Boron-Based Compounds

Name: Boron-Based Compounds | Potential and Emerging Applications in Medicine
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Potential and Emerging Applications in Medicine

Evamarie Hey-Hawkins Clara Viñas Teixidor(Herausgeber*in)

Wiley-Blackwell (Verlag)

1. Auflage

Erschienen am 3. April 2018

496 Seiten

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Intro
Title Page
Copyright Page
Contents
List of Contributors
Preface
Part 1 Design of New Boron-based Drugs
Chapter 1.1 Carboranes as Hydrophobic Pharmacophores: Applications for Design of Nuclear Receptor Ligands
1.1.1 Roles of Hydrophobic Pharmacophores in Medicinal Drug Design
1.1.2 Carboranes as Hydrophobic Structures for Medicinal Drug Design
1.1.3 Estrogen Receptor Ligands Bearing a Carborane Cage
1.1.3.1 Estrogen Agonists
1.1.3.2 Estrogen Antagonists and Selective Estrogen-Receptor Modulators (SERMs)
1.1.4 Androgen Receptor Ligands Bearing a Carborane Cage
1.1.4.1 Androgen Antagonists
1.1.4.2 Improvement of Carborane-Containing Androgen Antagonists as Candidates for Anti-Prostate Cancer Therapy
1.1.5 Retinoic Acid Receptor (RAR) and Retinoic Acid X Receptor (RXR) Ligands Bearing a Carborane Cage
1.1.5.1 RAR Agonists and Antagonists
1.1.5.2 RXR Agonists and Antagonists
1.1.6 Vitamin D Receptor Ligands Bearing a Carborane Cage
1.1.7 Determination of the Hydrophobicity Constant p for Carboranes and Quantitative Structure-Activity Relationships in ER Ligands
1.1.7.1 Determination of the Hydrophobicity Constant p for Carboranes
1.1.7.2 Quantitative Structure-Activity Relationships of Carboranylphenols with Estrogenic Activity
1.1.8 Conclusion and Prospects
References
Chapter 1.2 Boron Cluster Modifications with Antiviral, Anticancer, and Modulation of Purinergic Receptors' Activities Based on Nucleoside Structures
1.2.1 Introduction
1.2.2 Boron Clusters as Tools in Medicinal Chemistry
1.2.3 Modification of Selected Antiviral Drugs with Lipophilic Boron Cluster Modulators and New Antiviral Nucleosides Bearing Boron Clusters
1.2.4 In Vitro Antileukemic Activity of Adenosine Derivatives Bearing Boron Cluster Modification
1.2.5 Adenosine-Boron Cluster Conjugates as Prospective Modulators of Purinergic Receptor Activity
1.2.6 Summary
Acknowledgments
References
Chapter 1.3 Design of Carborane-Based Hypoxia-Inducible Factor Inhibitors
1.3.1 Introduction
1.3.2 Boron-Containing Phenoxyacetanilides
1.3.2.1 Synthesis of Boron-Containing Phenoxyacetanilides
1.3.2.2 Biological Activity of Boron-Containing Phenoxyacetanilides
1.3.3 Target Identification of GN26361
1.3.3.1 Design of GN26361 Chemical Probes
1.3.3.2 Synthesis of GN26361 Chemical Probes
1.3.3.3 Target Identification of GN26361
1.3.4 Carborane-Containing HSP60 Inhibitors
1.3.4.1 Design of Ortho- and Meta-Carborane Analogs of GN26361
1.3.4.2 Synthesis of GN26361 Analogs
1.3.4.3 HIF Inhibitory Activity of Carborane Analogs of GN26361
1.3.4.4 HSP60 Inhibitory Activity of Carborane Analogs of GN26361
1.3.5 Carborane-Containing Manassantin Mimics
1.3.5.1 Synthesis of Carborane-Containing Manassantin Mimics
1.3.5.2 Biological Activity of Carborane-Containing Manassantin Mimics
