Table of Contents

Cover

Title Page

Copyright
Dedication

About the Editors

Preface

Acknowledgments

Section I: Introduction

Chapter 1: Karen J. Brewer (1961–2014): A Bright Star that Burned Out Far Too Soon
1. 1.1 Introduction
2. 1.2 Early Years
3. 1.3 Graduate Studies and Clemson University
4. 1.4 Postdoctoral Research and the University of California, Berkeley
5. 1.5 Washington State University: Beginning an Independent Career
6. 1.6 Move to Virginia Tech
7. 1.7 Collaboration with Brenda Winkel and the Study of Metal-DNA Interactions
8. 1.8 A Return to Where It All Started: Photochemical H₂ Production
9. 1.9 A Career Cut Tragically Short
10. 1.10 Karen's Legacy
11. Acknowledgments
12. References
Chapter 2: Basic Coordination Chemistry of Ruthenium
1. 2.1 Coordination Chemistry of Ruthenium
2. References

Section II: Artificial Photosynthesis

Chapter 3: Water Oxidation Catalysis with Ruthenium
1. 3.1 Introduction
2. 3.2 Ruthenium in Water Oxidation Catalyst
3. 3.3 Conclusions and Perspectives
4. References
Chapter 4: Ruthenium- and Cobalt-Containing Complexes and Hydrogenases for Hydrogen Production
1. 4.1 Introduction
2. 4.2 (A) Ruthenium- and Cobalt-Containing Complexes for Hydrogen Production
3. 4.3 (B) Ruthenium(II)-Containing Complexes and Hydrogenases for Hydrogen Generation in Aqueous Solution
4. 4.4 Conclusions
5. References

Section III: Applications in Medicine

Chapter 5: Ligand Photosubstitution Reactions with Ruthenium Compounds: Applications in Chemical Biology and Medicinal Chemistry
1. 5.1 Introduction
2. 5.2 Caging and Uncaging Biologically Active Ligands with a Nontoxic Ruthenium Complex
3. 5.3 Caging Cytotoxic Ruthenium Complexes with Organic Ligands
4. 5.4 Low-Energy Photosubstitution
5. 5.5 Conclusions
6. References
Chapter 6: Use of Ruthenium Complexes as Photosensitizers in Photodynamic Therapy
1. 6.1 Introduction
2. 6.2 The Basics of Photodynamic Therapy
3. 6.3 Status of Ru Photosensitizing Complexes
4. 6.4 Issues to Be Considered to Further Develop Ru-Based Photosensitizers
5. 6.5 Future Directions for Ru-PS Research
6. 6.6 Conclusion
7. References
Chapter 7: Photodynamic Therapy in Medicine with Mixed-Metal/Supramolecular Complexes
1. 7.1 Introduction
2. 7.2 Platinum and Rhodium Centers as Bioactive Sites
3. 7.3 Supramolecular Complexes as DNA Photomodification Agents
4. 7.4 Mixed-Metal Complexes as Photodynamic Therapeutic Agents
5. 7.5 Summary and Conclusions
6. Abbreviations
7. References
Chapter 8: Ruthenium Anticancer Agents En Route to the Tumor: From Plasma Protein Binding Agents to Targeted Delivery
1. 8.1 Introduction
2. 8.2 Protein Binding Ru^III Anticancer Drug Candidates
3. 8.3 Functionalization of Macromolecular Carrier Systems with Ru Anticancer Agents
4. 8.4 Hormones, Vitamins, and Sugars: Ruthenium Complexes Targeting Small Molecule Receptors
5. 8.5 Peptides as Transporters for Ruthenium Complexes into Tumor Cells and Cell Compartments
6. 8.6 Polynuclear Ruthenium Complexes for the Delivery of a Cytotoxic Payload
7. 8.7 Summary and Conclusions
8. Acknowledgments
9. References
Chapter 9: Design Aspects of Ruthenium Complexes as DNA Probes and Therapeutic Agents
1. 9.1 Introduction
2. 9.2 Physical Interaction to Disrupt DNA Structure
3. 9.3 Biological Consequences of Ru-Complex/DNA Interactions
4. 9.4 Effects of Ru Complexes on Topoisomerases and Telomerase
5. 9.5 Summary and Conclusions
6. References
Chapter 10: Ruthenium-Based Anticancer Compounds: Insights into Their Cellular Targeting and Mechanism of Action
1. 10.1 Introduction
2. 10.2 Cellular Uptake
3. 10.3 DNA and DNA-Related Cellular Targets
4. 10.4 Targeting Signaling Pathways
5. 10.5 Targeting Enzymes of Specific Cell Functions
6. 10.6 Targeting Glycolytic Pathways
7. 10.7 Macromolecular Ruthenium Conjugates: A New Approach to Targeting
8. 10.8 Conclusions
9. References
Chapter 11: Targeting cellular DNA with Luminescent Ruthenium(II) Polypyridyl Complexes
1. 11.1 Introduction
2. 11.2 [Ru(bpy)₂(dppz)]²⁺ and the DNA “Light-Switch” Effect
3. 11.3 Cellular Uptake of RPCs and Application as DNA-Imaging Agents
4. 11.4 Alternative Techniques to Assess Cellular Uptake and Localization
5. 11.5 Toward Theranostics: luminescent RPCs as Anticancer Therapeutics
6. 11.6 Summary and Conclusions
7. References
Chapter 12: Biological Activity of Ruthenium Complexes With Quinoline Antibacterial and Antimalarial Drugs
1. 12.1 Introduction
2. 12.2 Antibacterial (Fluoro)quinolones
3. 12.3 Antibacterial 8-Hydroxyquinolines
4. 12.4 Antimalarial 4-Aminoquinolines
5. 12.5 Metallocene Analogues of Chloroquine
6. 12.6 Conclusions
7. References
Chapter 13: Ruthenium Complexes as NO Donors: Perspectives and Photobiological Applications
1. 13.1 Introduction
2. 13.2 Photochemical Processes of Some Nitrogen Oxide Derivative–Ruthenium Complexes
3. 13.3 Photobiological Applications of Nitrogen Oxide Compounds
4. References
Chapter 14: Trends and Perspectives of Ruthenium Anticancer Compounds (Non-PDT)
1. 14.1 Introduction
2. 14.2 Ruthenium(III) Compounds
3. 14.3 Organoruthenium(II) Compounds
4. References
Chapter 15: Ruthenium Complexes as Antifungal Agents
1. 15.1 Introduction
2. 15.2 Antifungal Activity Investigations of Ruthenium Complexes
3. 15.3 Conclusion
4. References
Index

