Boron-Based Compounds E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 941

Veröffentlichungsjahr: 2018

Beschreibung

Noted experts review the current status of boron-containing drugs and materials for molecular medical diagnostics Boron-Based Compounds offers a summary of the present status and promotes the further development of new boron-containing drugs and advanced materials, mostly boron clusters, for molecular medical diagnostics. The knowledge accumulated during the past decades on the chemistry and biology of bioorganic and organometallic boron compounds laid the foundation for the emergence of a new area of study and application of boron compounds as lipophilic pharmacophores and modulators of biologically active molecules.This important text brings together in one comprehensive volume contributions from renowned experts in the field of medicinal chemistry of boron compounds. The authors cover a range of the most relevant topics including boron compounds as modulators of the bioactivity of biomolecules, boron clusters as pharmacophores or for drug delivery, boron compounds for boron neutron capture therapy (BNCT) and for diagnostics, as well as in silico molecular modeling of boron- and carborane-containing compounds in drug design. Authoritative and accessible, Boron-Based Compounds: * Contains contributions from a panel of internationally renowned experts in the field * Offers a concise summary of the current status of boron-containing drugs and materials used for molecular diagnostics * Highlights the range and capacity of boron-based compounds in medical applications * Includes information on boron neutron capture therapy and diagnostics Designed for academic and industrial scientists, this important resource offers the cutting-edge information needed to understand the current state of boron-containing drugs and materials for molecular medical diagnostics.

Leseprobe

Table of Contents

Cover

Title Page

List of Contributors

Preface

Part 1: Design of New Boron‐based Drugs

1.1 Carboranes as Hydrophobic Pharmacophores

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

1.1.4 Androgen Receptor Ligands Bearing a Carborane Cage

1.1.5 Retinoic Acid Receptor (RAR) and Retinoic Acid X Receptor (RXR) Ligands Bearing a Carborane Cage

1.1.6 Vitamin D Receptor Ligands Bearing a Carborane Cage

1.1.7 Determination of the Hydrophobicity Constant π for Carboranes and Quantitative Structure–Activity Relationships in ER Ligands

1.1.8 Conclusion and Prospects

References

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

1.3 Design of Carborane‐Based Hypoxia‐Inducible Factor Inhibitors

1.3.1 Introduction

1.3.2 Boron‐Containing Phenoxyacetanilides

1.3.3 Target Identification of GN26361

1.3.4 Carborane‐Containing HSP60 Inhibitors

1.3.5 Carborane‐Containing Manassantin Mimics

1.3.6 Carborane‐Containing Combretastatin A‐4 Mimics

1.3.7 Conclusion

References

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

1.4.4 Conclusions and Future Challenges

Appendix: Abbreviations

Acknowledgments

References

1.5 Ionic Boron Clusters as Superchaotropic Anions

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

1.5.5 Implications for Drug Design

1.5.6 Conclusions

References

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

1.6.4 Boron Cluster Interactions with Proteins

1.6.5 Conclusions

References

Part 2: Boron Compounds in Drug Delivery and Imaging

2.1 Closomers

2.1.1 Introduction

2.1.2 Synthesis and Chemistry of [closo‐B12H12]

2.1.3 Hydroxylation of [closo‐B12H12]

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

2.1.8 Conclusions

References

2.2 Cobaltabisdicarbollide‐based Synthetic Vesicles

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

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

2.3.4 Colorimetric Sensors

2.3.5 Conclusions

References

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

2.4.6 Future Perspectives

Appendix: Companies Offering Imaging Instruments and Reagents

References

2.5 Radiolabeling Strategies for Boron Clusters

2.5.1 Boron Neutron Capture Therapy

2.5.2 Boron Clusters

2.5.3 Nuclear Imaging: Definition and History

2.5.4 Radiolabeling of Boron Clusters

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

3.1 Twenty Years of Research on 3‐Carboranyl Thymidine Analogs (3CTAs)

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

3.1.6 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

3.2 Recent Advances in Boron Delivery Agents for Boron Neutron Capture Therapy (BNCT)

3.2.1 Introduction

3.2.2 Amino Acids and Peptides

3.2.3 Nucleosides

3.2.4 Antibodies

3.2.5 Porphyrin Derivatives

3.2.6 Boron Dipyrromethenes

3.2.7 Liposomes

3.2.8 Nanoparticles

3.2.9 Conclusions

References

3.3 Carborane Derivatives of Porphyrins and Chlorins for Photodynamic and Boron Neutron Capture Therapies

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

3.3.5 Conclusion

Acknowledgments

References

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)

3.4.3 Summary and Outlook

References

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

3.5.3 Targeted BNCT: Personalization of in vivo Boron‐Selective Distribution

3.5.4 Combination of BNCT with Other Conventional and Nonconventional Therapies

3.5.5 Conclusions

References

3.6 Optimizing the Therapeutic Efficacy of Boron Neutron Capture Therapy (BNCT) for Different Pathologies

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

3.6.7 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

End User License Agreement

List of Tables

Chapter 1.1

Table 1.1.1 Partition constant log

P

, hydrophobic parameter π, pK

a

, and binding affinity for ERα of carboranylphenols

Chapter 1.3

Table 1.3.1 Inhibition of HIF1 transcriptional activity in cell‐based HRE reporter gene assay and cell growth inhibition

Table 1.3.2 Inhibition of HIF1 transcriptional activity in HeLa cell‐based HRE and CMV dual luciferase assay and cell growth inhibition

Table 1.3.3 Inhibition of HIF1 transcriptional activity in cell‐based HRE reporter gene assay and cell growth inhibition

Table 1.3.4 Optimization of the reaction conditions for decaborane coupling

Table 1.3.5 Inhibition of HIF1 transcriptional activity by

ortho

‐carborane analogs of combretastatin A4 in hypoxic cancer cells

Chapter 1.4

Table 1.4.1 Selected results of EDA analysis on structures A, B, and C from Figure 1.4.3 [49]

Table 1.4.2 Binding affinities (

K

i

) of rhenacarborane complexes

3

,

5

, and

7

and reference compound WAY100635 for 5‐HT1A, 5‐HT2B, and 5‐HT7 serotonin receptors and α

1A

, α

1B

, α

1D

, and α

2C

adrenergic receptors

Table 1.4.3 Selectivity ratios for nitric oxide synthases (NOS) inhibition of compounds

23

–

26

[58]

Table 1.4.4 IC

50

values for PMPA (a known PSMA inhibitor) and compounds

31

–

34

[77]

Table 1.4.5 Uptake efficiency (%) by PC3 and PNT2 cells, amounts of

10

B taken up by PC3 cells (atoms/cell), and accumulation ratios (PC3:PNT2) [122]

Table 1.4.6 Results of the cytotoxicity studies (IC

50

values) for the tested DLC salts and reference compound

48

[131]

Table 1.4.7 Results of the cytotoxicity studies (IC

50

values) of aspirin and asborin as well as their hydrolysis products [62]

Table 1.4.8 Results of the cytotoxicity test (CC

50

value) of compounds

55

–

58

with different mycobacterial cell lines [66]

Chapter 1.5

Table 1.5.1 Water‐structural entropies of different anions (Δ

S

struct

) and net effects on the number of surrounding hydrogen bonds (Δ

HB

) [24]

Table 1.5.2 Association constants (

K

a

) of dodecaborate cluster anions with γ‐CDs and associated thermodynamic parameters (in kcal/mol)

Chapter 2.3

Table 2.3.1 The binding constants of phenylboronic acid and polyols in water at 25 °C

Chapter 2.4

Table 2.4.1 Different molecular imaging modalities

Table 2.4.2 Common isotopes used in nuclear medicine

Chapter 2.5

Table 2.5.1 Typical single‐photon emitters (with half‐life and energy)

Table 2.5.2 Typical positron emitters (with half‐life and E

max

positron)

Chapter 3.2

Table 3.2.1 Cytotoxicity and uptake for porphyrin conjugates in T98G cells, and permeability coefficients (

P

) for porphyrin conjugates in hCMEC/D3 cells [82,83]

Chapter 3.5

Table 3.5.1 Summary of novel small‐sized boron delivery systems for BNCT

Table 3.5.2 Summary of novel nanosized boron delivery systems for BNCT

Chapter 3.6

Table 3.6.1 Summary of experimental conditions and outcomes corresponding to the protocols as indicated

List of Illustrations

Chapter 1.1

Figure 1.1.1 Interactions of ligand with receptor (example for 17β‐estradiol with estrogen receptor‐α).

