Chemistry of Nucleic Acids / Edition 1

by Harri Lönnberg

Overview

Life in all its forms is based on nucleic acids which store and transfer genetic information. The book addresses the main aspects of synthesis, hydrolytic stability, solution equilibria of nucleosides and nucleotides as well as base modifications of nucleic acids. The author further describes their structural analogues used as therapeutic drugs, such as antivirals and anticancer agents, and prodrug strategies of nucleotides.

Product Details

ISBN-13:	9783110609271
Publisher:	De Gruyter
Publication date:	08/10/2020
Series:	De Gruyter Textbook
Pages:	364
Product dimensions:	6.69(w) x 9.45(h) x (d)
Age Range:	18 Years

About the Author

Harri Lönnberg, University of Turku, Finland.

Table of Contents

Preface V

1 Nucleosides: structure, nomenclature and solution equilibria 1

1.1 Nomenclature 1

1.2 Cyclonucleosides 2

1.3 C-Nucleosides and carbocyclic nucleosides 4

1.4 Minor nucleosides in nucleic acids 5

1.5 Tautomeric and protolytic equilibria 6

1.6 Metal ion complexes of nucleosides 10

1.7 Conformation of nucleosides 13

1.7.1 Puckering of the sugar ring 14

1.7.2 Rotation around the C1'-N bond 18

1.7.3 Rotation around the C4'-C5' bond 20

1.8 Optical properties of nucleosides 20

1.8.1 UV absorption 20

1.8.2 Circular dichroism 20

1.8.3 Fluorescent nucleosides 21

1.9 Base stacking 22

Further reading 24

References 25

2 Nucleosides: synthesis, reactions and use in chemotherapy 31

2.1 Synthesis of N-glycosidic bond 31

2.2 Transformation reactions 34

2.3 Synthesis of cyclonucleosides 40

2.4 Synthesis of C-nucleosides 42

2.5 Synthesis of carbocyclic nucleosides 45

2.6 Hydrolysis of N-glycosidic bond 45

2.6.1 Acid-catalyzed hydrolysis 45

2.6.2 Base-catalyzed and nucleophilic reactions 49

2.6.3 Effect of metal ions on hydrolysis of nucleosides 51

2.7 Nucleosides as drugs 51

2.7.1 Antiviral nucleosides 51

2.7.2 Anticancer drugs 54

2.7.3 Nucleoside analogs as antibiotics 55

Further reading 56

References 57

3 Nucleotides 63

3.1 Nomenclature 63

3.2 Protolytic equilibria and metal ion complexing 66

3.3 Dinucleoside(3',5')monopbosphates: interplay between conformation and intramolecular stacking 69

3.4 Synthesis of nucleotides and their congeners 70

3.5 Hydrolysis of nucleotides 76

3.6 Nucleotides as drugs 82

Further reading 87

References 87

4 Oligonucleotides: synthesis 93

4.1 Synthesis of oligodeoxyribonucleotides 93

4.1.1 Preparation of building blocks 93

4.1.2 Coupling chemistry 96

4.1.3 Global protecting group strategy 102

4.1.4 Solid supports and linkers 105

4.1.5 Phosphate and base moiety protecting groups 108

4.1.6 5'-O-Protecting groups 110

4.1.7 Trimeric building blocks 110

4.1.8 Deprotection and purification 111

4.2 Synthesis of oligoribonudeotides 114

4.3 Enzymatic synthesis of oligonucleotides 119

4.3.1 Synthesis of oligodeoxyribonucleotides 119

4.3.2 Synthesis of oligoribonudeotides 121

4.4 Synthesis of stereoregular phosphorothioate and borane phosphonate oligonucleotides 121

4.4.1 Stereoregular phosphorothioates 121

4.4.2 Borane phosphonate oligonucleotides 124

4.5 Solution phase synthesis of oligonucleotides 126

4.5.1 Convergent synthesis 126

4.5.2 Synthesis with solid-supported reagents 126

4.5.3 Synthesis on a soluble support 129

Further reading 135

References 136

5 Oligonucleotides: reactions of phosphodiester linkages 145

5.1 Cleavage and isomerization of oligoribonudeotides 145

5.1.1 Cleavage by Brönsted acids and bases 145

