Boron‐Based Compounds

Boron‐Based Compounds
 
Author:
Evamarie Hey‐Hawkins & Clara Viñas Teixidor
Publisher: John Wiley & Sons
ISBN No: 978-1119-2-7558-9
Release at: 2018
Pages: 492
Edition:
First Edition
File Size: 10 MB
File Type: pdf
Language: English



Description of Boron‐Based Compounds


2Today, medicinal chemistry is still clearly dominated by organic chemistry, and most commercial drugs are purely organic molecules, which, besides carbon and hydrogen, can incorporate nitrogen, oxygen, sulfur, phosphorus, and halogens, all of which are to the right of carbon in the periodic table, whereas boron is located to the left. Boron and carbon are elements that have the ability to build molecules of unlimited size by covalent self‐bonding. However, commercial boron‐based drugs are still rare.

Bortezomib, tavaborole (AN2690), crisaborole (AN2728), epetraborole (AN3365), SCYX‐7158 (AN5568), 4‐(dihydroxyboryl)phenylalanine (BPA), and sodium mercaptoundecahydro‐closo‐dodecaborate (BSH) are used as drugs, the last two compounds in boron neutron capture therapy (BNCT). All of these boron‐containing drugs are derivatives of boronic acids except BSH, which contains an anionic boron cluster. While the pharmacological uses of boron compounds have been known for several decades, recent progress is closely related to the discovery of further boron‐containing compounds as prospective drugs. 

While first developments of the medicinal chemistry of boron were stipulated by applications in BNCT of cancers, knowledge accumulated during the past decades on the chemistry and biology of bioorganic and bioinorganic boron compounds laid the foundation for the emergence of a new area of study and application of boron compounds as skeletal structures and hydrophobic pharmacophores for biologically active molecules. These and other recent findings clearly show that there is still a great, unexplored potential in medicinal applications of boron‐containing compounds. Boron and carbon are elements that have the ability to build molecules of unlimited size by covalent self‐bonding. However, commercial boron‐based drugs are still rare.

Bortezomib, tavaborole (AN2690), crisaborole (AN2728), epetraborole (AN3365), SCYX‐7158 (AN5568), 4‐(dihydroxyboryl)phenylalanine (BPA), and sodium mercaptoundecahydro‐closo‐dodecaborate (BSH) are used as drugs, the last two compounds in boron neutron capture therapy (BNCT). All of these boron‐containing drugs are derivatives of boronic acids except BSH, which contains an anionic boron cluster. While the pharmacological uses of boron compounds have been known for several decades, recent progress is closely related to the discovery of further boron‐containing compounds as prospective drugs. 

While first developments of the medicinal chemistry of boron were stipulated by applications in BNCT of cancers, knowledge accumulated during the past decades on the chemistry and biology of bioorganic and bioinorganic boron compounds laid the foundation for the emergence of a new area of study and application of boron compounds as skeletal structures and hydrophobic pharmacophores for biologically active molecules. These and other recent findings clearly show that there is still a great, unexplored potential in medicinal applications of boron‐containing compounds.

Content of Boron‐Based Compounds



Part 1 Design of New Boron‐based Drugs 1

1.1 Carboranes as Hydrophobic Pharmacophores: Applications for Design
of Nuclear Receptor Ligands 3
Yasuyuki Endo
1.1.1 Roles of Hydrophobic Pharmacophores in Medicinal Drug Design 3
1.1.2 Carboranes as Hydrophobic Structures for Medicinal Drug Design 4
1.1.3 Estrogen Receptor Ligands Bearing a Carborane Cage 5
1.1.3.1 Estrogen Agonists 5
1.1.3.2 Estrogen Antagonists and Selective Estrogen‐Receptor Modulators
(SERMs) 7
1.1.4 Androgen Receptor Ligands Bearing a Carborane Cage 7
1.1.4.1 Androgen Antagonists 7
1.1.4.2 Improvement of Carborane‐Containing Androgen Antagonists
as Candidates for Anti–Prostate Cancer Therapy 9
1.1.5 Retinoic Acid Receptor (RAR) and Retinoic Acid X Receptor (RXR)
Ligands Bearing a Carborane Cage 11
1.1.5.1 RAR Agonists and Antagonists 11
1.1.5.2 RXR Agonists and Antagonists 12
1.1.6 Vitamin D Receptor Ligands Bearing a Carborane Cage 12
1.1.7 Determination of the Hydrophobicity Constant π for Carboranes
and Quantitative Structure–Activity Relationships in ER Ligands 13
1.1.7.1 Determination of the Hydrophobicity Constant π for Carboranes 13
1.1.7.2 Quantitative Structure–Activity Relationships of Carboranylphenols
with Estrogenic Activity 14
1.1.8 Conclusion and Prospects 16
References 16