Figure 1.1.2 Structures of globular molecules and characteristics of carboranes.

Figure 1.1.3 Advantages of carborane skeleton for synthesis.

Figure 1.1.4 Structures of β‐estradiol and designed molecule bearing

p

‐carborane.

Figure 1.1.5 Structures of selective estrogen receptor modulators: tamoxifen and raloxifene, and designed molecules bearing carborane.

Figure 1.1.6 Structures of testosterone and designed molecules bearing carborane.

Figure 1.1.7 Structures of typical androgen receptor antagonists: hydroxyflutamide and bicalutamide, and designed molecules bearing carborane.

Figure 1.1.8 Structures of all‐

trans

‐retinoic acid and designed molecules bearing carborane as RAR ligands.

Figure 1.1.9 Structures of 9‐

cis

‐retinoic acid and designed molecule bearing carborane as RXR ligands.

Figure 1.1.10 Structures of 1α,25‐dihydroxyvitamin D

3

and designed molecule bearing carborane as VDR ligands.

Figure 1.1.11 Structures of carboranylphenols used for determination of hydrophobic parameters.

Figure 1.1.12 Correlation between log

P

and ER‐binding affinity of carboranylphenols.

Chapter 1.2

Figure 1.2.1 Examples of boron clusters used in medicinal chemistry: dicarba‐

closo

‐dodecaborane (carborane) isomers

ortho‐

(

1

),

meta‐

(

2

),

para‐

(

3

), and (C

2

B

10

H

12

)

closo

‐dodecaborate (B

12

H

12

2−

) (

4

), and 3‐cobalt‐

bis

(1,2‐dicarbollide)ate (

5

).

Figure 1.2.2 Anti‐HCMV boron cluster prodrugs: ganciclovir (GCV) (

6

), acyclovir (ACV) (

7

), and cidofovir (CDV) (

8

,

9

); the parent drug fragment is marked with a frame, and the center of chirality is marked with a star.

Figure 1.2.3 Example of boron cluster–modified pyrimidine nucleosides.

Figure 1.2.4 Examples of boron cluster–modified adenosine (purine nucleoside).

Chapter 1.3

Figure 1.3.1 Design of HIF1 inhibitors based on the structure of AC1‐001.

Scheme 1.3.1 Reagent and conditions: (a) ClCH

2

CO

2

Et, K

2

CO

3

, DMF, r.t.; (b) LiOH, THF/H

2

O; (c) 2‐benzyloxy‐5‐iodoaniline, ECF, NMM, TEA, THF, 20 °C, 72%; (d) i. pinacolatodiboron, PdCl

2

(dppf), AcOK, DMF, 80 °C, 63%; ii. Pd/C, H

2

,EtOH, 99%; (e) BBr

3

, CH

2

Cl

2

, 0 °C, 72%.

Scheme 1.3.2 Reagent and conditions: (a) ClCH

2

CO

2

Et, K

2

CO

3

, DMF, r.t.; (b) ethynyltrimethylsilane, PdCl

2

(PPh

3

)

2

, CuI,

N,N

‐diethylamine, DMF, microwave, 120 °C, 93%; (c) LiOH, THF–H

2

O, r.t., 82%; (d) BnBr, Na

2

CO

3

, DMF, r.t., 93%; (e) B

10

H

14

, CH

3

CN, toluene, reflux, 31%; (f) Pd/C, H

2

, EtOH, 96%; (g) 5‐pinacolatoboryl‐2‐hydroxyaniline, IBCF, 30%; (h) KHF

2

, MeOH, 83%.

Figure 1.3.2 Effect of compound

2

on hypoxia‐induced accumulation of HIF1α protein (a) and expression of VEGF and HIF1α mRNAs (b) in HeLa cells.

Figure 1.3.3 Design of GN26361 chemical probes for clarification of mechanism of action in HIF inhibition.

Scheme 1.3.3 Reagent and conditions: (a) EDCl, HOBt, DIPEA, DMF, r.t., overnight; (b) B

10

H

14

, CH

3

CN, toluene, reflux; (c) Pd/C, H

2

, EtOH/THF, r.t.; (d) propalgyl bromide, K

2

CO

3

, acetone, reflux.

Figure 1.3.4 Identification of target protein of

2

(GN26361) using chemical probes. (a) Effect of chemical probes

16a

and

16b

on the hypoxia‐induced HIF1α accumulation. The levels of each protein were detected by immunoblot analysis. (b) Fluorescent imaging of protein bound to the chemical probes. HeLa cell lysate was irradiated for 30 min at 360 nm in the presence of each probe (30, 100, and 300 μM), and then the probe was conjugated with Alexa Fluor 488 azide by click reaction. (c) Inhibition of HSP60 by

2

. Recombinant HSP60 (1 μM) was reacted with ATP (1 μM) for 30 min, and then ATP content was determined by luciferase reaction.

Figure 1.3.5 Design

ortho

‐ and

meta

‐carborane analogs of GN26361.

Scheme 1.3.4 Reagents and conditions: (a) BnBr, K

2

CO

3

, acetone, reflux, overnight, 85%; (b) 2,2′‐Bi‐1,3,2‐dioxaborolane, PdCl

2

, dppf, AcOK, dioxane, reflux, overnight, 93%; (c) Fe, NH

4

Cl, EtOH–H

2

O, reflux, 3 h, 74%; (d) bromoacetylbromide, pyridine, DMAP, r.t., 1.5 h, 80%.

Scheme 1.3.5 Reagents and conditions: (a) ethynyltrimethylsilane, PdCl

2

(PPh

3

)

2

, PPh

3

, CuI, diethylamine, THF, reflux, 5 h, 95%; (b) TBAF, THF, r.t., 30 min, 86%; (c) B

10

H

14

,

N

,

N

‐dimethylaniline, chlorobenzene, microwave, 130 °C, 10 min, 76%; (d) (i)

n

‐BuLi, THF, −10 °C, 30 min, (ii) RI, 1.5 h; (e) BBr

3

, CH

2

Cl

2

, r.t., overnight, 90–98%; (f)

21

, NaH, THF, r.t., 2 h; (g) H

2

, Pd/C, MeOH–THF, r.t., overnight, 60–85%. (h) (i) KHF

2

(4 M), MeOH, r.t., 2 h, (ii) HCl (1 N), r.t., overnight, 32–65%.

Scheme 1.3.6 Reagents and conditions: (a) methyl propiolate, DABCO, CH

2

Cl

2

, r.t., overnight, 80%; (b) LiOH, THF–H

2

O, r.t., overnight, 60%; (c) (i) oxalyl chloride, CH

2

Cl

2

, 0 °C, 2 h, (ii)

30

, triisobutylamine, THF, r.t., 2 h, 28%; (d) (i) KHF

2

(4 M), MeOH, r.t., 30 min, (ii) HCl (1 N), 1 h; (e) H

2

, Pd/C, MeOH–THF, r.t., overnight; (f) (i) KHF

2

(4 M), MeOH, r.t., 2 h, (ii) HCl (1 N), r.t., overnight, 64%.

