Bioorganic and Medicinal Chemistry of Fluorine

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  • Edition: 1st
  • Format: Hardcover
  • Copyright: 2008-05-27
  • Publisher: Wiley-Interscience

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Supplemental Materials

What is included with this book?


This book thoroughly overviews the role of fluorine in pharmaceutical science and development, including the classification of marketed and in-development fluorinated pharmaceuticals. The first part introduces the preparation of fluorinated compounds and their specific properties. The second part deals with fluorinated analogues of natural products, fluorinated amino acids and peptides, and derivatives of sugars. This section also includes a detailed chapter about the conception of enzyme inhibitors. In the final part, the main fluorinated pharmaceuticals, marketed or in development, are classified according to their therapeutic classes.

Author Biography

Jean-Pierre Begue, PHD, is Emeritus Director of Research at the Centre National de la recherche Scientifique (CNRS) in France. Danièle Bonnet-Delpon, PHD, is Director of Research at CNRS. The authors and their coworkers have developed the chemistry of fluorinated compounds, from organic synthesis to medicinal chemistry.

Table of Contents

Forewordp. xiii
Preface to the English Editionp. xvii
General Remarks on Structural, Physical, and Chemical Properties of Fluorinated Compoundsp. 1
Structural Effectsp. 2
Physical Propertiesp. 3
Boiling Pointp. 3
Surface Tension and Activityp. 5
Polarity-Solubilityp. 6
Lipophilicityp. 7
Effects on Electronic Properties and Reactivityp. 9
Effects of Fluorination on Bond Energies and Reactivityp. 9
Effects of Fluorination on the Electronic Repartition of a Moleculep. 10
Acidity, Basicity, and Hydrogen Bondp. 12
Steric Effectsp. 15
Fluorination Effects on the Stability of Reaction Intermediates (Carbocations, Carbanions, and Radicals)p. 16
Referencesp. 21
Overview on the Preparation of Fluorinated Compoundsp. 23
Preparation of Monofluorinated Compoundsp. 24
Nucleophilic Fluorinationp. 24
Electrophilic Fluorinationp. 26
Formation of Carbon-Carbon Bonds Starting from Monofluorinated Synthonsp. 27
Preparation of Difluorinated Compoundsp. 31
Nucleophilic Fluorinationp. 31
Electrophilic Fluorinationp. 31
Starting from Di- and Trifluoromethyl Compoundsp. 31
Preparation of Trifluoromethyl Compoundsp. 42
Fluorinationp. 42
Nucleophilic Trifluoromethylationp. 42
Electrophilic Trifluoromethylationp. 48
Radical Trifluoromethylationp. 49
Metal-Catalyzed Trifluoromethylationp. 49
Formation of Carbon-Carbon Bonds from Trifluoromethyl Compoundsp. 50
Synthesis of Perfluoroalkyl Compoundsp. 61
Referencesp. 62
Effects of Fluorine Substitution on Biological Propertiesp. 72
Affinity for the Macromolecule Targetp. 73
Steric Effectsp. 73
Conformational Changesp. 74
Dipolar Interactions and Electric Fieldp. 75
Hydrogen Bonds and Other Weak Interactionsp. 75
pK[subscript a] of Aminesp. 79
Fluorous Interactionsp. 80
Absorptionp. 80
Lipophilicityp. 80
pK[subscript a] and Solubilityp. 82
Metabolismp. 84
Oxidative Metabolismp. 84
Hydrolytic Metabolismp. 87
Modification of Chemical Reactivity: Enzyme Inhibitorsp. 89
Analogue of Substrates as Inhibitorsp. 90
Inhibition by Stabilization or Destabilization of Intermediates of Biological Processesp. 91
Irreversible Inhibition with Mechanism-Based Inhibitors (Suicide Substrates)p. 93
Referencesp. 95
Fluorinated Analogues of Natural Productsp. 99
Fluorinated Products in Naturep. 99
Steroidsp. 101
Corticosteroidsp. 101
Steroids with Trifluoromethyl Groups in Angular Positionp. 103
Fluorinated Analogues of Metabolites of Vitamin D[subscript 3]p. 105
Other Fluorinated Steroidsp. 108
Terpenesp. 108
Artemisininp. 108
Taxolp. 110
Pigments and Vitaminsp. 111
Retinoidsp. 111
Carotenoidsp. 115
Vitamin Dp. 116
Vitamins E and Kp. 116
Porphyrinsp. 117
Lipids and Prostanoidsp. 119
Pheromones and Toxinsp. 125
Alkaloidsp. 129
Vinca Alkaloidsp. 129
Cinchona Alkaloidsp. 131
Camptothecinp. 132
Other Fluorinated Alkaloidsp. 133
Macrolidesp. 133
Epothilonep. 133
Erythromycinp. 134
Amphotericin Bp. 135
Avermectinp. 136
Anthracyclinesp. 138
Referencesp. 139
Fluorinated Derivatives of [alpha]-amino Acids and Proteinsp. 146
Fluorinated Aliphatic Amino Acidsp. 147
Alaninesp. 147
Valines, Leucines, and Isoleucinesp. 151
Prolinesp. 154
Aromatic Amino Acids: Phenylalanine, Tyrosine, Histidine, and Tryptophanp. 156