End User License Agreement

List of Illustrations

Chapter 1: Karen J. Brewer (1961–2014): A Bright Star that Burned Out Far Too Soon

Figure 1.1 Karen J. Brewer (1961–2014) in the Spring of 2014.
Figure 1.2 Publications per year from 1985 to 2015.
Figure 1.3 Karen in kindergarten at age 5.
Figure 1.4 Karen in her senior year of high school at age 17.
Figure 1.5 John D. Petersen (b. 1947).
Figure 1.6 Karen Brewer's academic genealogy.
Figure 1.7 Basic design of bimetallic complexes capable of efficient photochemical processes.
Figure 1.8 Polypyridyl ligands referenced throughout the chapter.
Figure 1.9 Melvin Calvin.
Figure 1.10 Mixed-valence manganese μ-oxo dimers of macrocyclic tetradentate ligands.
Figure 1.11 Brewer Group, Spring 1990 (L to R): Eric Kimble (undergrad), Bob Williamson (undergrad), Seth Rasmussen (undergrad), Keith Blomgren (undergrad), Karen Brewer (Asst. Prof.), Sumner Jones (undergrad), Mark Richter (grad student), and Jon Bridgewater (undergrad).
Figure 1.12 The terdentate bridging ligand 2,3,5,6-tetrakis(2-pyridyl)pyrazine.
Figure 1.13 Karen J. Brewer and collaborator Brenda Winkel in 2005.

Chapter 2: Basic Coordination Chemistry of Ruthenium

Figure 2.1 The two stabilizing interactions that constitute the Dewar–Chatt–Duncanson model for bonding in metal–olefin interactions.
Figure 2.2 (a) Representation of the M-C σ-bond to the unshared electron pair of the C atom. (b) Representation of the M-C π-bond (back-bonding). The other orbitals are omitted for clarity.
Figure 2.3 Dichloro(p-cymene)ruthenium(II) dimer. An example of a ruthenium-arene.
Figure 2.4 Structure of Ru(CO)₂(P^tBu₂Me)₂.
Figure 2.5 Qualitative MO analysis of the nature of metal–metal and metal–carbonyl bonding in the Ru₃(CO)₁₂ trimer.
Figure 2.6 Structure of [(SiP^iPr₃)Ru(N₂)].
Scheme 2.1 Examples of various approaches to prepare Ru(II) species.
Figure 2.7 Some selected reactions utilizing low-valent ruthenium.
Figure 2.8 An example of a cross-metathesis reaction.
Figure 2.9 A representation of oxo-centered trinuclear ruthenium(III) acetate. L represents coordinating solvents such as H₂O, ROH, py, and so on.
Scheme 2.2 Typical reactions of RuO₄.

Chapter 3: Water Oxidation Catalysis with Ruthenium

Figure 3.1 Schematic representation of the Z-scheme of photosynthesis, within the energy diagram representing the main electron-transfer processes and the redox reactions involved.
Figure 3.2 Structural representation of the Mn₄ OEC (obtained from the crystallographic data in Ref [9a]), and the Kok cycle.
Figure 3.3 Dependence of overpotential for water oxidation on the enthalpy of oxygen adsorption on transition metals for different heterogeneous metal oxides.
Figure 3.4 Molecular WOC discussed in section.
Figure 3.5 Proposed pathway leading to oxygen evolution with Ru-Hbpp (tpy ligands of Ru-Hbpp are omitted for reasons of clarity) [27].
Figure 3.6 Mechanism of water oxidation with the Meyer's. (left: Reprinted with permission from [28]. Copyright (2008) American Chemical Society.) and Thummel's (right: Reprinted with permission from [29b]. Copyright (2013) Royal Society of Chemistry.) single-site catalysts.
Figure 3.7 (a) Crystal structure of the Ru(bda)pic₂ dimer showing the [HOHOH]⁻ bridge. (Reprinted with permission from [32a]. Copyright (2009) American Chemical Society.) (b) Calculated bimolecular complex of the Ru(bda)isoq₂ catalyst. (Reprinted with permission from [33]. Copyright (2012) Nature Publishing Group.) (c) Synthesis of the macrocycle trimer [Ru(bda)bpb]₃.
Figure 3.8 Structure of [Ru^IV₄(μ-O)₄(μ-OH)₂(H₂O)₄(γ-SiW₁₀O₃₆)₂]^10- (a) and of the adamantane-like [Ru^IV₄(μ-O)₄(μ-OH)₂(H₂O)₄]⁶⁺ tetraruthenium-oxo core (b).