Scheme 1.3.7 Reagents and conditions: (a) Ethyl 4‐bromobutyrate, K

2

CO

3

, DMF, r.t., overnight, 57%; (b) LiOH, THF–H

2

O, r.t., overnight, 93%; (c)

30

, HATU, DIPEA, DMF, r.t., overnight, 48%; (d) (i) KHF

2

(4 M), MeOH, r.t., 2 h, (ii) HCl (1 N), r.t., overnight, 58%.

Scheme 1.3.8 Reagents and conditions: (a) ethynyltrimethylsilane, PdCl

2

(PPh

3

)

2

, PPh

3

, CuI, diethylamine, THF, reflux, 5 h, quant.; (b) KOH, MeOH, r.t., 6 h, 78%; (c) B

10

H

14

,

N

,

N

‐dimethylaniline, chlorobenzene, microwave, 130 °C, 37%; (d) BBr

3

, CH

2

Cl

2

, r.t., overnight, 100%; (e)

21

, NaH, THF, r.t., 2 h, 72%; (f) H

2

, Pd/C, MeOH–THF, r.t., overnight, 54%.

Scheme 1.3.9 Synthesis of

meta

‐carborane analogs. Reagents and conditions: (a) (i)

n

‐BuLi, DME, 0 °C, 30 min, (ii) CuCl, r.t., 1.5 h, (iii) 4‐iodoanisole, pyridine, reflux, 48 h, 26%; (b) (i)

n

‐BuLi, THF, −10 °C, 30 min, (ii) RI, −10 °C, 1.5 h; (c) BBr

3

, CH

2

Cl

2

, r.t., overnight, 40‐91%; (d)

21

, NaH, THF, r.t., 2 h; (e) H

2

, Pd/C, MeOH–THF, r.t., overnight.

Figure 1.3.6 HSP60 chaperone activity analyzed by using MDH as substrate.

Figure 1.3.7 Dose‐dependent inhibition of human HSP60 chaperone activity by compound

27g

. IC

50

value was calculated to be 0.35 ± 0.08 μM.

Figure 1.3.8 Design of carborane‐containing manassantin mimics

44

and

45

.

Scheme 1.3.10 Reagents and conditions: (a) Pd(PPh

3

)

4

(10 mol%), CuI, TEA, THF, reflux, overnight, 84%; (b) B

10

H

14

,

N,N

‐dimethylaniline, chlorobenzene, MW, 120 °C, 15 min, 52%; (c) conc. HCl/MeOH, CH

2

Cl

2

, 12 h, 87%.

Scheme 1.3.11 Reagents and conditions: (a)

51

, K

2

CO

3

, DMF, r.t., 2 h, 51%; (b) NaBH

4

, MeOH, 0 °C, 1.5 h, 92%; (c) homoveratric acid, DCC, DMAP, THF, 50 °C, 3 h, 52%.

Scheme 1.3.12 Reagents and conditions: (a) (i)

n

‐BuLi, CuCl, pyridine/DME,

54

, (ii) TBAF, THF; (b)

51

, K

2

CO

3

, DMF, r.t., 4 h, 90%; (c) NaBH

4

, MeOH, 0 °C, 1.5 h, 64%; (d) homoveratric acid, EDCI, HOBt, DIPEA, DMF, r.t., overnight, 99%.

Figure 1.3.9 Effects of compounds

44

and

45

on hypoxia‐induced accumulation of HIF1α protein and expression of HIF1α mRNA in HeLa cells. (a) The levels of each protein were detected by western blot analysis with HIF1α‐ or tubulin‐specific antibodies. Tubulin was used as the loading control, and “–” was DMSO used as the control. (b) HIF1α and GAPDH mRNA expression was detected by RT‐PCR.

Figure 1.3.10 Design of

ortho

‐carborane analogs of combretastatin A4.

Scheme 1.3.13 Synthesis of

ortho

‐carborane analogs. Reagents and conditions: (a) ArI, Pd(PPh

3

)

4

, CuI, TEA/THF, reflux, 4–6 h; (b) (i) B

10

H

14

, CH

3

CN/toluene, 110 °C, 24 h or (ii) B

10

H

14

,

N

,

N

‐dimethylanline/chlorobenzene, microwave, 150 °C, 15 min.

Figure 1.3.11 Effect of carborane analogs

61a

and

61d

on the hypoxia‐induced HIF1 activation and tubulin binding of biotin probe. (a) HeLa cells were incubated with carborane analogs under hypoxic condition for 4 h. The levels of HIF1α and VEGF mRNA were detected by RT‐PCR analysis. (b) The levels of each protein were detected by immunoblot analysis. (c) The structure of a biotinylated probe of a carborane analog. (d) Pull‐down assay was performed to detect protein bound to a biotinylated carborane analog in HeLa cell lysate. The proteins were separated by SDS‐PAGE, and tubulin was detected by immunoblot analysis.

Chapter 1.4

Scheme 1.4.1 Treatment of 1,2‐dicarba‐

closo

‐dodecaborane(12) (

1

) and 7,8‐dicarba‐

nido

‐dodecahydro undecaborate(–1) (

2

) with

n

‐BuLi [25,26].

Figure 1.4.1 Numbering scheme for

closo

‐ (left) and

nido

‐carborane(–1) (middle) clusters. Metallacarboranes, where the metal center is “π‐like‐coordinated” to the upper belt, are classified as

closo

structures (right). For a detailed description of the numbering scheme in metallacarborane complexes refer to [6c]. Here, only one isomer is shown.

Scheme 1.4.2 Examples of carborane‐containing compounds derived from 12‐vertex 1,2‐dicarba‐

closo

‐dodecaborane(12) and 7,8‐dicarba‐

nido

‐dodecahydroundecaborate(–1) with applications in catalysis, medicine, and materials science [11,16,38,40–45].

Figure 1.4.2 General structure of η

5

‐coordinating Cb

2–

and Cp

–

ligands to a metal center.

Figure 1.4.3 Mixed‐sandwich group 9 metallacarborane complexes incorporating a Cp

–

ligand subject to EDA analysis by Kudinov

et al.

[49]. The two fragmentation patterns studied are shown.

Scheme 1.4.3 Mechanism of deboronation of commercially available

ortho

‐carborane [25].

Figure 1.4.4 (a)

11

B and (b)

11

B{

1

H} NMR spectra of a C‐mono‐substituted

nido

‐carborane(–1) anion (in CD

3

CN at 128.4 MHz). The signal corresponding to the borane derivative is observed at 20.1 ppm, whereas the signals of the

nido

‐carborane(–1) are found in the region between –35.4 and –8.5 ppm with the pattern 2:1:2:2:1:1.

Figure 1.4.5 Anionic Re

I

– and

99m

Tc

I

–dicarbollide complexes, where the cluster bears a 1‐(2‐methoxyphenyl)‐piperazine substituent at one carbon vertex. The counterion (Na

+

) is omitted [59,60].

Figure 1.4.6

closo

‐Carboranes bearing a guanidine substituent at one

C

‐vertex. The nitrogen atom N

3

of the guanidine group carries different substituents to modify basicity properties [69].

Figure 1.4.7 WAY100635 [N‐[2‐[4‐(2‐methoxyphenyl)piperazin‐1‐yl]ethyl]‐N‐pyridin‐2‐ylcyclohexanecarboxamide] (top left), a potent and selective 5‐HT1A receptor antagonist [93]; Alberto’s WAY–[CpRe(CO)

3

] derivative (top right) [87]; and Valliant’s Re

I

– and

99m

Tc

I

–dicarbollide complexes

7

and

8

[59,60]. The counterions (Na

+

) of

7

and

8

are omitted.

Scheme 1.4.4 Synthesis of complexes

11

–

14

(reaction conditions: aq. EtOH, room temperature [3 h] or 35 °C [1 h]), according to Ref. [69]. The nitrogen atom N

3

of the guanidine group carries different substituents to modify basicity properties.

Figure 1.4.8 Rhenacarborane complexes incorporating a nitrosyl ligand at the rhenium(I) center (

15

–

20

) and an oxygen‐based tether at the β–B vertex (

16

–

20

) [75,76]. Position of the β–B vertex (B(8))is shown. The counterion ([BF

4

]

–

) of

20

is omitted.

