Ideas in Chemistry and Molecular Sciences: Where Chemistry Meets Life

Ideas in Chemistry and Molecular Sciences......Page 3
Contents......Page 7
Preface......Page 15
List of Contributors......Page 21
Part I Biochemical Studies......Page 25
1.1 Introduction......Page 27
1.2 Metal Ions in the Brain......Page 28
1.3 Brain Copper Homeostasis......Page 29
1.4 Brain Copper and Neurodegenerative Disorders......Page 32
1.5 The Role of Ubiquitin in Protein Degradation......Page 33
1.6 Failure of the Ubiquitin System in Neurodegenerative Disorders......Page 37
1.7.2 Spectroscopic Characterization of CuII Binding......Page 39
1.7.4 CuII-Induced Self-Oligomerization of Ub......Page 41
1.7.5 Cooperativity between CuII-Binding and Solvent Polarity......Page 42
1.7.6 Comparison with Other Metal Ions......Page 43
1.8.1 The Redox State of Cellular Copper......Page 45
1.8.2 Ubiquitin and Phospholipids......Page 46
1.9 Conclusions and Perspectives......Page 47
References......Page 48
2.1 Introduction......Page 55
2.2.1 Dinuclear Type-3 Copper Enzymes......Page 57
2.2.2 Particulate Methano Monooxygenase (pMMO)......Page 60
2.2.3 Mononuclear Monooxygenating Copper-based Enzymes......Page 62
2.2.4 Trinuclear Copper Models for Laccase......Page 64
2.3 Organometallic CuIII Species in Organic Transformations......Page 65
2.3.1.1 Conjugate Addition to α-Enones......Page 66
2.3.1.3 SN2 and SN2  Alkylations......Page 67
2.3.2 Aryl–Heteroatom Bond Formation in Cu-mediated Cross-coupling Processes......Page 68
2.3.3.1 Catalytic Systems......Page 69
2.3.3.2 Stoichiometric Systems......Page 71
2.5 Overview and Future Targets......Page 75
References......Page 76
3.1 Introducing Diversity by Posttranslational Modification......Page 83
3.2 Chemistry: A Route to Modi.ed Proteins......Page 84
3.4 Traditional Methods for Protein Modification......Page 85
3.4.1.3 Reductive Alkylation......Page 86
3.4.1.4 IME Reagents......Page 87
3.4.3 Cysteine......Page 88
3.4.3.1 Alkylation......Page 89
3.4.3.2 Disulfides......Page 90
3.4.3.3 Desulfurization at Cysteine......Page 93
3.5 Recent Innovations in Site-Selective Protein Modification......Page 94
3.5.2 Metal-Mediated Protein Modification......Page 95
3.5.2.1 Modification at Natural Residues......Page 96
3.5.2.3 Modification of Unnatural Residues......Page 98
3.5.2.4 Olefin Metathesis at S-Allyl Cysteine......Page 101
3.5.3.1 Oxime Ligation at Aldehydes and Ketones......Page 102
3.5.3.2 Azide and Alkyne Modification......Page 103
3.5.3.3 Selective Modification of Tetrazole-Containing Proteins......Page 104
3.6 Conclusion and Outlook......Page 105
References......Page 106
Part II Drug Delivery......Page 117
4.1 Introduction......Page 119
4.2 Transport Mechanism......Page 120
4.3.1 Adenosylcobalamin-Dependent Reactions......Page 121
4.4.2 b-, d-, e-Cobalamin Derivatives......Page 123
4.4.3 Modifications on the Ribose Moiety......Page 125
4.4.4.1 Cobalamin Alkylation......Page 126
4.4.4.2 Heterodinuclear Concept......Page 127
Acknowledgments......Page 132
References......Page 133
5.1.2.1 Liposomes......Page 141
5.1.2.4 Nanomaterials......Page 142
5.2.1.1 Preparation......Page 143
5.2.2.2 Preparation......Page 144
5.2.3.2 Fmoc Chemistry on Microspheres......Page 145
5.2.3.3 Dual Functionality of Microspheres......Page 146
5.2.3.4 Coupling Agents......Page 148
5.2.4.1 Microsphere-based Intracellular Sensing......Page 150
5.2.4.2 siRNA Delivery......Page 151
5.2.5.1 Ester Bonds......Page 154
5.2.5.2 Disulfide Bonds......Page 156
5.2.6 Bioconjugation......Page 157
5.2.6.1 Streptavidin–Biotin......Page 10
References......Page 159
Part III Research in Therapeutics......Page 165
6.1 Radiation Damage and the Role of Low-Energy Electrons......Page 167
6.1.1 How Chemical Bonds are Broken by Low-energy Electrons......Page 169
6.1.2 DEA Studies of Gas-Phase DNA Building Blocks: The Nucleobases......Page 171
6.2.1 Electron Attachment to d-Ribose......Page 172
6.2.2 Cross-Ring Cleavage of d-Ribose Proceeds with Selective Charge Retention......Page 174
6.2.3 The Nature of the Transient Negative d-Ribose Anions......Page 178
6.2.4 One Step Further: Tetraacetyl-d-Ribose......Page 179
6.2.6 Sugar–Phosphate Cleavage Induced by 0 eV Electrons: DEA to d-Ribose-5 -Phosphate......Page 183
