benzoylguanidines .............................. 193
6.4.12 Pentafluorosulfanyl-containing diarylamine
trypanothione reductase inhibitors ............. 193
6.4.13 A pentafluorosulfanyl-containing quinoline,
a mefloquine analogue .......................... 196
6.4.14 Fluoxetine analogues ........................... 197
6.4.15 Fenfluramine and norfenfluramine ............... 199
6.4.16 5-Hydroxytryptamine ............................ 200
6.5 Conclusions and Outlook ................................ 202
Acknowledgements ........................................... 202
References ................................................. 202
7 Strategic Incorporation of Fluorine into Taxoid
Anticancer Agents .......................................... 209
Antonella Pepe, Liang Sun and Iwao Ojima
7.1 Introduction .......................................... 209
7.2 Paclitaxel, Docetaxel and New-Generation Taxoids ...... 210
7.3 Synthesis and Biological Evaluation of Fluorine-
Containing New-Generation Taxoids ..................... 213
7.4 Synthesis and Biological Evaluation of Fluorine-
Containing C-Seco-Taxoids ............................. 221
7.5 Use of Solid-State 19F NMR and Computational
Analysis for the Determination of Bioactive
Conformation of Paclitaxel and Fluorinated Taxoids .... 226
7.6 Use of Fluorine in Tumour-Targeting Anticancer
Agents ................................................ 232
Acknowledgements ........................................... 234
References ................................................. 235
8 Synthesis and Antiviral, Antitumour Activities of
Fluorinated Sugar Nucleosides .............................. 241
Feng Zheng, Xiao-Long Qiu and Feng-Ling Qing
8.1 Introduction .......................................... 241
8.2 Nucleosides Fluorinated at C2' ........................ 242
8.2.1 2'-α-Fluoro nucleosides ........................ 243
8.2.2 2'-β-Fluoro nucleosides ........................ 246
8.2.3 2', 2'-Difluoronucleosides ..................... 250
8.2.4 2'-Fluoro-2', 3'-didehydro-2', 3'-dideoxy
nucleosides .................................... 252
8.3 Nucleosides Fluorinated at C3' ........................ 254
8.3.1 3'-α-Fluoro nucleosides ........................ 254
8.3.2 3'-β-Fluoro nucleosides ........................ 256
8.3.3 3',3'-Difiuoro nucleosides ..................... 258
8.3.4 3'-Fluoro-2', 3'-didehydro-2', 3'-dideoxy
nucleosides .................................... 260
8.4 Nucleosides Fluorinated at C4' ........................ 261
8.5 Nucleosides Fluorinated at C6' ........................ 263
8.6 5'-Fluorinated and Phosphonodifluoromefhylenated
Nucleosides ........................................... 269
8.7 Nucleosides Bearing Exocyclic Fluorocarbon
Substituents at C2', C3' and C4' ...................... 272
8.7.1 Nucleosides containing a trifluoromethyl
group .......................................... 272
8.7.2 Nucleosides containing a difluoromethylene,
fluoromethylene or difluoromefhyl group ........ 274
8.8 Other Fluorinated Nucleosides ......................... 276
8.8.1 Fluorinated cyclopropyl nucleosides ............ 276
8.8.2 Fluorinated cyclobutyl and oxetanosyl
nucleosides .................................... 278
8.8.3 Fluorinated pyranosyl nucleosides .............. 278
8.9 Conformational Studies of Fluorinated Nucleosides ..... 280
8.10 Conclusion ............................................ 284
References ................................................. 284
9 Synthesis of Fluorinated Neurotransmitter Analogues ........ 299
Margit Winkler and David O'Hagan
9.1 Introduction .......................................... 299
9.2 Adenosine Receptors ................................... 300
9.3 Adrenoreceptors ....................................... 305
9.3.1 Epinephrine (adrenaline) ....................... 305
9.3.2 Norepinephrine (noradrenaline) ................. 306
9.3.3 Octopamine ..................................... 307
9.3.4 Tyramine ....................................... 308
9.4 Cannabinoid Receptors ................................. 308
9.5 Dopamine Receptors .................................... 310
9.5.1 Dopamine ....................................... 310
9.5.2 L-DOPA ......................................... 311
9.6 GABA Receptors ........................................ 312
9.7 Glutamate Receptors ................................... 314
9.8 Histamine Receptors ................................... 317
9.9 Muscarinic Receptors .................................. 318
9.10 Nicotinic Acetylcholine Receptors ..................... 319
9.11 Serotonin Receptors ................................... 321
9.12 Melatonin Receptors ................................... 323
9.13 Vanilloid Receptors ................................... 323
9.14 Capsaicin ............................................. 323
9.15 Anandamide ............................................ 324
9.16 Conclusion ............................................ 324
References ................................................. 325