Chapter 4: Ruthenium- and Cobalt-Containing Complexes and Hydrogenases for Hydrogen Production

Figure 4.1 Examples of cobalt-containing catalysts that are able to produce hydrogen in the presence of a ruthenium photosensitizer.
Figure 4.2 Proposed mechanisms for the production of hydrogen in acidic media [14c].
Figure 4.3 (a and b) Homogeneous systems for photocatalytic H₂ production with a sacrificial electron donor D. (a) Multicomponent system consisting of [Ru(bpy)₃]Cl₂ and a cobaloxime, [Co(dmgH)₂(H₂O)₂] [17]. (b) Binuclear mixed-metal ruthenium(II)–cobalt(II) complex, where the ruthenium(II) photosensitizer is covalently linked to the cobaloxime [18].
Figure 4.4 Binuclear mixed-metal complexes used for the production of hydrogen in acidic media [14c, 21, 22].
Figure 4.5 Schematic representation of photo-H₂ evolution with RuP/CoP-modified TiO₂.
Figure 4.6 Possible photochemical mechanisms for catalyst reduction in a homogeneous system for hydrogen production involving a hydrogen evolution catalyst (HEC) [10a, 25, 26].
Figure 4.7 Two different types of [FeFe]- and [NiFe]-hydrogenases [30].
Figure 4.8 Scheme of photoinduced hydrogen evolution system [33].
Figure 4.9 Various ruthenium(II) photosensitizers used with hydrogenase for hydrogen production.
Figure 4.10 Hydrogenase covalently linked to a Ru(II) complex with EDTA as a sacrificial reductant and methyl viologen (MV) as a redox mediator for hydrogen production.

Chapter 5: Ligand Photosubstitution Reactions with Ruthenium Compounds: Applications in Chemical Biology and Medicinal Chemistry

Figure 5.1 Photosubstitution of a ligand L bound to a Ru(II) or Ru(III) center in chemical biology. Either the ruthenium complex, or the ligand, or both, can have a biological function.
Figure 5.2 (a) Photosubstitution reactions of ruthenium polypyridyl complexes leading to phototoxicity in vitro, (b) photosubstitutionally active ruthenium polypyridyl complexes with phototoxicity in vitro, and (c) photosubstitutionally active ruthenium arene complexes.
Figure 5.3 Dose–response curves for compound [21]²⁺ (a) and [22]²⁺ (b) in HL60 leukemia cells in the dark (circles) and after white light irradiation (squares, >450 nm light, 410 W, 3 min).
Figure 5.4 Förster resonance and Dexter energy transfer mechanisms, (a) forward FRET (b) showing donor and acceptor excitation (solid) and emission (dashed), and (c) reverse FRET (d) showing donor and acceptor excitation (solid) and emission (dashed).
Figure 5.5 Ruthenium-chromophore molecular dyads for low-energy photosubstitution reactions via chromophore-to-ruthenium nonradiative energy transfer.
Figure 5.6 Triplet–triplet annihilation upconversion (TTA-UC) scheme for PdTPBP (sensitizer PS) and perylene (annihilator A). Irradiation (630 nm) of the TTA-UC couple results in excitation of ¹PS to ³PS*, which undergoes Dexter energy transfer (DET) to the annihilator. Two annihilators in the triplet state ³A* undergo TTA, which finally results in the emission of higher energy light (473 nm). The luminescence spectrum of the sensitizer and annihilator in toluene (298 K) is shown with excitation and emission wavelengths.
Figure 5.7 Two-liposome system for red light activation of ruthenium polypyridyl compound, [49]²⁺ using triplet–triplet annihilation upconversion (TTA-UC). TTA-UC liposomes consist of DMPC liposomes with 4 mol% DSPE-mPEG-2000 loaded with PdTPBP as the photosensitizer, and perylene as the annihilator. They were mixed in a 1 : 1 volume ratio with Ru-loaded liposomes made of a 96 : 4 : 4 DMPC:DSPE-mPEG-2000:[49]²⁺ lipid mixture.
Figure 5.8 Lanthanide-doped NaYF₄:Yb³⁺/Tm³⁺ upconverting nanoparticle for photorelease of [Ru(bpy)₂(PMe₃)(L)]²⁺ (L = NH₂(CH₂)₃Si(OC₂H₅)₃] to deliver doxorubicin.