Scheme 1.4.5 Conversion of

L

‐arginine to

L

‐citrulline and nitric oxide (NO) as catalyzed by NOS. Flavin, (6

R

)‐5,6,7,8‐tetrahydrobiopterin, and heme act as co‐factors in both steps (not shown).

Figure 1.4.9 Selected examples of organic compounds with known nitric oxide synthase (NOS) inhibition activities, available on the market for laboratory use [105,107,111].

Figure 1.4.10 Selected examples of mixed‐sandwich ferracarborane (

21

–

22

) and full‐sandwich cobaltacarborane (

23

–

26

) complexes tested as NOS inhibitors [58].

Figure 1.4.11 Ruthenacarborane complexes (

27

–

29

) incorporating different arene ligands, tested as potential novel cytotoxic agents [113].

Figure 1.4.12 BSH‐encapsulation with liposomes made of 10% distearoyl boron lipid (DSBL) or fluorescence‐labeled boron lipid (FL‐SBL) and 90% distearoylphosphatidylcholine (DSPC) [118].

Figure 1.4.13 Schematic structures of the tested potent

closo

‐carborane,

nido

‐carborane(–1), and iodo‐

nido

‐carborane(–1) conjugates and 2‐(phosphonomethyl)pentane‐1,5‐dioic acid (PMPA) [77].

Scheme 1.4.6 Schematic structure of the

closo

‐carborane‐ and

nido

‐carborane(–1)‐containing tetrazines and

trans

‐cyclooctene (Tz‐TCO) in a click reaction. Four possible isomers are formed: 4a‐(

R

)‐7‐ol, 4a‐(

R

)‐8‐ol, 4a‐(

S

)‐7‐ol, and 4a‐(

S

)‐8‐ol [63].

Scheme 1.4.7 Schematic structures of the DLC salts studied by Calabrese

et al.

[122,130,131].

Scheme 1.4.8 Hydrolysis mechanism of aspirin and asborin [62].

Figure 1.4.14 Schematic structures of the

closo

‐carborane– and

nido

‐carborane(–1)–thymine conjugates by Leśnikowski and coworkers (the counterion Cs

+

was omitted) [66].

Figure 1.4.15 Indomethacin methyl ester (top), a potent COX‐1 inhibitor, and two

nido

‐carborane(–1)‐containing analogs (

59

and

60

; bottom [only one enantiomer is shown]). The counterions (Na

+

) for

59

and

60

are omitted [19].

Chapter 1.5

Figure 1.5.1 Chemical structures of selected neutral and ionic boron clusters:

closo

C

2

B

12

H

12

,

closo

[CB

11

H

12

]

−

,

nido

[C

2

B

9

H

12

]

−

,

closo

[B

12

H

12

]

2−

,

closo

[B

10

H

10

]

2−

, and

closo

[B

21

H

18

]

−

, and metalla‐bisdicarbollides[3,3′‐M(1,2‐C

2

B

9

H

11

)

2

]

−

.

Figure 1.5.2 Electrostatic potential map of carborane and dodecaborate anions [24].

Figure 1.5.3 Water structure around dodecaborate anion B

12

H

12

2−

. “A” indicates dihydrogen bonds; “B” indicates a bifurcated dihydrogen bond [26].

Figure 1.5.4 XRD structures of the

o

‐carborane complex with (a) calix[5]arenes [36] and (b) cyclotriveratrylene [39]. The C–H vectors of the carborane point toward the aromatic rings of the host cavity.

Figure 1.5.5 Chemical structure of common cyclodextrins (CDs).

Figure 1.5.6 XRD structures of the inclusion entrapment of the B

12

Br

12

2−

cluster into the γ‐CD dimer [24].

Figure 1.5.7 (a) Dodecaborate‐anchor 7‐nitrobenzofurazan (NBD) dyes A and B for CD binding (46). (b) Illustration represents the principle of the indicator displacement assay: the encapsulation of the dye inside the host cavity changes its optical properties (e.g., fluorescence); the addition of an analyte is expected to revert the optical changes.

Figure 1.5.8 Pt(II) complexes containing carborane residue.

Figure 1.5.9 Chemical structures of boron clusters tested as inhibitors for carbonic anhydrase [54]. The

in vitro

inhibition constants (

K

i

in μM) of the sulfonamide‐based derivatives with the human CA isozyme II (CAII) are given below the structures.

Figure 1.5.10 Crystal structure of CAII in complex with

5

(a) and

8

(b); PDB codes: 4MDL and 4MDM. Yellow: hydrophobic side chains; blue: hydrophilic side chains; pink: boron; black: carbon.

Figure 1.5.11 COX inhibitors: indomethacin and its

nido

‐carborane derivatives [59].

Figure 1.5.12 Binding of

12

to COX. PDB code: 4Z01. Yellow: hydrophobic side chains; blue: hydrophilic side chains; pink: boron; black: carbon.

Figure 1.5.13 Cobaltabisdicarbollide binding to HIV protease. PDB code: 1ZTZ. Yellow: hydrophobic side chains; blue: hydrophilic side chains; pink: boron; black: carbon.

Figure 1.5.14 Suggested mechanisms of the interaction between dodecaborate clusters and liposome. (a) A barrel‐stave pore; (b) a toroidal pore.

Chapter 1.6

Figure 1.6.1 Molecular structures of (substituted) heteroboranes and their computed electrostatic potentials (ESPs) on 0.001 a.u. molecular surface at the HF/cc‐pVDZ level. Color range of ESPs in kcal/mol.

Figure 1.6.2 Model systems of protein–heteroborane interactions. (a) C–H···π. (b) Dihydrogen bonding. (c) Halogen bonding (Br···O). (d) Chalcogen bonding (S···π). Black: carbon; white: hydrogen; yellow: sulfur; pink: boron; green: bromine. Distances in Å. Partial charges in

e

.

Figure 1.6.3 (a) Four COSAN molecules in the active site of HIV PR (gray ribbon) [73]. (b) Five low‐energy conformers of a dual‐COSAN inhibitor (GB80) in HIV PR obtained by MD and QM/MM calculations [75]. Yellow spheres: Co

3+

; blue spheres: Na

+

; gray/black: carbon; pink: boron; blue: nitrogen. Hydrogen atoms are omitted for clarity.

Figure 1.6.4 (a) An overlay of hCAII–inhibitor QM/MM optimized structures. The

nido

and

closo

carborane cages of the inhibitor are in magenta and pink, respectively. (b) Dihydrogen bonding in the hCAII–inhibitor complex.

Chapter 2.1

Figure 2.1.1 A representative closomer structure with 12 copies of the dansyl payload.

Scheme 2.1.1 Carbamate closomer synthesis. (i)

m

‐Cl‐Ph‐OC(O)Cl (fivefold excess per vertex), pyridine (fivefold excess), acetonitrile, reflux; (ii) NH

2

‐(CH

2

)

2

(CH

2

O)

3

OC(O)NH(CH

2

)

2

NH‐Dansyl, DMF, RT.

Figure 2.1.2 Various hydroxy

closo

‐dodecaborate anions.

Figure 2.1.3 Solid‐state structures of (a)

closo

dodecaacetate ester closomer and (b)

hypercloso

dodecabenzyl ether closomer; the B–B bonds shown in red are elongated due to Jahn–Teller distortion.

Scheme 2.1.2 Synthesis of the multinuclear Gd‐DTTA‐based closomer MRI contrast agent. (i) Excess (ClCH

2

CO)

2

O, CH

3

CN, 7 days, reflux; (ii) NaN

3

, 10 days, RT; (iii) CuI, Hünigs base, 48 h, RT; (iv) 80% TFA/CH

2

Cl

2

, 3 h, RT; (v) GdCl

3

⋅6H

2

O, pH 7.5–8, 12 h, RT.

