Bioorganic and Medicinal Chemistry of Fluorine

by Bé; gué; , Jean-Pierre; Bonnet-Delpon, Daniele

• ISBN13: 9780470278307
• ISBN10: 0470278307
• Edition: 1st
• Format: Hardcover
• Copyright: 2008-05-27
• Publisher: Wiley-Interscience

Summary

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

Foreword	p. xiii
Preface to the English Edition	p. xvii
General Remarks on Structural, Physical, and Chemical Properties of Fluorinated Compounds	p. 1
Structural Effects	p. 2
Physical Properties	p. 3
Boiling Point	p. 3
Surface Tension and Activity	p. 5
Polarity-Solubility	p. 6
Lipophilicity	p. 7
Effects on Electronic Properties and Reactivity	p. 9
Effects of Fluorination on Bond Energies and Reactivity	p. 9
Effects of Fluorination on the Electronic Repartition of a Molecule	p. 10
Acidity, Basicity, and Hydrogen Bond	p. 12
Steric Effects	p. 15
Fluorination Effects on the Stability of Reaction Intermediates (Carbocations, Carbanions, and Radicals)	p. 16
References	p. 21
Overview on the Preparation of Fluorinated Compounds	p. 23
Preparation of Monofluorinated Compounds	p. 24
Nucleophilic Fluorination	p. 24
Electrophilic Fluorination	p. 26
Formation of Carbon-Carbon Bonds Starting from Monofluorinated Synthons	p. 27
Preparation of Difluorinated Compounds	p. 31
Nucleophilic Fluorination	p. 31
Electrophilic Fluorination	p. 31
Starting from Di- and Trifluoromethyl Compounds	p. 31
Preparation of Trifluoromethyl Compounds	p. 42
Fluorination	p. 42
Nucleophilic Trifluoromethylation	p. 42
Electrophilic Trifluoromethylation	p. 48
Radical Trifluoromethylation	p. 49
Metal-Catalyzed Trifluoromethylation	p. 49
Formation of Carbon-Carbon Bonds from Trifluoromethyl Compounds	p. 50
Synthesis of Perfluoroalkyl Compounds	p. 61
References	p. 62
Effects of Fluorine Substitution on Biological Properties	p. 72
Affinity for the Macromolecule Target	p. 73
Steric Effects	p. 73
Conformational Changes	p. 74
Dipolar Interactions and Electric Field	p. 75
Hydrogen Bonds and Other Weak Interactions	p. 75
pK[subscript a] of Amines	p. 79
Fluorous Interactions	p. 80
Absorption	p. 80
Lipophilicity	p. 80
pK[subscript a] and Solubility	p. 82
Metabolism	p. 84
Oxidative Metabolism	p. 84
Hydrolytic Metabolism	p. 87
Modification of Chemical Reactivity: Enzyme Inhibitors	p. 89
Analogue of Substrates as Inhibitors	p. 90
Inhibition by Stabilization or Destabilization of Intermediates of Biological Processes	p. 91
Irreversible Inhibition with Mechanism-Based Inhibitors (Suicide Substrates)	p. 93
References	p. 95
Fluorinated Analogues of Natural Products	p. 99
Fluorinated Products in Nature	p. 99
Steroids	p. 101
Corticosteroids	p. 101
Steroids with Trifluoromethyl Groups in Angular Position	p. 103
Fluorinated Analogues of Metabolites of Vitamin D[subscript 3]	p. 105
Other Fluorinated Steroids	p. 108
Terpenes	p. 108
Artemisinin	p. 108
Taxol	p. 110
Pigments and Vitamins	p. 111
Retinoids	p. 111
Carotenoids	p. 115
Vitamin D	p. 116
Vitamins E and K	p. 116
Porphyrins	p. 117
Lipids and Prostanoids	p. 119
Pheromones and Toxins	p. 125
Alkaloids	p. 129
Vinca Alkaloids	p. 129
Cinchona Alkaloids	p. 131
Camptothecin	p. 132
Other Fluorinated Alkaloids	p. 133
Macrolides	p. 133
Epothilone	p. 133
Erythromycin	p. 134
Amphotericin B	p. 135
Avermectin	p. 136
Anthracyclines	p. 138
References	p. 139
Fluorinated Derivatives of [alpha]-amino Acids and Proteins	p. 146
Fluorinated Aliphatic Amino Acids	p. 147
Alanines	p. 147
Valines, Leucines, and Isoleucines	p. 151
Prolines	p. 154
Aromatic Amino Acids: Phenylalanine, Tyrosine, Histidine, and Tryptophan	p. 156
Functional Fluorinated Amino Acids	p. 158
Serines and Threonines	p. 158
Aspartic Acids and Arginines	p. 159
Glutamic Acids and Glutamines	p. 161
Lysine, Ornithine, and Arginine	p. 161
Cysteines and Methionines	p. 163
[alpha]-Fluoroalkyl Amino Acids	p. 164
Mono- and Difluoromethyl Amino Acids	p. 165
[alpha]-Trifluoromethyl Amino Acids	p. 165
Incorporation of Fluorinated Amino Acids into Peptides and Proteins	p. 169
Polypeptides	p. 169