Chapter 6: Use of Ruthenium Complexes as Photosensitizers in Photodynamic Therapy

Figure 6.1 Type I/II photochemical reactions for PS, here indicated as Ru-PS, resulting in the generation of short- and long-lived reactive oxygen species (ROS) with various lifetimes as indicated.
Figure 6.2 Molar absorptivity (extinction) coefficient (MEC) of a 10 μM TLD1433 solution in DI-water (dotted), in incomplete DMEM (dashed black) and in complete DMEM (solid black) as function of wavelength.

Chapter 7: Photodynamic Therapy in Medicine with Mixed-Metal/Supramolecular Complexes

Figure 7.1 (a) Aquation of cisplatin. (b) Second-generation derivatives of cisplatin carboplatin and oxaliplatin.
Figure 7.2 Structural representations of (a) [Rh(phen)₂Cl₂]⁺, (b) [Rh(Me₄phen)₂Cl₂]⁺, and (c) [Rh(phen)(dppz)Cl₂]⁺.
Figure 7.3 Structural representation of [(bpy)₂(Ru(dpb)PtCl₂]²⁺.
Figure 7.4 Structural representation of [Ru(bpy)₂{μ-bpy(CONH(CH₂)₃NH₂)₂}PtCl₂]²⁺.
Figure 7.5 Structural representation of [{(bpy)₂Ru(dpp)}₂Ru(dpp)PtCl₂]⁶⁺.
Figure 7.6 Imaged agarose gel showing the photocleavage of pUC18 and pBluescript plasmid by [{(bpy)₂Ru(dpp)}₂RhCl₂]⁵⁺, and [{(tpy)RuCl(dpp)}₂RhCl₂]³⁺ in the absence of molecular oxygen. Lanes λ are the λ molecular-weight standards, lanes C are the plasmid controls, lanes MC are the dark plasmid controls incubated at 37 °C (2 h) in the presence of the metal complex at a 1 : 5 metal complex:base pair ratio, and lanes hν, MC are the plasmids irradiated at λ ≥ 475 nm for 20 min in the presence of the metal complex at a 1 : 5 metal complex:base pair ratio.
Figure 7.7 Phase-contrast images of Vero cells after uptake of 8 (a) dark, (b) dark 48 h, (c) preillumination (0 h), (d) postillumination (48 h). (e) Inhibition of Vero cell replication by 8.
Figure 7.8 Phase-contrast image of HFF (upper panel) and A431 cells (lower panel). (a) (dark) and (b) (light) toxicity with [Ru(pbt)₂(tpphz)VO(sal-l-tryp)]Cl₂. (c) (dark) and (d) (light) toxicity with [Ru(pbt)₂(phen₂DTT)VO(sal-l-tryp)]Cl_2. Magnification = 10×.

Chapter 8: Ruthenium Anticancer Agents En Route to the Tumor: From Plasma Protein Binding Agents to Targeted Delivery

Figure 8.1 Structures of promising Ru anticancer agents.
Figure 8.2 Delivery strategies for Ru anticancer agents to the tumor and into tumor cells.
Figure 8.3 The enhanced permeability and retention effect allows macromolecules to accumulate in tumor tissue.
Figure 8.4 Structures of Ru(arene) compounds designed to utilize HSA as a vector to the tumor.
Figure 8.5 Structure of a NAMI derivative for incorporation in micelles.
Figure 8.6 Chemical structures of organometallic hormone receptor targeting agents.
Figure 8.7 Docking results of a biotinylated Ru(arene) complex to the biotin binding site of streptavidin [70].
Figure 8.8 Chemical structure of a Ru complex conjugated to a tetraarginine residue for targeting the cell nucleus of cells.
Figure 8.9 Molecular structure of Pt(acac)₂ trapped in a hexanuclear Ru complex [89].

Chapter 9: Design Aspects of Ruthenium Complexes as DNA Probes and Therapeutic Agents

Figure 9.1 Structures of ruthenium complexes.

Chapter 10: Ruthenium-Based Anticancer Compounds: Insights into Their Cellular Targeting and Mechanism of Action