5.1.2 Cleavage by multifunctional entities 152

5.1.3 Reactions of internucleosidic phosphotriester linkages 154

5.1.4 The effect of secondary structure and base sequence on the cleavage of oligoribonucleotides 154

5.1.5 Reactions of oligoribonudeotide phosphorothioates and phosphorothiolates 155

5.2 Metal-ion-promoted cleavage of oligoribonudeotides 158

5.2.1 Mechanism of the cleavage by metal ion complexes 158

5.2.2 Nucleobase and sequence-selective cleavage: artificial ribonudeases 161

5.2.3 Nanoparticle supported metal ion complexes as cleaving agents 164

5.3 Cleavage of oligodeoxyribonudeotides 165

5.3.1 Cleavage by Brönsted acids and bases 165

5.3.2 Metal-ion-promoted cleavage 166

Further reading 167

References 168

6 Oligonucleotide conjugates 175

6.1 Introduction 175

6.2 Reactions used for conjugation 175

6.3 Solid-supported synthesis of 5'-O-conjugates 177

6.4 5'-O-Phosphorylation 179

6.5 Solid-supported synthesis of 3'-O-conjugates 181

6.6 Solid-supported synthesis of intrachain conjugates 183

6.7 Glycocluster conjugates 185

6.8 Peptide conjugates 186

Further reading 189

References 189

7 Nucleic acids 195

7.1 Structure of DNA 195

7.2 Parallel DNA 202

7.3 Triple helical DNA 203

7.4 DNA quadruplexes 205

7.5 Structure of RNA 206

7.6 Stability of nucleic acids secondary structure 208

7.7 Groove binders and intercalators 213

7.7.1 Groove binding 213

7.7.2 Intercalation 213

7.8 Metal-ion-mediated base pairs 215

7.9 Hybridization diagnostics 218

7.10 DNA sequencing 223

7.11 DNA base modifications 226

7.11.1 Depurination and deamination as a source of mutagenesis 226

7.11.2 Oxidation of nucleobases 227

7.11.3 Base modifications by nucleophilic substitution 230

7.11.4 Base modifications by electrophilic substitution 230

Further reading 232

References 233

8 Catalytic nucleic acids 241

8.1 Introduction 241

8.2 Small ribozymes 241

8.2.1 Hammerhead ribozyme 242

8.2.2 Hairpin ribozyme 243

8.2.3 VS ribozyme 245

8.2.4 HDV ribozyme 246

8.2.5 Glucosamine 6-phosphate riboswitch 247

8.2.6 Twister, pistol, TS and hatchet ribozymes 248

8.3 Large ribozymes 249

8.3.1 Introduction 249

8.3.2 Ribonuclease P 249

8.3.3 Group I introns 251

8.3.4 Group II introns 253

8.3.5 Spliceosome 253

8.3.6 Ribosome 255

8.4 Deoxyribozymes 256

Further reading 260

References 261

9 Nucleic acids as drugs and drug targets 1: antisense, splice-switching, triplex-forming and immune-stimulatory oligonucleotides 267

9.1 Introduction 267

9.2 Antisense oligonucleotides 268

9.2.1 Structural modifications 268

9.2.2 Antisense oligonucleotide drugs 272

9.3 Splice-switching oligonucleotides 274

9.3.1 Mechanism of action 274

9.3.2 Splice-switching oligonucleotides as drugs 276

9.4 Triplex-forming oligonucleotides 277

9.5 Immune-stimulatory oligonucleotides 280

Further reading 282

References 283

10 Nucleic acids as drugs and drug targets 2: RNA interference, 2',5'-oligoadenylates and riboswitches 291

10.1 Small interfering RNAs 291

10.2 MicroRNAs 295

10.3 2',5'-Oligoadenylates (2-5A-ORNs) 296

10.4 Riboswitches 299

Further reading 302

References 303

11 Nucleic acids as drugs and drug targets 3: target recognition and delivery 309

11.1 Aptamers 309

11.2 Transfection of unconjugated therapeutic ONs 313

11.3 Receptor-mediated delivery of ON conjugates 316

11.4 Prodrugs of therapeutic ONs 323

11.5 Genome targeting by CRISPR/Cas9 330

Further reading 332

References 332

Abbreviations 343

Index 347