Section 3 ..................................................... 333
10 18F-Radionuclide Chemistry ................................. 335
Romain Bejot and Veronique Gouverneur
10.1 Introduction .......................................... 335
10.1.1 Radioisotope 18F ............................... 335
10.1.2 Nuclear reactions .............................. 335
10.1.3 Production of 18F .............................. 337
10.1.4 Positron emission tomography (PET) ............. 338
10.1.5 Specific activity .............................. 339
10.1.6 Kinetics and radiochemical yield ............... 341
10.2 Carrier-Added 18F-Labelled Probes ..................... 342
10.2.1 Carrier-added [18F]fluoride .................... 342
10.2.2 Surface interactions with 18F-labelled probes .. 344
10.2.3 Catalytic fluorination ......................... 345
10.3 Nucleophilic 18F-Radiolabelling ....................... 345
10.3.1 Reactive [18F]fluoride ......................... 346
10.3.2 Nucleophilic carbon-fluorine bond formation .... 348
10.3.3 Silicon-fluorine bond formation ................ 357
10.3.4 Boron-fluorine bond formation .................. 358
10.3.5 Aluminium-fluorine bond formation .............. 359
10.3.6 Phosphorus-fluorine bond formation ............. 359
10.4 Electrophilic 18F-Radiolabelling ...................... 360
10.4.1 Electrophilic fluorination agents .............. 360
10.4.2 Electrophilic carbon-fluorine bond formation ... 364
10.5 Prosthetic Groups ..................................... 367
10.6 Purification ......................................... 369
Acknowledgements ........................................... 370
References ................................................. 370
11 18F-Labelled Tracers for PET Oncology and Neurology
Applications ............................................... 383
Sajinder K. Luthra and Edward G. Robins
11.1 Introduction to Molecular Imaging ..................... 383
11.2 Positron Emission Tomography (PET) .................... 384
11.3 Biological Imaging Targets ............................ 385
11.4 Tracer Development .................................... 385
11.5 Oncology Applications ................................. 388
11.6 2-[18F]Fluoro-2-Deoxy-D-Glucose ([18F]FDG) ............ 389
11.7 3'-Deoxy-3'- [18F] Fluoro-L-Thymidine ([18F] FLT) ..... 391
11.8 Imaging Tumour Angiogenesis ........................... 396
11.9 Choline Metabolism .................................... 404
11.10 Apoptosis ............................................ 408
11.10.1 PS targeting radiotracers .................... 408
11.11 Caspase Targeting Radiotracers ....................... 411
11.12 CNS Neurosciences Applications ....................... 413
11.13 Beta-Amyloid Plaques and Neurofibrillary Tangles ..... 414
11.13.1 FDDNP ......................................... 415
11.13.2 BTA derivatives ............................... 417
11.13.3 Stilbenes ..................................... 421
11.14 Peripheral Benzodiazepine Binding Sites or TSPO-
18kDa ................................................. 423
11.14.1 Aryloxyanilide-based ligands .................. 424
11.14.2 [18F]FEDAA1106 ................................ 425
11.14.3 [18F]FEAC and [18F]FEDAC ...................... 426
11.14.4 PBR06 ......................................... 426
11.14.5 [18F]FEPPA .................................... 428
11.14.6 Pyrazolopyrimidine ligands .................... 429
11.15 Serotonin 5-HT1A Antagonists and Agonists ............ 431
11.16 Imaging the Cannabinoid 1 Receptor (CB1) ............. 435
11.17 Ion Channels ......................................... 440
11.18 Summary .............................................. 440
Acknowledgements ........................................... 441
References ................................................. 441
12 19F NMR: Clinical and Molecular Imaging Applications ....... 461
Vikram D. Kodibagkar, Rami R. Hallac, Dawen Zhao,
Jian-Xin Yu and Ralph P. Mason
12.1 Introduction .......................................... 461
12.2 Clinical Applications and Drug Metabolism ............. 468
12.3 Reporter Molecule Strategies .......................... 473
12.3.1 Physical interactions .......................... 474
12.3.2 Chemical association ........................... 480
12.3.3 Chemical interactions .......................... 484
12.4 Passive Reporter Molecules ............................ 490
12.5 Recent Innovations, Novelties and Future
Improvements .......................................... 492
12.5.1 Chemistry and molecular engineering ............ 492
12.5.2 Biology ........................................ 495
12.5.3 Physics ........................................ 496
12.5.4 Innovative new applications .................... 496
12.6 Context of 19F NMR in Biomedicine Today ......... 497
Acknowledgments ............................................ 500
References ................................................. 500
Index ......................................................... 525
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