Figure 10.1 Chemical structures of ruthenium-based compounds reported to have anticancer activity (Ph = phenyl).
Figure 10.2 Acid phosphatase (AcP) activity in the cancer cell line MDAMB231. Cytochemical localization of AcP was done by a cerium-based method [44]. The Ru^II(η⁵-C₅H₅) complex TM34 enters the cells probably by endocytosis, and inhibits AcP activity in a dose-dependent mode. The same trend was observed for NaF and vanadate, respectively noncompetitive and competitive inhibitors of the enzyme [75]. Ultrastructural analysis by TEM showed that the complex also causes disruption and vesiculation of the Golgi apparatus, which suggested the endosomal/lysosomal system as a possible target [44].
Figure 10.3 TPMET activity in the high glycolytic breast cancer cells MDAMB231 (simplified proposed model). TPMET activity was measured by reduction of ferricyanide. Mitochondrial NADH production is linked to ferricyanide reduction via the mitochondrial electron transport system (MET). TPMET can ameliorate intracellular reductive stress, which originates from the mitochondrial tricarboxylic acid (TCA) cycle. We propose that the inhibition of this pathway leads to the decrease in the viability of MDAMB231 cells, which rely on tPMET activity for survival. Results indicated that the Ru complexes TM34, TM85 and TM102 can inhibit ferricyanide reductase and lactate production in a manner dependent on their anticancer potential. 2-Deoxyglucose was used as a control inhibitor, as it targets hexokinase which is the first step of glycolysis, and inhibits tPMET by depletion of pyruvate and ATP levels [49].
Figure 10.4 Chemical structure of d-glucose end-capped polylactide ruthenium-cyclopentadienyl complex (RuPMC) and its proposed cellular uptake mechanism $c010-math-001$ .
Figure 10.5 Interaction between supercoiled phiX174 plasmid DNA and the ruthenium complexes TM34 (1 μM) and RuPMC (25 μM) after 24-h incubation at 37 °C in phosphate buffer (pH 7.2). Forms I and II are supercoiled and nicked circular isoforms of DNA, respectively. The concentrations of complex used were equivalent to the IC₅₀ values found at 24-h incubation.
Figure 10.6 Ultrastructural analysis by TEM of the MCF7 cancer cells after 24-h treatment with RuPMC and TM34: (a) cells treated with RuPMC (25 μM); (b) cells treated with TM34 (1 μM); inset) control cells (no treatment). Mitochondrial alterations were detected in Ru-treated cells, consisting of edema and disorganization of the cristae. In particular, intramitochondrial dense inclusions are present in TM34-treated cells and mitochondrial edema seemed increased in RuPMC-treated cells. M, mitochondria; N, nucleus.

Chapter 11: Targeting cellular DNA with Luminescent Ruthenium(II) Polypyridyl Complexes

Figure 11.1 (a) DNA-imaging agent DAPI (top) and X-ray crystal structure of DAPI bound to duplex DNA in minor groove (bottom, PDB: 1D30). (b) Ethidium bromide (EB) and crystal structure of EB intercalating between DNA base pairs (NDB: DRB006). (c) The anticancer drug cisplatin, which forms cisplatin-DNA inter-/intrastrand adducts (PDB: 1A84, [7]).
Figure 11.2 (a) Octahedral Ru(II) tris(phenanthroline) complexes and derivatives, showing stereochemistry of Λ and Δ enantiomers. (b) Structure of Ru(N^N)₂(dppz)²⁺ (N^N = bpy or phen) metallointercalators. (c) Increase in luminescence of Ru(bpy)₂(dppz)²⁺ with addition of DNA. (Reproduced with permission from [21], © 1990 American Chemical Society (ACS)). (d) Schematic of electronic transitions of RPC MLCT emission (MLCT = metal-to-ligand charge-transfer, GS = ground state). (e) X-ray crystal structure of 2.1 and DNA showing side-by-side intercalation (*) and insertion (→) binding modes (PDB: 4E1U, [22]).
Figure 11.3 (a) Hydrophobic Ru(dppz) intercalator and intracellular localization in HeLa cervical cancer cells (bottom). (Reproduced with permission from [36], © 2007 ACS). (b) Series of Ru(dppz) complexes substituted with alkyl chains and localization in fixed and permeabilized Chinese hamster ovary (CHO) cells (scale bars = 20 µm). (Reproduced with permission from [38], © 2011 Elsevier). (c) Ru(tpphz) complexes and live-cell uptake by MCF7 human breast cancer cells showing strong nuclear emission (right, see Ref. [39]).
Figure 11.4 (a) Examples of polypyridyl bridging ligands. (b) Dinuclear Ru-tpphz-Ru complexes. (c) Live-cell uptake of dinuclear Ru(tpphz) complexes by MCF7 human breast cancer cells showing nuclear staining by 5.2 and endoplasmic reticulum (ER) staining by 5.3 (scale bars = 20 μM). (d) Co-staining of MCF7 nucleus with 5.2 and DAPI showing overlap of signals (emission cross section, right). (Adapted from data featured within Refs [44, 45].)
Figure 11.5 (a) Cyclometallated Ru(dppz) monocation. (b) Hetero bimetallic Ru(II)−Ir(III) tpphz complexes. (c) Isolated HeLa chromosomes stained with 7.1. (Adapted from Ref. [52a]). (d) HeLa cells incubated with 7.2 or 7.3 showing high nuclear accumulation (emission profile of 7.2, center, see Refs. [52]). (e) Hetero bimetallic Ru(II)−Ir(III) tpphz complex employing flexible alkyl chain and (f) nucleoli accumulation in MCF7 cells. (Reproduced with permission from [53], © 2014 Royal Society of Chemistry (RSC).)
Figure 11.6 (a) Two-photon PLIM (phosphorescent lifetime emission microscopy) imaging of 7.2-treated MCF7 cells. (Reproduced with permission from Ref. [56], © 2014 Wiley VCH). (b) Transmission electron micrograph of MCF7 cell pretreated with 7.2. Key: pm = plasma membrane, C = cytosol, N = nucleus, het = heterochromatin. See Ref. [44]. (c) RPC-labeled cell-penetrating peptide (top) and resonance Raman intensity map of a live myeloma cell treated with complex (bottom right). Reproduced with permission from Ref. [57], © 2010 RSC. (d) Quantification of nuclear and cytoplasmic uptake of a series of RPCs by ICP-MS (inductively coupled plasma mass spectroscopy). (Reproduced with permission from Ref. [54], © 2014 ACS.)
Figure 11.7 Theranostic ruthenium(II) polypyridyl complexes. Key: N = nuclear uptake, M = mitochondrial uptake. PS = photosensitizer.