1.3.6 Carborane-Containing Combretastatin A-4 Mimics
1.3.6.1 Design of Ortho-Carborane Analogs of Combretastatin A-4
1.3.6.2 Synthesis of Carborane Analogs of Combretastatin A4
1.3.6.3 HIF Inhibitory Activity of Carborane Analogs of Combretastatin A4
1.3.7 Conclusion
References
Chapter 1.4 Half- and Mixed-Sandwich Transition Metal Dicarbollides and nido-Carboranes(-1) for Medicinal Applications
1.4.1 Introduction
1.4.2 Synthetic Approaches to nido-Carborane [C2B9H12]- Derivatives
1.4.3 Biologically Active Organometallic nido-Carborane Complexes and Organic nido-Carborane Derivatives
1.4.3.1 Biologically Active Half- and Mixed-Sandwich Metallacarborane Complexes
1.4.3.1.1 Half-Sandwich Complexes of Rhenium(I) and Technetium(I)-99?m as Radio-Imaging and Radiotherapeutic Agents
1.4.3.1.2 nido-Carborane(-1) Anions as Pharmacophores for Metal-Based Drugs
1.4.3.2 Biologically Active Compounds Containing a nido-Carborane(-1) Core
1.4.3.2.1 Radiotherapy and Radio-Imaging
1.4.3.2.2 Pharmacophores
1.4.4 Conclusions and Future Challenges
Appendix: Abbreviations
Acknowledgments
References
Chapter 1.5 Ionic Boron Clusters as Superchaotropic Anions: Implications for Drug Design
1.5.1 Introduction
1.5.2 Water Structure and Coordinating Properties
1.5.3 Host-Guest Chemistry of Boron Clusters
1.5.4 Ionic Boron Clusters in Protein Interactions
1.5.4.1 Interactions of Boron Clusters with Lipid Bilayers
1.5.5 Implications for Drug Design
1.5.5.1 Binding to Proteins
1.5.5.2 Penetration through Membranes
1.5.5.3 Computational Methods
1.5.6 Conclusions
References
Chapter 1.6 Quantum Mechanical and Molecular Mechanical Calculations on Substituted Boron Clusters and Their Interactions with Proteins
1.6.1 Introduction
1.6.2 Plethora of Noncovalent Interactions of Boron Clusters
1.6.3 Computational Methods
1.6.3.1 Advanced Methods for Models Systems in Vacuum
1.6.3.2 Approximate Methods for Extended Systems Including the Environment
1.6.3.2.1 SQM Methods
1.6.3.2.2 MM Methods
1.6.3.2.3 Solvation and Ion Models
1.6.3.2.4 pKa Calculations
1.6.3.2.5 Docking and Scoring
1.6.4 Boron Cluster Interactions with Proteins
1.6.5 Conclusions
References
Part 2 Boron Compounds in Drug Delivery and Imaging
Chapter 2.1 Closomers: An Icosahedral Platform for Drug Delivery
2.1.1 Introduction
2.1.2 Synthesis and Chemistry of [closo-B12H12]2-
2.1.3 Hydroxylation of [closo-B12H12]2-
2.1.4 Ether and Ester Closomers
2.1.5 Carbonate and Carbamate Closomers
2.1.6 Azido Closomers
2.1.7 Methods of Vertex Differentiation for Multifunctional Closomers
2.1.7.1 Vertex Differentiation by Selective Derivatization of [closo-B12(OH)12]2-, 1
2.1.7.2 Vertex Differentiation by Functionalizing the B122- Core Prior to the Cage Hydroxylation
2.1.8 Conclusions
References
Chapter 2.2 Cobaltabisdicarbollide-based Synthetic Vesicles: From Biological Interaction to in vivo Imaging
2.2.1 Introduction
2.2.2 A Synthetic Membrane System
2.2.3 Crossing Lipid Bilayers
2.2.4 Visualization of COSAN within Cells
2.2.5 COSAN Interactions with Living Cells
2.2.6 Enhancing Cellular Effects of COSAN
2.2.7 Tracking the in vivo Distribution of I-COSAN
2.2.8 Discussion and Potential Applications