1.2 Boron Cluster Modifications with Antiviral, Anticancer, and Modulation
of Purinergic Receptors’ Activities Based on Nucleoside Structures 20
Anna Adamska‐Bartłomiejczyk, Katarzyna Bednarska, Magdalena Białek‐Pietras,
Zofia M. Kiliańska, Adam Mieczkowski, Agnieszka B. Olejniczak, Edyta Paradowska,
Mirosława Studzińska, Zofia Sułowska, Jolanta D. Żołnierczyk, and
Zbigniew J. Lesnikowski
1.2.1 Introduction 20
1.2.2 Boron Clusters as Tools in Medicinal Chemistry 21
1.2.3 Modification of Selected Antiviral Drugs with Lipophilic Boron Cluster
Modulators and New Antiviral Nucleosides Bearing Boron Clusters 23
1.2.4 In Vitro Antileukemic Activity of Adenosine Derivatives Bearing Boron
Cluster Modification 26
1.2.5 Adenosine–Boron Cluster Conjugates as Prospective Modulators
of Purinergic Receptor Activity 28
1.2.6 Summary 30
Acknowledgments 30
References 30

1.3 Design of Carborane‐Based Hypoxia‐Inducible Factor Inhibitors 35
Guangzhe Li, Hyun Seung Ban, and Hiroyuki Nakamura
1.3.1 Introduction 35
1.3.2 Boron‐Containing Phenoxyacetanilides 36
1.3.2.1 Synthesis of Boron‐Containing Phenoxyacetanilides 36
1.3.2.2 Biological Activity of Boron‐Containing Phenoxyacetanilides 38
1.3.3 Target Identification of GN26361 39
1.3.3.1 Design of GN26361 Chemical Probes 39
1.3.3.2 Synthesis of GN26361 Chemical Probes 39
1.3.3.3 Target Identification of GN26361 40
1.3.4 Carborane‐Containing HSP60 Inhibitors 40
1.3.4.1 Design of Ortho‐ and Meta‐Carborane Analogs of GN26361 40
1.3.4.2 Synthesis of GN26361 Analogs 41
1.3.4.3 HIF Inhibitory Activity of Carborane Analogs of GN26361 46
1.3.4.4 HSP60 Inhibitory Activity of Carborane Analogs of GN26361 47
1.3.5 Carborane‐Containing Manassantin Mimics 49
1.3.5.1 Synthesis of Carborane‐Containing Manassantin Mimics 49
1.3.5.2 Biological Activity of Carborane‐Containing Manassantin Mimics 51
1.3.6 Carborane‐Containing Combretastatin A‐4 Mimics 52
1.3.6.1 Design of Ortho‐Carborane Analogs of Combretastatin A‐4 52
1.3.6.2 Synthesis of Carborane Analogs of Combretastatin A4 53
1.3.6.3 HIF Inhibitory Activity of Carborane Analogs of Combretastatin A4 54
1.3.7 Conclusion 56
References 57

1.4 Half‐ and Mixed‐Sandwich Transition Metal Dicarbollides and
nido‐Carboranes(–1) for Medicinal Applications 60
Benedikt Schwarze, Marta Gozzi, and Evamarie Hey‐Hawkins
1.4.1 Introduction 60
1.4.2 Synthetic Approaches to nido‐Carborane [C2B9H12]–Derivatives 66
1.4.3 Biologically Active Organometallic nido‐Carborane Complexes and Organic
nido‐Carborane Derivatives 72
1.4.3.1 Biologically Active Half‐ and Mixed‐Sandwich Metallacarborane
Complexes 72
1.4.3.1.1 Half‐Sandwich Complexes of Rhenium(I) and Technetium(I)‐99m as
Radio‐Imaging and Radiotherapeutic Agents 72
1.4.3.1.2 nido‐Carborane(–1) Anions as Pharmacophores for Metal‐Based
Drugs 79
1.4.3.2 Biologically Active Compounds Containing a nido‐Carborane(–1) Core 83
1.4.3.2.1 Radiotherapy and Radio‐Imaging 83
1.4.3.2.2 Pharmacophores 91
1.4.4 Conclusions and Future Challenges 95
Appendix: Abbreviations 96
Acknowledgments 97
References 98