Figure 2.1.4 Trifunctionalized closomer delivery system.

Scheme 2.1.3 Single vertex differentiation based on a monoether functionalized closomer. (i) Large excess of

1

, DIPA, CH

3

CN; (ii)

m‐

Cl‐C

6

H

4

‐OCOCl, pyridine, CH

3

CN; (iii) H

2

N‐Linker‐X (X: passenger payload).

Scheme 2.1.4 Synthesis of a

α

v

β

3

integrin targeted closomer MRI contrast agent.

Scheme 2.1.5 Synthesis of a fluorescence‐labeled closomer–carboplatin prodrug. (i) Phenyl chloroformate, pyridine, CH

3

CN, 80 °C, 24 h; (ii) Raney nickel, 70 bar H

2

, MeOH, 40 °C, 24 h; (iii) 2‐

azidoethanamine

, CH

3

CN, 40 °C, 72 h; (iv)

t

Boc‐GABA

‐

NHS ester, DBU, CH

3

CN, rt, 24 h, 86%; (v) 2‐

azidoethanamine,

CH

3

CN, 40 °C, 72 h, 76%; (vi) 80% TFA, 40 min, 98%, 5(6)‐carboxyfluorescein succinimidyl ester,

Et

3

N, CH

2

Cl

2

, 66%; (vii) CuSO

4

×5H

2

O, sodium ascorbate, TBTA, MeOH/CH

2

Cl

2

, rt, 72 h, 52%; (viii) TFA, rt, 16 h, 97%, 1 M NaOH, pH 7, [Pt(NH

3

)

2

(H

2

O)

2

](NO

3

)

2

, H

2

O, rt, 16 h, 46%.

Scheme 2.1.6 Convergent synthesis of the trifunctional closomer drug delivery system.

Chapter 2.2

Figure 2.2.1 (a) Chemical structure of cobaltabisdicarbollide [3,3′‐Co(1,2‐C

2

B

9

H

11

)

2

] COSAN. (b) Scale diagram of COSAN. (c) A schematic lipid bilayer to show relative differences in membrane thickness.

Figure 2.2.2 (a) [COSAN]

−

ion transition measurements through lipid bilayer membranes using the Montal Mueller technique. (b) A typical current recording against time obtained when COSAN is applied to one side of a planar bilayer formed from DOPC. Current initiates as a strong, but transient, depolarization before stabilizing as a continuous, steady negative current across the membrane. (c) The negative current is accompanied by a steady flow of COSAN across a neutral planar membrane, as measured by ICP‐MS. Commencing with the application of 100 μM COSAN to one side, permeation rates across the membrane vary according to the counterion of Na

+

 or H

+

. All show zero‐order kinetics. Error bars are standard deviations resulting from ten independent experiments [9].

Figure 2.2.3 (a) CryoTEM image of COSAN:liposomes (1:4) suspended in vitreous ice at 15,000× magnification. Circles highlight fusion between COSAN vesicles and liposomes. Scale bar: 200 nm. (b) CryoTEM image of COSAN:liposomes (1:3) suspended in vitreous ice at 20,000× magnification. The circles highlight the joining of two or more liposome units linked by COSAN. Arrows indicate the complete penetration of the COSAN inside the liposome and the recovery of the monolayer vesicle form. Scale bar: 200 nm. Insert shows 50,000× magnification of the planar multilayer morphology of COSAN at the interface of two liposomes [9].

Figure 2.2.4 (a) Spectral fingerprints of HEK293 cells treated with 25 mM COSAN for 1 hour, followed by measurements of the same cells 4 hours and 4 days after the compounds have been removed. (b) Cellular imaging of HEK293 cell treated with 2 mM COSAN. Images show phase contrast image (PC) and Raman chemical images at 2570 cm

−1

(B–H peak) and 2950 cm

−1

(C–H peak). Pink zones in the Raman images show COSAN accumulation inside the cell [10]. (c) A simple schematic representation of the COSAN’s uptake by the cells.

Figure 2.2.5 Phase contrast images of HEK293 (top panel) and HeLa cells (middle panel) grown in the presence or absence of 200 μM COSAN for 24 hours. Wash shows cells grown in the presence of 200 μM COSAN for 5 hours, before the cells were washed and replated in COSAN‐free medium. HEK293 cells show a blebbing morphology often associated with apoptotic cells. HeLa cells show an unusual, highly vacuolated morphology within the perinuclear cytoplasm.

Dictyostelium

cells were photographed before treatment, 30 min following addition of 10 μM COSAN, and 2 hours after COSAN was removed [11].

Figure 2.2.6 A chemical series based on [COSAN]

−

reveals increased potency of [I

2

‐COSAN]

−

on living cells. The ED

50

values on

Dictyostelium

are given for each compound.

Figure 2.2.7 (a) COSAN was labeled with either

125

I (gamma emitter) or

124

I (positron emitter; not shown) via palladium‐catalyzed isotopic exchange reaction. (b) Structure of iodine‐labeled and PEGylated COSAN. (c) Accumulation in different organs of [

125

I‐COSAN]

−

/ [

124

I‐COSAN]

−

(top) and [

125

I‐PEG‐COSAN]

−

/[

124

I‐PEG‐COSAN]

−

(bottom). Left: Accumulation of

125

I‐radiolabeled compounds were measured following dissection of organs and gamma counting at selected time points (10, 30, and 120 min.) after administration. Results are expressed as percentage of injected dose (%ID) per gram of tissue. Right: Accumulation of

124

I‐labeled compounds were visualized by PET‐C. Results are expressed as percentage of injected dose (%ID) per cubic centimeter of tissue. Mean ± standard deviation values are presented (

n

 = 3). Herrmann’s catalyst is a highly efficient palladacycle catalyst that corresponds to

trans

‐di‐μ‐acetatobis[2‐[bis(2‐methylphenyl)phosphino]benzyl]dipalladium. Lu: Lungs; H: heart; K: kidneys; S: spleen; T: testicles; L: liver; SI: small intestine; LI: large intestine; Br: brain; C: cerebellum; U: urine; BL: blood; St: stomach [25].

Chapter 2.3

Figure 2.3.1 Common naturally occurring monosaccharides (β‐forms).

Figure 2.3.2

D

‐Glucose in various forms with percentage composition at equilibrium in D

2

O at 27 °C (for acyclic form; equilibrated at 37 °C).

Scheme 2.3.1

Scheme 2.3.2

Figure 2.3.3 The dual fluorescence of an intramolecular charge transfer fluorophore.

Scheme 2.3.3

Chart 2.3.1

Chart 2.3.2

Scheme 2.3.4

Scheme 2.3.5

Chart 2.3.3

Chart 2.3.4

Chart 2.3.5

Chart 2.3.6

Figure 2.3.4 Excitation and emission fluorescence spectra of BODIPY‐containing boronic acids in ethanol.

Figure 2.3.5 Fluorescence responses of BODIPY‐containing boronic acids after incubation with

D

‐fructose.

Figure 2.3.6 Selectivity of Fructose Orange against 24 different sugars, glycerol, ethylene glycol, and fructose 6‐phosphate at different concentrations in HEPES buffer (pH: 7.4).

Figure 2.3.7 Principles of sugar sensing by boronic acid–based PET sensors, and structure of the first rationally designed fluorescent PET sensor.

Chart 2.3.7

Chart 2.3.8

Figure 2.3.8 (a) X‐ray structures of the R,R‐chiral diboronic acid, and (b) the S,S‐chiral diboronic acid–tartrate complex.

Figure 2.3.9 X‐ray structure of the complex of

ortho‐N,N

‐tetramethyleneaminomethyl phenylboronic acid with catechol and methanol.

Figure 2.3.10 X‐ray structures of 9‐{[

N

‐Methyl‐

N

‐(

ortho

‐boronobenzyl)amino]methyl}anthracene crystallized from (a) dichloromethane and (b) methanol, and its complexes with (c) catechol and (d) 4‐nitrocatechol.