6.3 Outlook and Future Prospects......Page 185
Acknowledgments......Page 186
References......Page 187
7.1 Introduction......Page 191
7.2 Isoprenoids and the Nonmevalonate Pathway......Page 193
7.2.3 Active Site of IspE......Page 194
7.3.1 Design......Page 198
7.3.1.1 Possible Ribose Analogues......Page 199
7.3.2 Optimization of the Ribose Analogue......Page 200
7.3.3 Importance of the Vector......Page 202
7.3.4.1 The ‘‘55% Rule’’......Page 203
7.3.4.2 Evaluation of Inhibitors Featuring Different Sulfone Substituents......Page 204
7.4.1 Design of Water-Soluble Inhibitors......Page 206
7.4.2 Enzyme Assays of Inhibitors Designed to be Water Soluble......Page 207
7.4.3 Structural Analysis......Page 208
7.5.1 Conclusions......Page 209
List of Abbreviations......Page 210
References......Page 211
8.1.2 Structure and Composition of Membranes......Page 215
8.1.3 Dynamic Molecular Organization of Membranes......Page 217
8.2.2.1 Contribution for Drug Development......Page 219
8.2.2.2 Understanding Therapeutic and Toxic Effect of Drugs......Page 221
8.2.2.4 Controlling Enzymatic Inhibition......Page 222
8.3.1 Membrane Model Systems......Page 223
8.3.2 Experimental Techniques......Page 224
8.4 Drug–Membrane Interactions Applied to the Study of Nonsteroidal Anti-inflammatory Drugs (NSAIDs)......Page 225
8.4.1 Drug Fundamental Physical–Chemical Studies......Page 226
8.4.2 Membrane Structural and Dynamic Studies......Page 227
8.4.3 Results......Page 229
Acknowledgments......Page 230
References......Page 231
9.1 Introduction......Page 239
9.2 High-Throughput Screening of Chemical Libraries......Page 240
9.3 High-Throughput Screening of Biosynthesized Libraries......Page 244
9.3.1 Cyclic Peptide Inhibitors of AICAR Transformylase Activity......Page 246
9.3.2 Cyclic Peptide Inhibitors of HIV Budding......Page 248
9.4.1 Small Molecule Inhibitors of Tumor Hypoxia Response Network......Page 250
9.4.2 Targeting Protein–Protein Interactions in Asthma......Page 252
9.4.3 Targeting the Protein Interaction Networks of Influenza Virus......Page 254
References......Page 256
10.1.2 Carbohydrate-Based Drugs......Page 263
10.1.3 Carbohydrate Synthesis......Page 264
10.1.3.1 Chemical Synthesis......Page 265
10.1.3.2 Enzymatic Synthesis......Page 267
10.1.3.3 Glycoprotein Synthesis......Page 268
10.1.4.1 Mass Spectrometry......Page 269
10.1.4.3 Cell, Tissue, and Metabolic Labeling......Page 270
10.2.1 Microwave-Assisted Glycosylation for the Synthesis of Glycopeptides......Page 271
10.2.2 Highly Efficient Chemoenzymatic Synthesis of Novel Branched Thiooligosaccharides by Substrate Direction with Glucansucrases......Page 275
10.2.3 Identification of New Acceptor Specificities of Glycosyltransferase R with the Aid of Substrate Microarrays......Page 281
Acknowledgments......Page 283
References......Page 284
Part IV Enzyme Chemistry......Page 289
11.1 General Introduction: O2 Activation and Model Systems......Page 291
11.2 Copper Proteins Involved in O2 Activation......Page 292
11.2.1 Hemocyanin......Page 293
11.2.2 Tyrosinase......Page 294
11.3.1 Copper–Dioxygen Adducts......Page 296
11.3.2 Ligand Architecture: In.uence on Reactivity toward O2......Page 299
11.3.3.1 Intramolecular Aromatic Hydroxylation......Page 302
11.3.3.2 Intermolecular ortho-Hydroxylation of Phenolic Compounds......Page 304
11.4 Concluding Remarks......Page 309
References......Page 310
Part V Structure–Property Relationship and Biosensing......Page 315
12.1.1 Molecular Chirality in Living Systems......Page 317
12.1.2 Protein Secondary Structures......Page 319
12.1.3 Protein Secondary Structure Assignment......Page 320
12.2 Computational Techniques for Studying Protein Dynamics......Page 321
12.3.1 The Chirality Index......Page 322
12.3.2 Using Chirality to Understand Protein Structure......Page 324
12.3.3 Chirality Index as a Tool for Monitoring Protein Dynamics......Page 326
12.3.4 Chirality and Circular Dichroism......Page 329
12.4 Perspectives......Page 332
Acknowledgments......Page 333
References......Page 334
13.1 Introduction......Page 337
13.2 E-DNA Signaling Mechanism......Page 339
13.3 E-DNA Sensor for DNA Binding Proteins Detection......Page 343
13.4 Conclusions and Future Perspectives......Page 345
References......Page 348
Index......Page 351