2.2.9 Summary
Appendix: Abbreviations
Acknowledgments
References
Chapter 2.3 Boronic Acid-Based Sensors for Determination of Sugars
2.3.1 Introduction
2.3.2 Interactions of Boronic Acids with Carbohydrates
2.3.3 Fluorescence Carbohydrate Sensors
2.3.3.1 Intramolecular Charge Transfer Sensors
2.3.3.2 Photoinduced Electron Transfer Sensors
2.3.3.3 Fluorescence Resonance Energy Transfer Sensors
2.3.4 Colorimetric Sensors
2.3.5 Conclusions
References
Chapter 2.4 Boron Compounds in Molecular Imaging
2.4.1 Introduction
2.4.2 Molecular Imaging in Biomedical Research
2.4.3 Molecular Imaging Modalities
2.4.4 Boron Compounds in Molecular Imaging
2.4.5 Boron-Based Imaging Probes
2.4.5.1 Boron-Based Optical Probes
2.4.5.2 Boron-Based Nuclear Probes
2.4.5.3 Boron-Based MRI Probes
2.4.5.4 Boron-Based Molecular Probes for Disease
2.4.6 Future Perspectives
Appendix: Companies Offering Imaging Instruments and Reagents
References
Chapter 2.5 Radiolabeling Strategies for Boron Clusters: Toward Fast Development and Efficient Assessment of BNCT Drug Candidates
2.5.1 Boron Neutron Capture Therapy
2.5.1.1 Boron: The Element
2.5.1.2 The Principle behind Boron Neutron Capture Therapy (BNCT)
2.5.2 Boron Clusters
2.5.2.1 Boranes
2.5.2.2 Carboranes
2.5.2.3 Metallocarboranes
2.5.3 Nuclear Imaging: Definition and History
2.5.3.1 Radioactivity: The Basis of Nuclear Imaging
2.5.3.2 Single-Photon Emission Computerized Tomography
2.5.3.3 Positron Emission Tomography
2.5.3.4 Multimodal Imaging
2.5.3.5 Nuclear Imaging and the Need for Radiolabeling
2.5.4 Radiolabeling of Boron Clusters
2.5.4.1 Radiohalogenation
2.5.4.1.1 Radioastatination of Boron Clusters
2.5.4.1.2 Radioiodination of Boron Clusters
2.5.4.1.3 Radiofluorination of Boron Clusters
2.5.4.1.4 Radiobromination of Boron Clusters
2.5.4.2 Radiometallation
2.5.4.2.1 Radiolabeling using other Radionuclides
2.5.5 The use of Radiolabeling in BNCT Drug Development: Illustrative Examples
2.5.6 Conclusion and Future Perspectives
References
Part 3 Boron Compounds for Boron Neutron Capture Therapy
Chapter 3.1 Twenty Years of Research on 3-Carboranyl Thymidine Analogs (3CTAs): A Critical Perspective
3.1.1 Introduction
3.1.2 Boron Neutron Capture Therapy
3.1.3 Carboranes
3.1.4 Rational Design of 3CTAs
3.1.5 Synthesis and Initial Screening of 3CTAs as TK1 Substrates
3.1.5.1 First-Generation 3CTAs
3.1.5.2 Second-Generation 3CTAs
3.1.6 Enzyme Kinetic and Inhibitory Studies
3.1.7 Cell Culture Studies
3.1.8 Metabolic Studies
3.1.9 Cellular Influx and Efflux Studies
3.1.10 In vivo Uptake and Preclinical BNCT Studies
3.1.11 Potential Non-BNCT Applications for 3CTAs
3.1.12 Conclusion
Acknowledgments
References
Chapter 3.2 Recent Advances in Boron Delivery Agents for Boron Neutron Capture Therapy (BNCT)
3.2.1 Introduction
3.2.1.1 Mechanisms of BNCT
3.2.1.2 General Criteria for BNCT Agents
3.2.1.3 Main Categories of BNCT Agents
3.2.2 Amino Acids and Peptides
3.2.3 Nucleosides
3.2.4 Antibodies
3.2.5 Porphyrin Derivatives
3.2.5.1 Porphyrin Macrocycles
3.2.5.2 Chlorin Macrocycles
3.2.5.3 Phthalocyanine Macrocycles
3.2.6 Boron Dipyrromethenes
3.2.7 Liposomes
3.2.8 Nanoparticles
3.2.9 Conclusions