Proteins	p. 171
References	p. 173
Saccharidic Fluorinated Derivatives	p. 180
Glycosyl Fluorides	p. 181
Mono- and Difluorinated Analogues of Sugars	p. 181
Fluorinated Furanoses and Nucleosides	p. 181
Fluorinated Pyranoses	p. 190
Fluoromethyl Derivatives of Sugars	p. 197
Difluorovinyl Compounds	p. 197
Difluoromethylene-C-Glycosides	p. 197
C-Difluoromethyl Glycosides	p. 200
Trifluoromethylated Sugars	p. 202
Perfluoroalkylated Sugars	p. 209
Preparation of C-Perfluoroalkyl Sugars	p. 210
O- and S-Fluoroalkyl Glycosides	p. 211
Applications of Amphiphilic Fluoroalkyl Sugars	p. 214
References	p. 216
Inhibition of Enzymes by Fluorinated Compounds	p. 223
Substrate Analogues	p. 225
Fluorine Replaces a Hydrogen Involved in the Catalytic Cycle	p. 225
Fluorine Replaces a Hydroxyl	p. 227
Fluorinated Analogoues of Substrates in Which Fluorine is Not Directly Involved in the Inhibition	p. 230
Destabilization of Reaction Intermediates (or of Transition States) of Enzymatic Processes by Fluorinated Groups	p. 242
Prenyl Transfer	p. 242
Inhibition of Glycosidases and Glycosyltransferases	p. 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 Ketones	p. 246
Serine Enzymes	p. 246
Inhibition of Aspartyl Enzymes	p. 250
Inhibition of Metalloproteases	p. 254
Cysteine Protease and Thiol Enzymes	p. 254
Mechanism-Based Inhibitors	p. 256
Inhibition of Pyridoxal Phosphate Enzymes	p. 257
Thymidylate Synthase	p. 261
Inhibition of Monoamine Oxidases	p. 262
d-Ala-d-Ala Dipeptidase (VanX)	p. 264
Inhibition of Ribonucleotide Diphosphate Reductase	p. 264
Inhibition of S-Adenosylhomocysteine Hydrolase	p. 265
Inhibition of Cytidine-5'-diphosphate-d-Glucose 4,6-Dehydratase (CDP d-Glucose 4,6-Dehydratase)	p. 266
Other Irreversible Inhibitors	p. 267
Fluorinated Inhibitors Involving a Still Unknown Mechanism	p. 268
Inhibition of the Steroid C[subscript 17(20)]lyase	p. 268
Phosphatidylinositol Phospholipase C (PI-PLC)	p. 268
Inhibition of the Protein of Transfer of Cholesteryl Esters	p. 269
[beta]-Fluoropolyamines as Inhibitors of the Biosynthesis of Polyamines	p. 270
Inhibition of the Biosynthesis of Cholesterol	p. 272
References	p. 272
Fluorinated Drugs	p. 279
Antitumor and Antiviral Fluorinated Drugs	p. 280
Fluoronucleosides	p. 280
Other Antitumor and Antiviral Drugs	p. 284
Anti-infectious Drugs	p. 289
Fluorinated Antibiotic Drugs	p. 289
Antifungal Drugs	p. 297
Fluorinated Drugs for Parasitic Diseases	p. 299
Drugs for CNS Disorders	p. 300
Neuroleptics	p. 300
Drugs for Depressive Disorders	p. 302
Anxiolytics and Sedatives	p. 304
Other Drugs for CNS Disorders	p. 304
Drugs of Inflammatory and Immunity Disorders	p. 308
Fluorocorticosteroids	p. 308
H[subscript 1] Antagonist Antiallergics	p. 314
Drugs for Asthma and Respiratory Disorders	p. 314
Analgesic and Antiarthritic Drugs	p. 316
Drugs for Cardiovascular Disorders	p. 320
Cholesterol Lowering Drugs	p. 320
Drugs for Hypertension	p. 321
Drugs for Arrhythmias	p. 324
Antithrombosis and Anticoagulant Fluorinated Agents	p. 324
Drugs for Gastrointestinal Disorders	p. 325
Prevention and Treatment of Ulcer	p. 325
Antiemetic Agents	p. 326
Drugs for Bowel Disorders	p. 327
Drugs for Endocrine and Metabolic Disorders	p. 327
Drugs Acting on Steroid Hormone Receptors	p. 327
Drugs for Benign Prostatic Hypertrophy (BPH)	p. 329
Drugs for Other Urologic Disorders	p. 330
Drugs for Calcemia Disorders	p. 331
Drugs for Diabetes	p. 331
Drugs for Hepatic Disorders	p. 333
Miscellaneous	p. 334
Drugs for Ophthalmic Disorders	p. 334
Drugs for Genetic Disease	p. 334
Contrast and Diagnostic Agents	p. 334
Highly Fluorinated Compounds with Clinical Uses	p. 335
General Anesthetics	p. 335
Therapeutic Uses of Perfluorocarbons	p. 338
Fluorinated Functions and Motifs in Medicinal Chemistry	p. 339
Fluorinated Ethers	p. 339
Fluorinated Alcohols and Amines	p. 340
Fluorinated Ketones	p. 340
Fluoroalkyl Groups	p. 341
INN and Trademark Names	p. 342
References	p. 347
Index	p. 353
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