Chart 2.3.9

Figure 2.3.11 X‐ray structures of (a) catechol

ortho

‐(

N,N

‐tetramethyleneaminomethyl) phenylboronate and (b) dimethyl

ortho

‐(

N

‐benzylaminomethyl)phenylboronate.

Chart 2.3.10

Figure 2.3.12 Relative stability constants of diboronic acid versus monoboronic acid with carbohydrates.

Chart 2.3.11

Chart 2.3.12

Figure 2.3.13 Relative stability constants of diboronic acid versus the corresponding monoboronic acids with carbohydrates.

Scheme 2.3.6

Chart 2.3.13

Chart 2.3.14

Chart 2.3.15

Chart 2.3.16

Figure 2.3.14 UV‐visible absorption spectra of the azo dye boronic acid in the absence and presence of

D

‐fructose, measured in a methanol–water solution (1:1, v/v) at pH 10.0 (CHES buffer).

Chapter 2.4

Figure 2.4.1 Boron‐based molecular imaging probes.

Figure 2.4.2 Overview of molecular probes in imaging.

Figure 2.4.3 Boron‐based

18

F‐radiotracers.

Figure 2.4.4 Reaction pathways for ArBF

3

−

stability.

Figure 2.4.5 One‐pot, two‐step labeling to synthesize an [

18

F] compound.

Figure 2.4.6 Different B–

18

F bond containing probes.

Figure 2.4.7 Boronate fluorescent probes visualizing endogenous H

2

O

2

.

Figure 2.4.8 Reaction conditions for monoboronate fluorescent probes in the presence of H

2

O

2.

Figure 2.4.9 Visualizing changes in H

2

O

2

levels in living cells by bioluminescent imaging.

Figure 2.4.10 Iodination of

nido

‐carborane anion.

Figure 2.4.11 Tritium is introduced to

closo

‐carboranes.

Figure 2.4.12 Venus flytrap complex (VFC) with radio cobalt (

57

Co) conjugated to a monoclonal antibody.

Figure 2.4.13 [

18

F]‐AMBF

3

−

octreotate as a probe for blocked and unblocked mice.

Figure 2.4.14 Structure of RGD‐

18

F‐ArBF

3

−

with very high specific activity.

Figure 2.4.15

18

F‐exchange to synthesize AmBF

3

−

B9858.

Figure 2.4.16 Longitudinal data to predict AD conversion.

Figure 2.4.17 Oxidation of HKGreen (

34

) with peroxynitrite.

Figure 2.4.18 The structure and binding mode of a BODIPY–rhodamine chemodosimeter.

Figure 2.4.19 Application of click reaction to synthesize boron probes.

Figure 2.4.20 Detection of NaOCl using boron probes.

Figure 2.4.21 Synthesis routes and reaction mechanism of o‐MOPB and p‐MOPB with NO.

Figure 2.4.22 Pt–BODIPY as imaging agents.

Chapter 2.5

Figure 2.5.1 Schematic representation of the principle behind BNCT: if

10

B atoms preferentially accumulate in cancer cells (1), subsequent neutron irradiation (2) produces the rapid nuclear reaction

10

B(n, α, γ)

7

Li. α‐particles and

7

Li ions have high linear energy transfer, triggering cell damage and death (3) while sparing healthy surrounding cells.

Figure 2.5.2 Fictitious curves representing the concentration of

10

B in the tumor (blue line), surrounding tissue (green line), and blood (red line), after administration of a BNCT drug candidate. Determination of these curves enables the identification of the optimal time window for applying neutron irradiation (in purple) and predicting the therapeutic efficacy.

Figure 2.5.3 Structure of (left) sodium borocaptate (BSH), and (right)

p

‐boronophenylalanine (BPA).

Figure 2.5.4 (Left to right) Structures of

o

‐,

m

‐, and

p

‐carborane.

Figure 2.5.5 Strategy for the preparation of C

c

‐substituted

o

‐carboranes by reaction of decaborane with alkynes.

Figure 2.5.6 Structure of (left) [(3,3’‐Fe(1,2‐C

2

B

9

H

1 1

)

2

]

−

and (right) ferrocene.

Figure 2.5.7 Schematic representation of the detection of photons using SPECT. Only a fraction (~0.001%) of the emitted γ‐rays reach the detectors, while others are absorbed in the collimator.

Figure 2.5.8 (Left) Schematic representation of the annihilation process of one positron and one electron, with subsequent emission of two γ‐rays. (Right) Representation of a PET camera. The two photons emitted after the annihilation process are detected simultaneously by two detectors on the ring, placed around the subject under investigation.

Figure 2.5.9 Examples of radioiodinated dicarba‐

closo

‐dodecaboranes and dodecaborates. Labeling yields are included under the chemical structure. Radiolabeled

o

‐carborane derivatives using a completely different approach were recently reported by Gona

et al.

(see Figure 2.5.10) [101].

Figure 2.5.10 Synthesis and purification of 1‐iododecaborane, radiolabeling by catalytic isotopic exchange using

125

I, and subsequent reaction for the preparation of

125

I‐labeled

o

‐carborane derivatives using microwave (MW) heating and acetonitrile (MeCN) as both the solvent and the Lewis base (one‐pot, one‐step reaction). The same strategy can be used for the preparation of

131

I‐labeled analogs. HC: Herrmann’s catalyst.

Figure 2.5.11 Iodinated derivatives of COSAN. (Left) [3,3’‐Co(8‐I‐1,2‐C

2

B

9

H

10

)(1’,2’‐C

2

B

9

H

11

)]; (right) [3,3’‐Co(8‐I‐1,2‐C

2

B

9

H

10

)(8’‐(OCH

2

CH

2

)

2

COOC

6

H

5

‐1’,2’‐C

2

B

9

H

10

)]

−

.

Figure 2.5.12 (a) PET coronal projection (co‐registered with CT image) resulting from averaged images obtained after administration of [3,3’‐Co(8‐

125

I‐1,2‐C

2

B

9

H

10

)(8’‐(OCH

2

CH

2

)

2

COOC

6

H

5

‐1’,2’‐C

2

B

9

H

10

)]

−

; (b) biodistribution of [3,3’‐Co(8‐

125

I‐1,2‐C

2

B

9

H

10

)(8’‐(OCH

2

CH

2

)

2

COOC

6

H

5

‐1’,2’‐C

2

B

9

H

10

)]

−

in mice tissues using the dissection method. Radioactivity is expressed as the percentage of the injected dose (ID) per gram of tissue. LU: Lungs; H: heart; K: kidneys; S: spleen; T: testicles; L: liver; S.I.: small intestine; L.I.: large intestine; BR: brain; C: cerebellum; U: urine; BL: blood; ST: stomach.

Figure 2.5.13 Examples of radioiodinated boron clusters synthesized by radioiodination under oxidative conditions.

Figure 2.5.14 (Top) Synthesis of 9‐[

18

F]fluoro‐

o

‐carborane. (i) ICl–AlCl

3

in CH

2

Cl

2

, reflux, 4 h; (ii) NaBO

3

–Ac

2

O, RT, 90 min, then toluene–H

2

SO

4

(c), RT, 16h; (iii) Kryptofix

®

222–K

2

CO

3

, solvent. (Bottom) Syntheses of

18

F‐labeled C

c

‐substituted

o

‐carborane by reaction of 9‐[

18

F]fluoro‐

o

‐carborane with 4‐methoxybenzaldehyde (MBA). (iv) n‐BuLi, THF, Δ; then MBA in THF. RT: Room temperature; THF: tetrahydrofuran.

Figure 2.5.15 Mercapto‐

closo

‐undecahydrododecaborate (BSH) fused with a short arginine peptide (

n

 = 1, 2, or 3) and linked to a DOTA chelator to enable complexation with the positron emitter

64

Cu.