References
Chapter 3.3 Carborane Derivatives of Porphyrins and Chlorins for Photodynamic and Boron Neutron Capture Therapies: Synthetic Strategies
3.3.1 Introduction
3.3.2 Recent Synthetic Routes to Carboranyl-Substituted Derivatives of 5,10,15,20-Tetraphenylporphyrin
3.3.3 Synthesis of Carborane Containing Porphyrins and Chlorins from Pentafluorophenyl-Substituted Porphyrin
3.3.4 Carborane Containing Derivatives of Chlorins: New Properties for PDT and Beyond
3.3.4.1 Carborane Containing Derivatives of Pyropheophorbide a and Pheophorbide a
3.3.4.2 Carborane Containing Derivatives of Chlorin e6
3.3.4.3 Carborane Containing Derivatives of Purpurin-18 and Bacteriopurpurinimide
3.3.5 Conclusion
Acknowledgments
References
Chapter 3.4 Nanostructured Boron Compounds for Boron Neutron Capture Therapy (BNCT) in Cancer Treatment
3.4.1 Introduction
3.4.2 Boron Neutron Capture Therapy (BNCT)
3.4.2.1 Principles of BNCT
3.4.2.2 Liposome-Based BNCT Agents
3.4.2.3 Carbon Nanotubes
3.4.2.4 Boron and Boron Nitride Nanotubes
3.4.2.5 Magnetic Nanoparticles-Based BNCT Carriers
3.4.2.6 Other Boron-Enriched Nanoparticles
3.4.3 Summary and Outlook
References
Chapter 3.5 New Boronated Compounds for an Imaging-Guided Personalized Neutron Capture Therapy
3.5.1 General Introduction on BNCT: Rationale and Application
3.5.2 Imaging-Guided NCT: Personalization of the Neutron Irradiation Protocol
3.5.2.1 Positron Emission Tomography
3.5.2.2 Single-Photon Emission Computed Tomography
3.5.2.3 Magnetic Resonance Imaging and Spectroscopy
3.5.2.3.1 1H-MRI
3.5.2.3.2 MRS Spectroscopy
3.5.2.3.3 10B and 11B NMR
3.5.2.4 Optical Imaging
3.5.2.5 Boron Microdistribution
3.5.3 Targeted BNCT: Personalization of in vivo Boron-Selective Distribution
3.5.3.1 Small-Sized Boron Carriers
3.5.3.2 Nanosized Boron Carriers
3.5.4 Combination of BNCT with Other Conventional and Nonconventional Therapies
3.5.4.1 Chemotherapy
3.5.4.2 Photodynamic Therapy (PDT)
3.5.4.3 Standard Radiotherapy
3.5.5 Conclusions
References
Chapter 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
3.6.1 BNCT Radiobiology
3.6.2 An Ideal Boron Compound
3.6.3 Clinical Trials, Clinical Investigations, and Translational Research
3.6.4 Boron Carriers
3.6.5 Optimizing Boron Targeting of Tumors by Employing Boron Carriers Approved for Use in Humans
3.6.6 BNCT Studies in the Hamster Cheek Pouch Oral Cancer Model
3.6.6.1 The Hamster Cheek Pouch Oral Cancer Model
3.6.6.2 BNCT Mediated by BPA
3.6.6.3 BNCT Mediated by GB-10 or by GB-10 + BPA
3.6.6.4 Sequential BNCT
3.6.6.5 Tumor Blood Vessel Normalization to Improve Boron Targeting for BNCT
3.6.6.6 Tumor Blood Vessel Normalization?+?Seq-BNCT
3.6.6.7 Electroporation + BNCT
3.6.6.8 Assessing Novel Boron Compounds
3.6.7 BNCT Studies in a Model of Oral Precancer in the Hamster Cheek Pouch for Long-Term Follow-up
3.6.8 BNCT Studies in a Model of Liver Metastases in BDIX Rats
3.6.9 BNCT Studies in a Model of Diffuse Lung Metastases in BDIX Rats
3.6.10 BNCT Studies in a Model of Arthritis in Rabbits
3.6.11 Preclinical BNCT Studies in Cats and Dogs with Head and Neck Cancer with no Treatment Option
3.6.12 Future Perspectives
References
Index
EULA