Chapter 12: Biological Activity of Ruthenium Complexes With Quinoline Antibacterial and Antimalarial Drugs

Figure 12.1 Structural modifications for the inclusion of metal-containing moieties on a quinoline scaffold.
Figure 12.2 General structure of the three classes of quinoline antibacterial or antimalarial agents. (a–c) 8-hydroxyquinoline, 4-quinolone, and 4-aminoquinoline.
Figure 12.3 (a–c) Antibacterial agents nalidixic acid, oxolinic acid, cinoxacin; (d–f) antibacterial agents ciprofloxacin, levofloxacin, and HIV integrase inhibitor elvitegravir.
Figure 12.4 Crystal structure of the organoruthenium complex of quinolone ofloxacin (a). Circular DNA pRS in 5 mM NaCl on mica before (b) and after (c) exposure to 60 μM concentration of complex [(η⁶-p-cymene)RuCl(oflo)].
Figure 12.5 Hydroxyquinolines used in clinical practice: (a) clioquinol (cqH), broxyquinoline, and chloroquinaldol; (b) nitroxoline (nxH), chiniofon, and tilbroquinol.
Figure 12.6 Crystal structure of the organoruthenium complex of clioquinol [39].
Figure 12.7 Antimalarial drugs in clinical use: (a) chloroquine, amodiaquine, and mefloquine; (b) halofantrine, lumefantrine, and artemisinin.
Figure 12.8 Organoruthenium complexes of antimalarial drug chloroquine.
Figure 12.9 Chemical structure of (methyl)ferroquine and (methyl)ruthenoquine.

Chapter 13: Ruthenium Complexes as NO Donors: Perspectives and Photobiological Applications

Scheme 13.1
Figure 13.1 Trans configuration of nitrosyl ruthenium complexes (a) and d_π(Ru^II)−π*(NO⁺) back-bonding (b).
Scheme 13.2
Figure 13.2 Schematic structures of nitrosyl macrocyclic ruthenium complex.
Scheme 13.3
Figure 13.3 Schematic representation of binuclear ruthenium complex.
Scheme 13.4
Figure 13.4 Schematic representation of the conjugate Tb(phthalocyanine) – nitrosyl ruthenium complex.
Figure 13.5 Chemical structures of the nitrosyl phthalocyanine ruthenium complexes [RuNO₂(phthalocyanine)NO] (a) and [Ru(phthalocyanine)(pz)₂{Ru(bpy)₂NO}₂]⁶⁺ (b).
Scheme 13.5
Scheme 13.6 Vasodilation experiment: the thoracic aorta was isolated from male Wistar rat, cut into rings and placed between two stainless-steel stirrups and connected to an isometric force transducer. The responses were recorded using a computerized system to measure tension in the preparations. The tracheal rings were placed in a 10-ml organ chamber containing Krebs solution at pH 7.4, and gassed with 95% O₂ and 5% CO₂ at 37 °C. The rings were initially stretched to a basal tension of 1.5 g (optimal basal tone, previously determined by length–tension relationship experiments) before allowing them to equilibrate in the bathing medium. Aortic rings were precontracted with phenylephrine, a concentration that produced half-maximal contraction (EC50). When the contraction to phenylephrine had reached a plateau the nitrosyl ruthenium complex was added cumulatively.
Figure 13.6 Proposed nitric oxide release and vasodilation mechanism elicited by cis-[Ru^IICl(bpy)₂NO]²⁺ (RUNOCL). The colored circles represent atoms in the chemical structure. The hydrogen atom has been omitted in the structure. sGC, soluble guanylyl cyclase; GK, G kinase protein; Ca²⁺, calcium; K⁺, potassium; [Ca²⁺]c, cytosolic calcium concentration.

Chapter 14: Trends and Perspectives of Ruthenium Anticancer Compounds (Non-PDT)

Figure 14.1 Structural formulas of ruthenium(III) complexes NAMI-A (a), KP1019 (b), and NKP-1339 (c).
Figure 14.2 Two representatives of organoruthenium complexes in an advanced preclinical stage of development: RAPTA-C (a) and RM175 (b).
Figure 14.3 Selected anticancer organoruthenium complexes: diruthenium-1 (a), KP1582 (b), KP1796 (c), azopyridine Ru(II) complex (d), and organometallic staurosporine analogue (e).

Chapter 15: Ruthenium Complexes as Antifungal Agents

Figure 15.1 General structures of the pharmacophore ligands.