1.5 Ionic Boron Clusters as Superchaotropic Anions: Implications for Drug
Design 109
Khaleel I. Assaf, Joanna Wilińska, and Detlef Gabel
1.5.1 Introduction 109
1.5.2 Water Structure and Coordinating Properties 110
1.5.3 Host–Guest Chemistry of Boron Clusters 112
1.5.4 Ionic Boron Clusters in Protein Interactions 116
1.5.4.1 Interactions of Boron Clusters with Lipid Bilayers 118
1.5.5 Implications for Drug Design 120
1.5.5.1 Binding to Proteins 120
1.5.5.2 Penetration through Membranes 120
1.5.5.3 Computational Methods 120
1.5.6 Conclusions 121
References 121

1.6 Quantum Mechanical and Molecular Mechanical Calculations on Substituted
Boron Clusters and Their Interactions with Proteins 126
Jindřich Fanfrlík, Adam Pecina, Jan Řezáč, Pavel Hobza, and Martin Lepšík
1.6.1 Introduction 126
1.6.2 Plethora of Noncovalent Interactions of Boron Clusters 127
1.6.3 Computational Methods 129
1.6.3.1 Advanced Methods for Models Systems in Vacuum 129
1.6.3.2 Approximate Methods for Extended Systems Including the
Environment 129
1.6.3.2.1 SQM Methods 130
1.6.3.2.2 MM Methods 130
1.6.3.2.3 Solvation and Ion Models 131
1.6.3.2.4 pKa Calculations 131
1.6.3.2.5 Docking and Scoring 131
1.6.4 Boron Cluster Interactions with Proteins 131
1.6.5 Conclusions 135
References 135

Part 2 Boron Compounds in Drug Delivery and Imaging 139

2.1 Closomers: An Icosahedral Platform for Drug Delivery 141
Satish S. Jalisatgi
2.1.1 Introduction 141
2.1.2 Synthesis and Chemistry of [closo‐B12H12] 2− 143
2.1.3 Hydroxylation of [closo‐B12H12]2− 143
2.1.4 Ether and Ester Closomers 144
2.1.5 Carbonate and Carbamate Closomers 145
2.1.6 Azido Closomers 146
2.1.7 Methods of Vertex Differentiation for Multifunctional Closomers 148
2.1.7.1 Vertex Differentiation by Selective Derivatization of
[closo‐B12(OH)12]2−, 1 148
2.1.7.2 Vertex Differentiation by Functionalizing the B12 2− Core Prior
to the Cage Hydroxylation 151
2.1.8 Conclusions 155
References 155

2.2 Cobaltabisdicarbollide‐based Synthetic Vesicles: From Biological
Interaction to in vivo Imaging 159
Clara Viñas Teixidor, Francesc Teixidor, and Adrian J. Harwood
2.2.1 Introduction 159
2.2.2 A Synthetic Membrane System 160
2.2.3 Crossing Lipid Bilayers 161
2.2.4 Visualization of COSAN within Cells 162
2.2.5 COSAN Interactions with Living Cells 163
2.2.6 Enhancing Cellular Effects of COSAN 165
2.2.7 Tracking the in vivo Distribution of I‐COSAN 167
2.2.8 Discussion and Potential Applications 168
2.2.9 Summary 170
Appendix: Abbreviations 170
Acknowledgments 171
References 171

2.3 Boronic Acid–Based Sensors for Determination of Sugars 174
Igor B. Sivaev and Vladimir I. Bregadze
2.3.1 Introduction 174
2.3.2 Interactions of Boronic Acids with Carbohydrates 175
2.3.3 Fluorescence Carbohydrate Sensors 179
2.3.3.1 Intramolecular Charge Transfer Sensors 180
2.3.3.2 Photoinduced Electron Transfer Sensors 186
2.3.3.3 Fluorescence Resonance Energy Transfer Sensors 196
2.3.4 Colorimetric Sensors 197
2.3.5 Conclusions 199
References 199

2.4 Boron Compounds in Molecular Imaging 205
Bhaskar C. Das, Devi Prasan Ojha, Sasmita Das, and Todd Evans
2.4.1 Introduction 205
2.4.2 Molecular Imaging in Biomedical Research 207
2.4.3 Molecular Imaging Modalities 207
2.4.4 Boron Compounds in Molecular Imaging 210
2.4.5 Boron‐Based Imaging Probes 213
2.4.5.1 Boron‐Based Optical Probes 213
2.4.5.2 Boron‐Based Nuclear Probes 216
2.4.5.3 Boron‐Based MRI Probes 219
2.4.5.4 Boron‐Based Molecular Probes for Disease 220
2.4.6 Future Perspectives 224
Appendix: Companies Offering Imaging Instruments and
Reagents 225
References 225