Preface

Today, 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 mercapto-undecahydro-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.

This book summarizes the present status and further promotes the development of new boron-containing drugs and boron-based materials for diagnostics by bringing together renowned experts in the field of medicinal chemistry of boron compounds. It aims to provide a balanced overview of the vibrant and growing field of the emerging and potential applications of boron compounds in medicinal chemistry and chemical biology. The book is aimed at academics and professional researchers in this field, but also at scientists who want to get a better overview on the state of the art of this rapidly advancing area. It contains reviews of important topics, which are divided into three main sections: (1) "Design of New Boron-based Drugs", (2) "Boron Compounds in Drug Delivery and Imaging", and (3) "Boron Compounds for Boron Neutron Capture Therapy".

The first section, "Design of New Boron-Based Drugs", consists of six reviews dealing with the use of carborane derivatives for the development of novel drugs. In his review (Chapter 1.1), Yasuyuki Endo, one of the pioneers in the development of carboranes as hydrophobic pharmacophores almost 20 years ago, describes the development of a variety of potent nuclear receptor ligands with carborane structures as hydrophobic moieties. Nucleoside drugs have been in clinical use for several decades and have become cornerstones of treatment for patients with cancer or viral infections. One of the new developments in the medicinal chemistry of nucleosides is derivatives comprising a boron component such as a boron cluster, as described in the review by Zbigniew J. Lesnikowski and coworkers (Chapter 1.2), whose group has long-standing expertise in the introduction of boron clusters into molecules with diverse biological activity, where they serve as pharmacophores, building blocks, and modulators of the physicochemical and biological properties. An alternative approach to battling cancer is described by Hiroyuki Nakamura et al. in their chapter on the design of carborane-based hypoxia-inducible factor (HIF) inhibitors (Chapter 1.3). Overexpression of HIF1a has been observed in human cancers, including brain, breast, colon, lung, ovary, and prostate cancers; thus, HIF1a is a novel target of cancer therapy, and the Nakamura group has shown carborane-based HIF1 inhibitors to be very promising targets. Another emerging type of boron-based drugs are metallacarboranes. The group of Evamarie Hey-Hawkins has been involved in carborane chemistry for more than 20 years. In Chapter 1.4, they report recent examples of biologically active half- and mixed-sandwich metallacarborane complexes of the dicarbollide ligand, as well as hybrid organic-inorganic compounds containing a nido-carborane(-1) as appended moiety. Their potentially beneficial properties, such as stability in aqueous environments and new binding modes due to their lipophilicity, are described. Prospective applications in radio-imaging, radiotherapy, and drug design are envisaged. In Chapter 1.5, Detlef Gabel and coworkers focus on ionic boron clusters that are soluble in water as well as in nonpolar solvents. This highly interesting feature sets them apart from other ionic and nonionic pharmacophores and renders them interesting new entities for drug design. The final review (Chapter 1.6) by Pavel Hobza, Martin Lepsík, and coworkers on the current status of structure-based computer-aided drug design tools for boron-cluster-containing protein ligands concludes this first section.