List of Tables

Chapter 2: Basic Coordination Chemistry of Ruthenium

Table 2.1 Oxidation states and stereochemistry of ruthenium

Chapter 5: Ligand Photosubstitution Reactions with Ruthenium Compounds: Applications in Chemical Biology and Medicinal Chemistry

Table 5.1 Overview of biologically active ligands L caged with a nontoxic ruthenium complex
Table 5.2 Summary of the ruthenium-chromophore dyad photochemical properties
Table 5.3 Summary of two-photon absorption properties of selected compounds

Chapter 7: Photodynamic Therapy in Medicine with Mixed-Metal/Supramolecular Complexes

Table 7.1 Anti-proliferative data obtained for respective complexes in the presence of respective cell lines

Chapter 13: Ruthenium Complexes as NO Donors: Perspectives and Photobiological Applications

Table 13.1 Polypyridine nitrosyl ruthenium complex quantum yields (φ_NO) after flash photolysis at 355 nm in trifluoroacetate buffer solution (pH = 2.01)
Table 13.2 Polypyridine nitrosyl ruthenium complex quantum yields (φ_NO) after flash photolysis at 355 nm in phosphate-buffered solution (pH = 7.4)

Chapter 15: Ruthenium Complexes as Antifungal Agents

Table 15.1 General formulas of the studied ruthenium complexes with antifungal activity (selected fungus and relevant observations) and References

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About the Editors

Alvin A. Holder is an associate professor at Old Dominion University in Norfolk, USA. He graduated from the University of the West Indies (UWI), Mona Campus, Jamaica, with a BSc (special chemistry) in 1989 and acquired his PhD in inorganic chemistry in 1994 with Prof. Tara P. Dasgupta. He was a faculty member at the University of the West Indies, Cave Hill Campus, Barbados, and an assistant professor in chemistry at the University of Southern Mississippi. His current research involves transition metal chemistry and he has published more than 65 articles and several textbooks and book chapters. In 2012, he was awarded an NSF Career Award.

Lothar Lilge is a Senior Scientist at the Princess Margaret Cancer Centre and holds a professorship at the University of Toronto, Canada. He obtained his Diploma in physics from the Johann Wolfgang Goethe University in Frankfurt, Germany, and his PhD in biophysics from the Westfaehlische Wilhelms University in Muenster, Germany. Additional training was provided through the Wellman Laboratories of Photomedicine at Massachusetts General Hospital, Boston, USA, and during a post-doc at McMaster University in Hamilton, Canada. His work is focused on photodynamic therapy including the use of ruthenium-based photosensitizers and optical spectroscopy for diagnostic and risk assessment among a range of other biophotonic application in medicine.

Wesley R. Browne is an associate professor at Stratingh Institute for Chemistry at the University of Groningen, The Netherlands, since 2013. He completed his PhD at Dublin City University, Ireland, with Prof. J. G. Vos in 2002, followed by a post-doc under the joint guidance of Prof. J. G. Vos and Prof. J. J. McGarvey, Queens University Belfast, UK. Between 2003 and 2007 he was a postdoctoral research fellow in the group of Prof. B. L. Feringa at the University of Groningen. He was appointed assistant professor in 2008. His current research interests include transition-metal-based oxidation catalysis, electrochromic materials, and responsive surfaces. He is an advisory board member for the European Journal of Inorganic Chemistry, Particle & Particle Characterization (both Wiley) and Chemical Communications (RSC). He has (co-)authored over 150 research papers, reviews, and book chapters.

Mark A. W. Lawrence was a post-doctoral fellow at Old Dominion University in Norfolk, USA, in the group of Prof. A. Holder. He received his BSc degree in 2006 and his PhD degree in inorganic-physical chemistry in 2011 from the University of the West Indies (UWI), Mona Campus, Jamaica, with Prof. Tara P. Dasgupta. His research interests include synthesis of hydrazones and functionalized pyridyl benzothiazoles, their transition metal complexes and application to catalysis and biological processes.

Jimmie L. Bullock Jr is a PhD student at the University of Kentucky in Lexington, USA, in the department of Chemistry. He received his BSc from Longwood University, Farmville, USA, and his MS in biological inorganic chemistry from Old Dominion University, Norfolk, USA, in 2013 and 2016, respectively. His research interests include studying activation of signaling pathways induced by non-platinum-based chemotherapeutic agents and synthesis of lanthanide sensor molecules.

Preface

Ruthenium, a second-row transition metal, continues to attract much attention in scientific research, as it possesses a vast array of novel applications and properties. The enormous chemistry of ruthenium, much of which remains untapped, has been and continues to be investigated by numerous researchers. One such person was an icon, Prof. Karen J. Brewer. Karen, as she was affectionately called by many of her friends and research students, is being honored for her contribution to research on ruthenium with this textbook.

Ruthenium and its compounds are also paramount in catalysis and medicine, so it is not surprising that its biological activities and coordination chemistry remain very active areas of research. Ruthenium-containing complexes have long been known to be well suited for biological applications, and have long been studied as replacements to popular platinum-based drugs.