Functional Fluorinated Amino Acidsp. 158
Serines and Threoninesp. 158
Aspartic Acids and Argininesp. 159
Glutamic Acids and Glutaminesp. 161
Lysine, Ornithine, and Argininep. 161
Cysteines and Methioninesp. 163
[alpha]-Fluoroalkyl Amino Acidsp. 164
Mono- and Difluoromethyl Amino Acidsp. 165
[alpha]-Trifluoromethyl Amino Acidsp. 165
Incorporation of Fluorinated Amino Acids into Peptides and Proteinsp. 169
Polypeptidesp. 169
Proteinsp. 171
Referencesp. 173
Saccharidic Fluorinated Derivativesp. 180
Glycosyl Fluoridesp. 181
Mono- and Difluorinated Analogues of Sugarsp. 181
Fluorinated Furanoses and Nucleosidesp. 181
Fluorinated Pyranosesp. 190
Fluoromethyl Derivatives of Sugarsp. 197
Difluorovinyl Compoundsp. 197
Difluoromethylene-C-Glycosidesp. 197
C-Difluoromethyl Glycosidesp. 200
Trifluoromethylated Sugarsp. 202
Perfluoroalkylated Sugarsp. 209
Preparation of C-Perfluoroalkyl Sugarsp. 210
O- and S-Fluoroalkyl Glycosidesp. 211
Applications of Amphiphilic Fluoroalkyl Sugarsp. 214
Referencesp. 216
Inhibition of Enzymes by Fluorinated Compoundsp. 223
Substrate Analoguesp. 225
Fluorine Replaces a Hydrogen Involved in the Catalytic Cyclep. 225
Fluorine Replaces a Hydroxylp. 227
Fluorinated Analogoues of Substrates in Which Fluorine is Not Directly Involved in the Inhibitionp. 230
Destabilization of Reaction Intermediates (or of Transition States) of Enzymatic Processes by Fluorinated Groupsp. 242
Prenyl Transferp. 242
Inhibition of Glycosidases and Glycosyltransferasesp. 242
Inhibition of UDP-GlcNAC Enolpyruvyltransferase (MurZ)p. 244
Enolpyruvate Shikimate Phosphate Synthase (EPSPS)p. 245
Inhibitors that are Analogues of the Transition State: Di- and Trifluoromethyl Ketonesp. 246
Serine Enzymesp. 246
Inhibition of Aspartyl Enzymesp. 250
Inhibition of Metalloproteasesp. 254
Cysteine Protease and Thiol Enzymesp. 254
Mechanism-Based Inhibitorsp. 256
Inhibition of Pyridoxal Phosphate Enzymesp. 257
Thymidylate Synthasep. 261
Inhibition of Monoamine Oxidasesp. 262
d-Ala-d-Ala Dipeptidase (VanX)p. 264
Inhibition of Ribonucleotide Diphosphate Reductasep. 264
Inhibition of S-Adenosylhomocysteine Hydrolasep. 265
Inhibition of Cytidine-5'-diphosphate-d-Glucose 4,6-Dehydratase (CDP d-Glucose 4,6-Dehydratase)p. 266
Other Irreversible Inhibitorsp. 267
Fluorinated Inhibitors Involving a Still Unknown Mechanismp. 268
Inhibition of the Steroid C[subscript 17(20)]lyasep. 268
Phosphatidylinositol Phospholipase C (PI-PLC)p. 268
Inhibition of the Protein of Transfer of Cholesteryl Estersp. 269
[beta]-Fluoropolyamines as Inhibitors of the Biosynthesis of Polyaminesp. 270
Inhibition of the Biosynthesis of Cholesterolp. 272
Referencesp. 272
Fluorinated Drugsp. 279
Antitumor and Antiviral Fluorinated Drugsp. 280
Fluoronucleosidesp. 280
Other Antitumor and Antiviral Drugsp. 284
Anti-infectious Drugsp. 289
Fluorinated Antibiotic Drugsp. 289
Antifungal Drugsp. 297
Fluorinated Drugs for Parasitic Diseasesp. 299
Drugs for CNS Disordersp. 300
Neurolepticsp. 300
Drugs for Depressive Disordersp. 302
Anxiolytics and Sedativesp. 304
Other Drugs for CNS Disordersp. 304
Drugs of Inflammatory and Immunity Disordersp. 308
Fluorocorticosteroidsp. 308
H[subscript 1] Antagonist Antiallergicsp. 314
Drugs for Asthma and Respiratory Disordersp. 314
Analgesic and Antiarthritic Drugsp. 316
Drugs for Cardiovascular Disordersp. 320
Cholesterol Lowering Drugsp. 320
Drugs for Hypertensionp. 321
Drugs for Arrhythmiasp. 324
Antithrombosis and Anticoagulant Fluorinated Agentsp. 324
Drugs for Gastrointestinal Disordersp. 325
Prevention and Treatment of Ulcerp. 325
Antiemetic Agentsp. 326
Drugs for Bowel Disordersp. 327
Drugs for Endocrine and Metabolic Disordersp. 327
Drugs Acting on Steroid Hormone Receptorsp. 327
Drugs for Benign Prostatic Hypertrophy (BPH)p. 329
Drugs for Other Urologic Disordersp. 330
Drugs for Calcemia Disordersp. 331
Drugs for Diabetesp. 331
Drugs for Hepatic Disordersp. 333
Miscellaneousp. 334
Drugs for Ophthalmic Disordersp. 334
Drugs for Genetic Diseasep. 334
Contrast and Diagnostic Agentsp. 334
Highly Fluorinated Compounds with Clinical Usesp. 335
General Anestheticsp. 335
Therapeutic Uses of Perfluorocarbonsp. 338
Fluorinated Functions and Motifs in Medicinal Chemistryp. 339
Fluorinated Ethersp. 339
Fluorinated Alcohols and Aminesp. 340
Fluorinated Ketonesp. 340
Fluoroalkyl Groupsp. 341
INN and Trademark Namesp. 342
Referencesp. 347
Indexp. 353
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