2.5 Radiolabeling Strategies for Boron Clusters: Toward Fast Development
and Efficient Assessment of BNCT Drug Candidates 232
Kiran B. Gona, Vanessa Gómez‐Vallejo, Irina Manea, Jonas Malmquist,
Jacek Koziorowski, and Jordi Llop
2.5.1 Boron Neutron Capture Therapy 232
2.5.1.1 Boron: The Element 232
2.5.1.2 The Principle behind Boron Neutron Capture Therapy (BNCT) 232
2.5.2 Boron Clusters 235
2.5.2.1 Boranes 236
2.5.2.2 Carboranes 236
2.5.2.3 Metallocarboranes 238
2.5.3 Nuclear Imaging: Definition and History 238
2.5.3.1 Radioactivity: The Basis of Nuclear Imaging 239
2.5.3.2 Single‐Photon Emission Computerized Tomography 240
2.5.3.3 Positron Emission Tomography 241
2.5.3.4 Multimodal Imaging 243
2.5.3.5 Nuclear Imaging and the Need for Radiolabeling 243
2.5.4 Radiolabeling of Boron Clusters 244
2.5.4.1 Radiohalogenation 245
2.5.4.1.1 Radioastatination of Boron Clusters 245
2.5.4.1.2 Radioiodination of Boron Clusters 246
2.5.4.1.3 Radiofluorination of Boron Clusters 248
2.5.4.1.4 Radiobromination of Boron Clusters 250
2.5.4.2 Radiometallation 251
2.5.4.2.1 Radiolabeling using other Radionuclides 253
2.5.5 The use of Radiolabeling in BNCT Drug Development: Illustrative
Examples 254
2.5.6 Conclusion and Future Perspectives 259
References 259

Part 3 Boron Compounds for Boron Neutron Capture Therapy 269

3.1 Twenty Years of Research on 3‐Carboranyl Thymidine Analogs (3CTAs):
A Critical Perspective 271
Werner Tjarks
3.1.1 Introduction 271
3.1.2 Boron Neutron Capture Therapy 272
3.1.3 Carboranes 273
3.1.4 Rational Design of 3CTAs 274
3.1.5 Synthesis and Initial Screening of 3CTAs as TK1 Substrates 275
3.1.5.1 First‐Generation 3CTAs 275
3.1.5.2 Second‐Generation 3CTAs 277
3.1.6 Enzyme Kinetic and Inhibitory Studies 279
3.1.7 Cell Culture Studies 279
3.1.8 Metabolic Studies 280
3.1.9 Cellular Influx and Efflux Studies 282
3.1.10 In vivo Uptake and Preclinical BNCT Studies 282
3.1.11 Potential Non‐BNCT Applications for 3CTAs 284
3.1.12 Conclusion 285
Acknowledgments 286
References 286

3.2 Recent Advances in Boron Delivery Agents for Boron Neutron Capture
Therapy (BNCT) 298
Sunting Xuan and Maria da Graça H. Vicente
3.2.1 Introduction 298
3.2.1.1 Mechanisms of BNCT 298
3.2.1.2 General Criteria for BNCT Agents 299
3.2.1.3 Main Categories of BNCT Agents 299
3.2.2 Amino Acids and Peptides 300
3.2.3 Nucleosides 304
3.2.4 Antibodies 305
3.2.5 Porphyrin Derivatives 307
3.2.5.1 Porphyrin Macrocycles 307
3.2.5.2 Chlorin Macrocycles 314
3.2.5.3 Phthalocyanine Macrocycles 316
3.2.6 Boron Dipyrromethenes 318
3.2.7 Liposomes 321
3.2.8 Nanoparticles 324
3.2.9 Conclusions 330
References 331

3.3 Carborane Derivatives of Porphyrins and Chlorins for Photodynamic
and Boron Neutron Capture Therapies: Synthetic Strategies 343
Valentina A. Ol’shevskaya, Andrei V. Zaitsev, and Alexander A. Shtil
3.3.1 Introduction 343
3.3.2 Recent Synthetic Routes to Carboranyl‐Substituted Derivatives
of 5,10,15,20‐Tetraphenylporphyrin 344
3.3.3 Synthesis of Carborane Containing Porphyrins and Chlorins
from Pentafluorophenyl‐Substituted Porphyrin 350
3.3.4 Carborane Containing Derivatives of Chlorins: New Properties for PDT
and Beyond 355
3.3.4.1 Carborane Containing Derivatives of Pyropheophorbide a
and Pheophorbide a 356
3.3.4.2 Carborane Containing Derivatives of Chlorin e6 358
3.3.4.3 Carborane Containing Derivatives of Purpurin-18 and
Bacteriopurpurinimide 362
3.3.5 Conclusion 364
Acknowledgments 364
References 365