In the second section, the focus is on "Boron Compounds in Drug Delivery and Imaging". Satish S. Jalisatgi, a collaborator of Frederick Hawthorne, who was the pioneer of boron cluster chemistry almost 60 years ago, gives an overview of closomer drug delivery platforms based on an icosahedral polyhedral borane scaffold (Chapter 2.1). The resulting monodisperse nanostructures are capable of performing a combination of therapeutic, diagnostic, and targeting functions, which is highly useful for emerging applications. A complementary approach is described in the review by Clara Viñas Teixidor (Chapter 2.2), one of the founders of EuroBoron conference, and her colleagues. The anionic boron-based cobaltabis(dicarbollide) can form atypical monolayer membranes with the shape of vesicles and micelles with similar dimensions to those seen in nature, but of a very different chemical composition. These vesicles interact with liposomes and biological membranes to accumulate inside living cells. Their particular properties offer new opportunities for the development of nanoscale platforms to directly introduce new functionality for use in cancer therapy, drug design, and molecular delivery systems.

Diabetes is a chronic disease that has devastating human, social, and economic consequences. A tight control of blood glucose is the most important goal in dealing with diabetes. The majority of blood glucose monitoring tools relies on the glucose oxidase enzyme (GOx), but they have some drawbacks. A powerful approach for detecting glucose in fluids is the development of boronic acid-based saccharide sensors. The main principles of their design and factors governing their selectivity are discussed by Igor B. Sivaev and Vladimir I. Bregadze in Chapter 2.3.

Drug development is a lengthy process requiring identification of a biological target, validation of the target, and development of pharmacological agents designed and subsequently confirmed by in vivo studies. Molecular and functional imaging applied in the initial stages of drug development can provide evidence of biological activity and confirm on-target drug effects. In their contributions, Bhaskar C. Das et al. focus on various boron-containing molecular probes used in molecular imaging (Chapter 2.4), and Jordi Llop et al. provide an overview of nuclear imaging techniques, as well as the different radiolabeling strategies reported so far for the incorporation of positron and gamma emitters into boron clusters (Chapter 2.5). Finally, some illustrative examples on how radiolabeling and in vivo imaging can aid in the process of drug development are described, focusing on BNCT drug candidates containing boron clusters, linking this chapter to the third section dedicated to "Boron Compounds for Boron Neutron Capture Therapy".

Cancer is the second leading cause of death globally, and was responsible for 8.8 million deaths in 2015. Treatment typically comprises surgery, radiotherapy, and chemotherapy. BNCT is a unique binary therapy that was developed during the last five to six decades. With the availability of accelerator-based neutron sources at clinics, selective boron compounds for use in BNCT will become very important. In this third section, several novel classes of potential BNCT agents are described. Werner Tjarks critically reviews aspects of the design, synthesis, and biological evaluation of 3-carboranyl thymidine analogs (3CTAs) as boron delivery agents for BNCT over a time span of approximately 20 years (Chapter 3.1). Potential future non-BNCT applications of 3CTAs are also discussed, linking this review to the first section on boron-based drug design. Maria da Graça H. Vicente and Sunting Xuan describe different classes of third-generation boron delivery agents with enhanced tumor-localizing properties, which are under investigation for use in BNCT (Chapter 3.2), and the contribution by Valentina A. Ol'shevskaya and colleagues deals with synthetic approaches leading to tumor-selective boronated porphyrins and chlorins with potential applications in diagnosis, drug delivery, and treatment. This study emphasizes the role of boron in rendering the...

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