Figure 2.5.16 Cobaltacarborane with a pyrazole ring substituted with a carboxylate function as a handle for subsequent coupling. Green circle:

57

Co.

Figure 2.5.17 Reaction scheme for the formation of

99m

Tc‐labeled metallacarboranes.

Figure 2.5.18 Reaction scheme for the preparation of

11

C‐labeled carboranyl benzothiazoles.

Figure 2.5.19 (a,b) Brain PET images of U87DEGFR tumor‐bearing mice at 6 h, 12 h, and 24 h post injection of (a)

64

Cu‐labeled BSH‐3R‐DOTA and (b)

64

Cu‐labeled BSH‐DOTA. (c,d) Quantification analysis by PET images of radioactivity accumulation in the tumor, normal brain, and heart at 6 h, 12 h, and 24 h post injection of (c)

64

Cu‐labeled BSH‐DOTA and (d)

64

Cu‐labeled BSH‐3R‐DOTA.

Figure 2.5.20 Example of an oligomeric

nido

‐carborane phosphate diester derivative. Recently, two

124

I‐labeled COSAN analogs (see Figure 2.5.21) have been prepared by some of the authors using palladium0catalyzed iodine exchange, and subsequently evaluated in PANC‐1 (human pancreatic carcinoma) and A549 (carcinomic human alveolar basal epithelial cell line) xerograft mouse models [142,143]. [

18

F]FDG PET studies were conducted in the same animals to assess tumor metabolism.

Figure 2.5.21 Structure of the

124

I‐labeled COSAN analogs.

Figure 2.5.22 Biodistribution of [

18

F]FDG in subcutaneous PANC‐1 (human pancreatic carcinoma) and A549 (carcinomic human alveolar basal epithelial cell line) xerograft mouse models. Time–activity curves in the tumor, expressed as the percentage of the injected dose (%ID) per cubic centimeter of tissue, are shown in (a) and (b). PET sagittal (c) and coronal (d) slices resulting from averaged images obtained after administration of [

18

F]FDG in mice bearing A549 (c) and PANC‐1 (d) tumors are shown; optimal viewpoint and slides have been selected for correct visualization of the tumor.

Figure 2.5.23 Radioiodinated 7‐hydroxy‐

nido

‐carboranol (I‐

nido

‐carboranol,

1

and

4

),

nido

‐salborin (I‐

nido

‐salborin,

2

and

5

), and 7,8‐dicarba‐

nido

‐undecaborate‐7‐carboxylic acid (

3

and

6

).

Chapter 3.1

Figure 3.1.1 Representative structures of boronated nucleoside analogs that do not belong to the class of the 3CTAs.

Figure 3.1.2 Structures of carboranes used in the synthesis of 3CTAs discussed in this review: (a)

closo‐o

‐carborane, (b)

closo‐p

‐carborane, (c1)

closo‐m

‐carborane, (c2)

nido‐m

‐carborane. Generated by Chem 3D, Perkin Elmer, Cambridge, MA, USA.

Figure 3.1.3 (a) Possible binding interaction of TK1 with dThd in affinity chromatography. (b) Affinity chromatography–based model developed for the design of 3CTAs. (c) Docking pose of

N5 (6)

‐triphosphate into a homology model of TK1.

Figure 3.1.4 Representative structures of first‐generation 3CTAs (

6–11

), (radio)halogenated 3CTAs (

12

), and amino acid ester prodrugs of 3CTAs (

13

).

rac

‐N5‐2OH

(

7

) was prepared with normal boron distribution,

10

B‐enriched, and in tritiated form.

Figure 3.1.5 Representative second‐generation 3CTAs with hydrogen donor–acceptor modifications in the spacer between the dThd scaffold and carborane cluster.

Figure 3.1.6 Representative second‐generation 3CTAs with hydrophilic and ionic structural modifications at the carborane cluster.

Figure 3.1.7 Potential tumor cell‐related influx, efflux, and anabolic processes of 3CTAs. DNA Pol: DNA polymerase; NDPK: nucleoside diphosphate kinase; MRP4: multidrug resistance‐associated protein‐4; TK1: thymidine kinase‐1; TMPK: thymidine monophosphate kinase.

Chapter 3.2

Figure 3.2.1 The

10

B(n,α)

7

Li neutron capture and fission reactions [3].

Figure 3.2.2 Structures of BSH, BPA, and common boron clusters currently used in BNCT drug development. The cluster atom representation is used throughout this chapter [5].

Figure 3.2.3 Structures of boronated amino acids [35–38,46].

Figure 3.2.4 Structures of

ortho

‐carborane conjugated with [F

7

,P

34

]‐NPY and BSH/

ortho

‐carborane conjugated with cyclic RGD [53,55].

Figure 3.2.5 Structure of eight BSH‐fused polyarginine [57].

Figure 3.2.6 Structures of boronated nucleosides [59,64–66].

Figure 3.2.7 Monoclonal antibody (cetuximab or L8A4) conjugated to a boronated polyamidoamine [73].

Figure 3.2.8 Structures of boronated porphyrins [5,95].

Figure 3.2.9 Structures of H

2

OCP and ZnOCP [90].

Figure 3.2.10 Structures of cobaltabis(dicarbollide)‐containing porphyrins [85,87].

Figure 3.2.11 Fluorinated carboranylporphyrins [81].

Figure 3.2.12 Fluorinated carboranylporphyrins functionalized with polyamines and PEG [82,83].

Figure 3.2.13 Fluorinated carboranylporphyrins functionalized with polyamines, glucose, arginine, and peptide [82,83].

Figure 3.2.14 Structures of boronated chlorins [81,119].

Figure 3.2.15 Structures of chlorin e

6

–based boronated derivatives [117,118].

Figure 3.2.16 Structures of chlorin e

6

–based boronated derivatives bearing cobaltabis(dicarbollide) moieties [114,115].

Figure 3.2.17 Structures of chlorin e

6

–based boronated derivatives bearing BPA moieties [110].

Figure 3.2.18 Structures of chlorin e

6

–based boronated derivatives bearing BSH moieties [111].

Figure 3.2.19 Structures of boronated phthalocyanines [120,122].

Figure 3.2.20 Structures of phthalocyanines with high boron content [121–123].

Figure 3.2.21 Structures of BODIPYs, which are effective for neutron dynamic therapy [131].

Figure 3.2.22 Structures of a series of

closo

‐carboranyl BODIPYs [132].

Figure 3.2.23 Structures of a series of carboranyl BODIPYs [134].

Figure 3.2.24 Structure of a carboranyl

bis

‐BODIPY.

Figure 3.2.25 Structures of boronated lipids [142,143,146,148].

Figure 3.2.26 Liposomes carrying hydrophilic polyhedral borane TAC in the aqueous core and

nido

‐carborane MAC in the bilayer [151].

Figure 3.2.27 Schematic representation of the model design and synthesis of multifunctionalized Au NPs [156].

Figure 3.2.28 Mercaptocarborane‐capped Au NPs [157].

Figure 3.2.29 Au NPs incorporating

ortho

‐carboranes and PEG groups [159].

Figure 3.2.30 Dextran‐bounded APBA and boronated Si NPs [160,161].

Figure 3.2.31 FITC‐doped decaborate Si NPs, BPO

4

–folate NPs, PLMB, PEG‐b‐PMBSH, and PEG‐b‐PMNT [162,163,166,167].

Chapter 3.3

Figure 3.3.1 Carboranylporphyrins containing the aminomethylene bond.

Figure 3.3.2 Carboranylporphyrins with aminoalcohol and amide bonds.

Figure 3.3.3 Types of boronated porphyrins prepared from succinic and maleic aminoporphyrin derivatives.

Figure 3.3.4 Fluorinated porphyrin and chlorin conjugates with

closo

‐carborane polyhedra.

Figure 3.3.5 Fluorinated porphyrin conjugates with neutral and anionic

closo

‐carboranylthio‐substituents.

