Iminosugars (eBook)

From Synthesis to Therapeutic Applications

Philippe Compain, Olivier R. Martin (Herausgeber)

eBook Download: PDF

2007
John Wiley & Sons (Verlag)
978-0-470-51744-4 (ISBN)

Infos

Iminosugars form undoubtedly the most attractive of carbohydrate mimics reported so far. In these structures, the substitution of the endocyclic oxygen of sugars by a basic nitrogen atom leads to remarkable biological properties and raises many challenges in organic synthesis. Since the discovery of their biological activity as glycosidase inhibitors in the 1970's, these polyvalent molecules have progressively made their way from the laboratory to the clinic.

The impressive series of discoveries in the field over the past ten years indicates clearly that it is 'a boom time' for iminosugar chemistry and biology. The scope of their profile as inhibitors has been extended to a number of enzymes such as phosphorylases, glycosyltransferases or metalloproteinases, and iminosugars now constitute lead compounds for the development of new therapeutic agents for a wide range of diseases including diabetes, viral infections, lysosomal storage disorders and tumor metastasis.

Latest developments, from iminosugar synthesis to their use in clinical studies, are presented in this book, which contains contributions from over fifteen of the major chemists, biochemists and drug developers in this rapidly expanding field. An extensive table correlating the structures of more than 600 iminosugars of therapeutic interest with their biological activities is also included in the book and should prove particularly useful to aid with the design and the discovery of novel bioactive substances.

Iminosugars: From Synthesis to Therapeutic Application provides a unique resource for academic and industrial researchers working in the field of iminosugars and glycomimetics of biological and/or therapeutic interest: organic chemists, medicinal chemists, carbohydrate chemists and medical scientists.