3.4 Nanostructured Boron Compounds for Boron Neutron Capture Therapy
(BNCT) in Cancer Treatment 371
Shanmin Gao, Yinghuai Zhu, and Narayan Hosmane
3.4.1 Introduction 371
3.4.2 Boron Neutron Capture Therapy (BNCT) 373
3.4.2.1 Principles of BNCT 373
3.4.2.2 Liposome‐Based BNCT Agents 375
3.4.2.3 Carbon Nanotubes 377
3.4.2.4 Boron and Boron Nitride Nanotubes 377
3.4.2.5 Magnetic Nanoparticles‐Based BNCT Carriers 379
3.4.2.6 Other Boron‐Enriched Nanoparticles 382
3.4.3 Summary and Outlook 383
References 383

3.5 New Boronated Compounds for an Imaging-Guided Personalized Neutron
Capture Therapy 389
Nicoletta Protti, Annamaria Deagostino, Paolo Boggio, Diego Alberti, and
Simonetta Geninatti Crich
3.5.1 General Introduction on BNCT: Rationale and Application 389
3.5.2 Imaging‐Guided NCT: Personalization of the Neutron Irradiation
Protocol 392
3.5.2.1 Positron Emission Tomography 392
3.5.2.2 Single‐Photon Emission Computed Tomography 395
3.5.2.3 Magnetic Resonance Imaging and Spectroscopy 396
3.5.2.3.1 1 H‐MRI 396
3.5.2.3.2 MRS Spectroscopy 398
3.5.2.3.3 10B and 11B NMR 398
3.5.2.4 Optical Imaging 400
3.5.2.5 Boron Microdistribution 401
3.5.3 Targeted BNCT: Personalization of in vivo Boron‐Selective
Distribution 402
3.5.3.1 Small‐Sized Boron Carriers 402
3.5.3.2 Nanosized Boron Carriers 406
3.5.4 Combination of BNCT with Other Conventional and Nonconventional
Therapies 407
3.5.4.1 Chemotherapy 408
3.5.4.2 Photodynamic Therapy (PDT) 408
3.5.4.3 Standard Radiotherapy 408
3.5.5 Conclusions 410
References 410

3.6 Optimizing the Therapeutic Efficacy of Boron Neutron Capture Therapy (BNCT)
for Different Pathologies: Research in Animal Models Employing Different
Boron Compounds and Administration Strategies 416
Amanda E. Schwint, Andrea Monti Hughes, Marcela A. Garabalino, Emiliano C.C.
Pozzi, Elisa M. Heber, and Veronica A. Trivillin
3.6.1 BNCT Radiobiology 416
3.6.2 An Ideal Boron Compound 417
3.6.3 Clinical Trials, Clinical Investigations, and Translational Research 418
3.6.4 Boron Carriers 419
3.6.5 Optimizing Boron Targeting of Tumors by Employing Boron Carriers
Approved for Use in Humans 422
3.6.6 BNCT Studies in the Hamster Cheek Pouch Oral Cancer Model 422
3.6.6.1 The Hamster Cheek Pouch Oral Cancer Model 422
3.6.6.2 BNCT Mediated by BPA 425
3.6.6.3 BNCT Mediated by GB‐10 or by GB‐10 + BPA 425
3.6.6.4 Sequential BNCT 428
3.6.6.5 Tumor Blood Vessel Normalization to Improve Boron Targeting
for BNCT 430
3.6.6.6 Tumor Blood Vessel Normalization+Seq‐BNCT 432
3.6.6.7 Electroporation + BNCT 432
3.6.6.8 Assessing Novel Boron Compounds 433
3.6.7 BNCT Studies in a Model of Oral Precancer in the Hamster Cheek Pouch
for Long‐Term Follow‐up 435
3.6.8 BNCT Studies in a Model of Liver Metastases in BDIX Rats 438
3.6.9 BNCT Studies in a Model of Diffuse Lung Metastases in BDIX Rats 441
3.6.10 BNCT Studies in a Model of Arthritis in Rabbits 442
3.6.11 Preclinical BNCT Studies in Cats and Dogs with Head and Neck Cancer
with no Treatment Option 445
3.6.12 Future Perspectives 446
References 446

Index 462

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