The textbook entitled “Ruthenium Complexes: Photochemical and Biomedical Applications” focuses on the uses and application of ruthenium-containing complexes in medicine and renewable energy. This title is unique as it discusses potential applications of ruthenium complexes in solving some of the world's foremost problems. While the biological application of ruthenium-containing complexes has been known for years, their application as photosensitizers in the emerging field of photodynamic therapy, also known as photochemotherapy, is of special interest. Photodynamic therapy can be utilized to treat a wide range of medical conditions including macular degeneration and malignant cancers. Ruthenium-containing photosensitizers have been shown to be especially active in the latter, with often minimal dark toxicity. Light-activated ruthenium-containing complexes are also gaining much attention as molecular catalysts in artificial photosynthesis for the production of hydrogen gas in aqueous media, after water oxidation.

Our goal at the outset was to capture the full vibrancy of the biological and coordination chemistry of this very important element called ruthenium and, in this way, to reflect the insight and enthusiasm of the honoree, Karen. To do so, we have divided this textbook into three sections with 15 chapters: (1) Introduction (Chapters 1–2), (2) Artificial Photosynthesis (Chapters 3 and 4), and (3) Applications in Medicine (Chapters 5–15). As such, we invited experts in each of these areas to complete this project by contributing a chapter. The chapters are as follows: Chapter 1: Karen J. Brewer (1961–2014): A Bright Star that Burned Out Far Too Soon; Chapter 2: Basic Coordination Chemistry of Ruthenium; Chapter 3: Water Oxidation Catalysis with Ruthenium; Chapter 4: Ruthenium- and Cobalt-Containing Complexes and Hydrogenases for Hydrogen Production; Chapter 5: Ligand Photosubstitution Reactions with Ruthenium Compounds: Applications in Chemical Biology and Medicinal Chemistry; Chapter 6: Use of Ruthenium Complexes as Photosensitizers in Photodynamic Therapy; Chapter 7: Photodynamic Therapy in Medicine with Mixed-Metal/Supramolecular Complexes; Chapter 8: Ruthenium Anticancer Agents En Route to the Tumor: From Plasma Protein Binding Agents to Targeted Delivery; Chapter 9: Design Aspects of Ruthenium Complexes as DNA Probes and Therapeutic Agents; Chapter 10: Ruthenium-Based Anticancer Compounds: Insights into Their Cellular Targeting and Mechanism of Action; Chapter 11: Targeting cellular DNA with Luminescent Ruthenium(II) Polypyridyl Complexes; Chapter 12: Biological Activity of Ruthenium Complexes With Quinoline Antibacterial and Antimalarial Drugs; Chapter 13: Ruthenium Complexes as NO Donors: Perspectives and Photobiological Applications; Chapter 14: Trends and Perspectives of Ruthenium Anticancer Compounds (Non-PDT); and Chapter 15: Ruthenium Complexes as Antifungal Agents.

It has been our good fortune to work with so many exceptionally talented contributors from all over the world in compiling a textbook that we believe will be a valuable resource for graduate students, young investigators, and more senior scholars in the field of biological and coordination chemistry. We thank all the contributors for their hard work and their willingness to assist us whenever requested.

July 20, 2017

Alvin Holder
Co-Editor
Norfolk, Virginia, USA

Acknowledgments

This is my acknowledgment which is based on the influence of Professor Karen Brewer on my life as she taught me how to carry out good and sensible chemistry with osmium(II), ruthenium(II), and rhodium(III) complexes. Photodynamic therapeutic studies with pUC18 and pBluescript DNA plasmids and Vero cells were the order of the day! This research catalyzed my career and research in the USA.

The task of working with so many gifted authors has been a real treat for me. The project also presented many challenges. We would not have made it to the finish line without the assistance of so many colleagues. We have not lost any Soldados on this journey. Thank God!!

In an Invited Plenary Talk: 251st ACS National Meeting and Exposition, March 13–17, 2016, San Diego, California. Abstract # INOR-1141. Title: “Light that pleases the world in science: The Karen Brewer's effect on my academic career.” Author: Alvin A. Holder; I learnt about the seven (7) Ps from Professor Mark Richter and the Brew Crew, who attended the ACS conference. They are as follows:

The seven (7) Ps

Proper
Prior
Planning
Prevents
Piss
Poor
Performance

Credit for the seven (7) Ps must be given to my deceased former postdoctoral mentor, Professor Karen J. Brewer. She was a great Lady, who believed in “Family First”!! Please see http://www.chem.vt.edu/media/karen-brewer-obituary.pdf.

R.I.P.

I would like to thank the National Science Foundation (NSF) for a National Science Foundation CAREER Award as this material is based upon work supported by the National Science Foundation under CHE-1431172 (formerly CHE – 1151832). I would also like to thank Old Dominion University's Faculty Proposal Preparation Program (FP3), and also for the Old Dominion University start-up package that allowed for the successful completion of this work. Full gratitude to Professor Karen Brewer (R.I.P.), Professor Brenda Winkel, Professor Larry Taylor, Dr Myra Gordon, the research group (The Brew Crew), and all at Virginia Tech.

Personally, I would like to thank Dr. Anne Brennführer, Dr. Eva-Stina Müller, Ramprasad Jayakumar, Anne, Claudia Nussbeck, Dr. Eva-Stina Müller, and Samnaa Srinivas.

Alvin A. Holder
Co-Editor