Philippe Compain and Olivier R. Martin

CNRS, University of Orléans, France

Inhalt

Iminosugars 3
Contents 7
Foreword 11
Preface 13
List of contributors 15
1 Iminosugars: past, present and future 17
2 Naturally occurring iminosugars and related alkaloids: structure, activity and applications 23
2.1 Introduction 23
2.2 -Glucosidase inhibitors 24
2.3 -Glucosidase inhibitors 29
2.4 - and -Galactosidase inhibitors 33
2.5 -Mannosidase inhibitors 34
2.6 Concluding remarks and future prospects 36
References 37
3 General strategies for the synthesis of iminosugars and new approaches towards iminosugar libraries 41
3.1 Introduction 41
3.2 Monocyclic compounds 42
3.3 1-N-Iminosugars 49
3.4 Bicyclic compounds 51
3.5 Other bicyclic compounds 58
3.6 Iminosugar conjugates 62
3.7 Conclusions 73
References 74
4 Iminosugar C-glycosides: synthesis and biological activity 79
4.1 Introduction 79
4.2 Synthesis of iminosugar C-glycosides 80
4.3 Biological activity of iminosugar C-glycosides 92
4.4 Conclusion 99
References 100
5 Imino-C-disaccharides and analogues: synthesis and biological activity 103
5.1 Introduction 103
5.2 Synthesis of imino-C-disaccharides 106
5.3 Conformations of imino-C-disaccharides 125
5.4 Glycosidase inhibitory activities of imino-C-disaccharides 130
5.5 Efficient combinatorial method for the discovery of glycosidase inhibitors 132
5.6 Antitumour activity of new -mannosidase inhibitors 138
5.7 Conclusion 138
References 139
6 Isofagomine, noeuromycin and other 1-azasugars, iminosugar-related glycosidase inhibitors 147
6.1 Introduction 147
6.2 1-Azasugars that are piperidines (isofagomine, noeuromycin, etc.) 148
6.3 1-Azasugars that are hydrazines 157
6.4 1-Azasugars that are oxazines 159
6.5 1-Azasugars that are piperidones 159
6.6 Sulphur-containing analogues of 1-azasugars 160
6.7 Slow inhibition and thermodynamics of binding 162
6.8 Are 1-azasugars (and iminosugars) transition state analogues? 163
References 165
7 Iminosugar-based glycosyltransferase inhibitors 169
7.1 Biological role and structural features of glycosyltransferases 169
7.2 Development of inhibitors of glycosyltransferases 174
7.3 Conclusion 188
References 189
8 Transition state analogue inhibitors of N-ribosyltransferases 193
8.1 Introduction 193
8.2 Nucleoside hydrolases 195
8.3 Purine nucleoside phosphorylases (PNPs) 200
8.4 5’-Methylthioadenosine (MTA) nucleosidases and phosphorylases 210
8.5 Ricin A-chain 217
References 220
9 Iminosugars as antiviral agents 225
9.1 Introduction 225
9.2 The relationship between glucosidase inhibition and antiviral action 227
9.3 Fate of viral glycoproteins in glucosidase-inhibited cells 228
9.4 Specificity of glucosidase inhibition 233
9.5 N-Alkyl DNJs inhibit virus growth by non-glucosidase inhibitory mechanisms – other potential activities of these compounds 235
9.6 New directions for improving glucosidase inhibitors as antiviral agents 236
References 237
10 Iminosugars as active-site-specific chaperones for the treatment of lysosomal storage disorders 241
10.1 Introduction 241
10.2 Degradation of glycosphingolipids 242
10.3 Lysosomal enzyme biosynthesis and ER-associated degradation (ERAD) 244
10.4 Active-site-specific chaperones and iminosugars 246
10.5 Basic requirements for effective ASSCs 247
10.6 Identification of ASSCs 250
10.7 Examples of ASSC therapy for lysosomal storage disorders 252
10.8 Future perspectives 258
References 259
11 Iminosugar inhibitors for substrate reduction therapy for the lysosomal glycosphingolipidoses 265
11.1 Glycolipid lysosomal storage diseases 265
11.2 Options for glycosphingolipidosis therapy 266
11.3 Iminosugars for substrate reduction therapy 268
11.4 Iminosugars as inhibitors of glycolipid biosynthesis 271
11.5 SRT combination therapy 279
11.6 Prospects for iminosugars as therapeutics 280
References 281
12 Iminosugar-based antitumoural agents 285
12.1 Introduction 285
12.2 Hexose-mimetic iminosugars 287
12.3 Hexuronic acid-mimetic iminosugars 293
12.4 Concluding remarks 301
References 304
13 Medicinal use of iminosugars 311
13.1 Introduction 311
13.2 Recent pharmaceutical developments 313
13.3 Clinical application of iminosugars as medicines 315
13.4 Conclusions 336
References 339
14 Tables of iminosugars, their biological activities and their potential as therapeutic agents 343
14.1 Introduction 343
14.2 Type 2 diabetes 344
14.3 Antiviral activities 360
14.4 Antibacterial activities 377
14.5 Antiprotozoal activities 383
14.6 Antiparasitarial activities 393
14.7 Cancer 393
14.8 Lysosomal diseases 432
14.9 Immunomodulating agents 447
14.10 Antipsoriatic agents 454
14.11 Antifungal agents 455
14.12 Cystic fibrosis 457
14.13 Infertility inducing agents 457
14.14 Chondroprotective agents 458
14.15 Inflammatory diseases 460
14.16 Appetite suppressing agents 461
14.17 Nematicidal activity 461
14.18 Insecticidal activity 462
References 462
Index 473
Plates 484

Rezensionen

"This is book is a must buy for anyone interested in carbohydrate
and/or medicinal chemistry." (Journal of the American Chemical
Society, May 14, 2008)

"Given the recent resurgence of interest in this class of
compounds, the text is a welcome review of the area." (Journal
of Medicinal Chemistry, 2008)

Produkt-Details

• Erscheint lt. Verlag: 22.10.2007
• Sprache: englisch
• Themenwelt: Medizin / Pharmazie ► Gesundheitsfachberufe
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Pharmakologie / Pharmakotherapie
• Themenwelt: Naturwissenschaften ► Biologie ► Biochemie
• Themenwelt: Naturwissenschaften ► Biologie ► Mikrobiologie / Immunologie
• Themenwelt: Technik
• Schlagworte: Activity • atom leads • attractive • BASIC • biological • Biotechnologie • Biotechnologie i. d. Biowissenschaften • Biotechnology • Biowissenschaften • Carbohydrate • Chemie • Chemistry • Class • Clinic • Discovery • Drug Discovery & Development • endocyclic oxygen • Glycosidase • iminosugars • Inhibitors • Life Sciences • mimics • nitrogen • Organic Chemistry • Organische Chemie • Pharmaceutical & Medicinal Chemistry • Pharmazeutische u. Medizinische Chemie • polyvalent • Properties • reported • Structures • Substitution • Sugars • Wirkstoffforschung u. -entwicklung
• ISBN-10: 0-470-51744-1 / 0470517441
• ISBN-13: 978-0-470-51744-4 / 9780470517444