Figure 3.3.6 Polyamine, peptide, and glucose conjugates of fluorinated

p

‐carboranylmethylthio‐porphyrin.

Figure 3.3.7 Tetrakis(

p

‐carboranylthio‐tetrafluorophenyl)chlorin (TPFC).

Figure 3.3.8 Boronated derivatives of pyropheophorbide

a

.

Figure 3.3.9 Boronated derivatives of methylpheophorbide

a

.

Figure 3.3.10 Carborane‐substituted derivatives of chlorin e

6

.

Figure 3.3.11 Chlorin derivatives prepared from BSH‐containing protoporphyrin IX dimethyl ester.

Figure 3.3.12 BSH‐ and cobalt bis(dicarbollide) conjugates of chlorin e

6

.

Figure 3.3.13 Boronated ester and amide conjugates of purpurin‐18.

Figure 3.3.14 Boronated conjugates of N‐aminobacteriopurpurinimide.

Chapter 3.4

Figure 3.4.1 (a) Different axes of nanoparticle applications as theranostic agents. (b) The main properties influencing the distribution, elimination, and targeting of particles to tumors.

Figure 3.4.2

p

‐Borono‐l‐phenylalanine (BPA) and sodium mercaptododecaborate (BSH).

Figure 3.4.3

closo

‐Dodecaborate lipid. (a) Fluorescence‐labeled

closo

‐dodecaborate lipid and (b)

in vivo

image of the fluorescence‐labeled

closo

‐dodecaborate lipid‐labeled liposomes (green) in the colon of 26 tumor‐bearing mice (tumor tissues were stained in blue).

Figure 3.4.4 Synthesis of single‐walled carbon nanotube–supported

nido

‐carboranes.

Figure 3.4.5 Transferrin‐grafted boron–nitride nanotube.

Figure 3.4.6 Synthesis of encapsulated magnetic nanocomposites.

Figure 3.4.7 Boron concentration distribution in tissues using compound

3

. (a) Without external magnetic field, and (b) with external magnetic field.

Figure 3.4.8 Transmission electron microscopy (TEM) image representing the magnetic cores of compound

3

within tumor cells.

Figure 3.4.9 Preparation of carborane‐containing polymer nanoparticles.

Chapter 3.5

Figure 3.5.1

10

B capture reaction induced by thermal neutrons.

Figure 3.5.2 Structures of (A) BPA and (B) BSH.

Figure 3.5.3 Fluorine‐18 boronophenylalanine analog (

18

F‐FBPA).

Figure 3.5.4 (a) Cerebral blood volume and (b–d)

18

F‐BPA PET images of a patient with a sporadic right vestibular schwannoma. In spite of the small volume of the tumor, which measured 16 mm in diameter, the schwannoma is well visualized with

18

F‐BPA in (b), whereas the blood volume image obtained with inhaled [

15

O]CO shows only major cranial vessels. In (c), increased tracer uptake is seen in nasal mucosa and the parotid glands, while (d) indicates that the scalp has a higher uptake than the brain. This is in line with skin and mucosal toxicity seen in BNCT, where BPA is found to accumulate in these normal tissues.

Figure 3.5.5 A 3‐compartment model for

18

F‐BPA uptake. The rate constants K

1

, k

2

, k

3

, and k

4

define the transport between the central compartment Cp (plasma); the tissue compartment C1 represents nonspecifically bound

18

F‐BPA; and the deeper tissue compartment C2 represents

18

F‐BPA bound in the tissue (cell). K

1

and k

2

are the rate constants for forward and reverse transport of

10

B BPA across the blood–brain barrier, respectively. k

3

and k

4

are the anabolic and the reverse process rate constants.

Figure 3.5.6 Structure of (A) Gd‐DTPA‐BPA and (B) AT101.

Figure 3.5.7 Correlation between intracellular boron concentrations measured by ICP‐MS and MRI. Boron concentrations were measured in B16 murine melanoma cells (▪) and HepG2 human hepatocarcinoma cells (◽) after 16 h of incubation at different Gd‐B‐L/LDL particle concentrations.

Figure 3.5.8 (a,b) Representative T

1

‐weighted MR images of C57BL/6 mice grafted subcutaneously with B16 melanoma cells. (d,e) BALB/c mice with pulmonary metastases generated by the injection of breast cancer cells (TUBO). Images were acquired (a,d) before, (b) 4 h after, and (e) 3 h after the administration of AT101/LDL particles. The arrows indicate tumor regions. The graphs show the percentage of tumor volume increase, measured by MRI on (c) B16 tumors and (f) lung metastasis. Error bars indicate the SD.

Figure 3.5.9 Structures of (a) benzo[b]acridin‐12(7H)‐one and (b) FL‐SBL.

Figure 3.5.10 Fluorescent live‐cell imaging of the carboranylmethylbenzo[b]‐acridones: (Panel A) Figure 3.5.9a compound

a

and (Panel B) Figure 3.5.9a compound

c

in the U87 cells visualized by time‐lapse confocal microscopy. The whole cell or cell nuclei were stained with (Panel A) DHE shown in red or (Panel B) Hoechst 33342 shown in blue. After incubation with the dyes for 10 min, the cells were washed with phosphate‐buffered saline (PBS), and the compounds were added at 200 μM. Images in (Panel A) blue or (Panel B) green channels were acquired after a 30‐min time period.

Figure 3.5.11 Schematic representation of tumor cell destruction by BNCT using targeted boron carriers.

Figure 3.5.12 Schematic representation of the trifunctional agent DC‐1.

Figure 3.5.13 Schematic representation of 3‐[5‐{2‐(2,3‐dihydroxyprop‐1‐yl)‐o‐carboran‐1‐yl}pentan‐1‐yl] thymidine (N5–2OH).

Figure 3.5.14 Schematic representation of a liposome loaded with drugs and imaging agents.

Chapter 3.6

Figure 3.6.1 (a) Topical application of the carcinogen DMBA 0.5% in mineral oil in the hamster cheek pouch. The pouch can be readily everted for local treatment, such as irradiation (b) and macroscopic follow‐up (c).

Figure 3.6.2 An example of BNCT therapeutic effect on tumors: (a) Cancerized cheek pouch bearing tumors before BPA–BNCT at the RA‐6 Nuclear Reactor. (b) Cancerized cheek pouch of the same animal 28 days after BNCT, exhibiting tumor remission with slight mucositis in precancerous tissue.

Figure 3.6.3 (a) Subcapsular inoculation of syngeneic colon cancer cells (DHD/K12/TRb) in the liver of BDIX rats. (b) Tumor nodule, 2 weeks post inoculation (pretreatment). (c) Untreated tumor (time‐matched with BNCT‐treated tumor). (d) Tumor, 3 weeks post BNCT.

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Boron‐Based Compounds

Potential and Emerging Applications in Medicine

Edited by

Evamarie Hey‐Hawkins

Department of Inorganic Chemistry, Leipzig UniversityLeipzig, Germany

Clara Viñas Teixidor

Spanish Council for Scientific Research, Institut de Ciència de Materials de BarcelonaBarcelona, Spain

This edition first published 2018© 2018 John Wiley & Sons Ltd

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Library of Congress Cataloging‐in‐Publication Data

Names: Hey‐Hawkins, Evamarie, 1957– editor.Title: Boron‐based compounds : potential and emerging applications in medicine / edited by Evamarie Hey‐Hawkins, University of Leipzig, Leipzig, Germany, Clara Viñas Teixidor, Institut de Ciencia de Materials de Barcelona, Barcelona, Spain.Description: First edition. | Hoboken, NJ, USA : Wiley, [2018] | Includes bibliographical references and index. |Identifiers: LCCN 2017055295 (print) | LCCN 2018009581 (ebook) | ISBN 9781119275589 (pdf) | ISBN 9781119275596 (epub) | ISBN 9781119275558 (cloth)