Gold And Its Complexes In Anticancer Chemotherapy

This book presents an overview of cancer and the genesis, and development of different treatment strategies and modalities against cancer. The emergence of gold and its complexes as promising anticancer chemotherapeutic agents have the potential to substitute or replace the platinum based chemotherapeutic agents. Gold complexes have demonstrated considerable anti-proliferative properties, chiefly attributed to their anti-mitochondrial effects, they make gold complexes excellent candidates as anti-cancer agents compared to their platinum-based counterparts. This book provides a critical review of recent advances made in the development of gold complexes as anti-cancer agents. In this context, it examines a number of different ligand architectures, provides comprehensive information on gold complexes’ mechanism of action and toxicity issues and, in closing, outlines future research directions.

This thesis focuses on the development of gold- and non-classical platinum-based anti-cancer agents that display distinctively different anti-cancer mechanisms compared to the commonly used cisplatin. These metal complexes contain N-heterocyclic carbene (NHC) ligands which are able to form strong M-C(NHC) bonds, conferring high stability and favorable lipophilicity, reactivity and binding specificity of metal complexes on biomolecules. The author demonstrates significant advances made in anti-cancer gold(III), gold(I) and platinum(II) complexes. Detailed chemical synthesis, in vitro and/or in vivo anti-cancer activities are clearly presented including: (i) a class of Au(III) complexes containing a highly fluorescent N^N^N ligand and NHC ligand that simultaneously act as fluorescent thiol “switch-on” probes and anti-cancer agents; (ii) a dinuclear gold(I) complex with a mixed diphosphine and bis(NHC) ligand displaying favorable stability and showing significant inhibition of tumor growth in two independent mice models with no observable side effects; and (iii) a panel of stable luminescent cyclometalated platinum(II) complexes exhibiting high specificity to localize to the endoplasmic reticulum (ER) domain, inducing ER stress and cell apoptosis. These works highlight the clinical potential that gold and platinum complexes offer for cancer treatment.

Volume 18, entitled Metallo-Drugs: Development and Action of Anticancer Agents of the series Metal Ions in Life Sciences centers on biological, medicinal inorganic chemistry. The serendipitous discovery of the antitumor activity of cis-diamminodichloroplatinum(II) (cisplatin) by Barnett Rosenberg in the 1960s is a landmark in metallodrug-based chemotherapy. The success of cisplatin in the clinic, followed by oxaliplatin and carboplatin, along with their drawbacks relating mainly to resistance development and severe toxicity, initiated research on polynuclear platinum complexes and on Pt(IV) complexes as prodrugs. Furthermore, the indicated shortcomings led to the exploration of other transition and main group metal ions, among them Ru(II/III), Au(I/III), Ti(IV), V(IV/V), and Ga(III) including also the essential metal ions Fe(II/III), Cu(I/II), and Zn(II). Ionic as well as covalent and non-covalent interactions between structurally very different complexes and biomolecules like nucleic acids, proteins, and carbohydrates are studied and discussed with regard to their possible anticancer actions. Hence, MILS-18 summarizes the research at the forefront of medicinal inorganic chemistry, including studies on the next-generation, tailor-made anticancer drugs. All this and more is treated in an authoritative and timely manner in the 17 stimulating chapters of this book, written by 39 internationally recognized experts from 10 nations (from the US via Europe to China and Australia). The impact of this vibrant research area is manifested by more than 2700 references, nearly 150 illustrations (more than half in color) and several comprehensive tables. Metallo-Drugs: Development and Action of Anticancer Agents is an essential resource for scientists working in the wide range from enzymology, material sciences, analytical, organic, and inorganic biochemistry all the way through to medicine including the clinic ... not forgetting that it also provides excellent information for teaching.

The discovery of the antitumour activity of cisplatin in 1965 and its subsequent introduction into clinical trials in 1971 was the catalyst for a major international research effort investigating the potential of metal compounds in cancer therapy. Cisplatin now occupies an important place in the armamentarium of the oncologist due to its effectiveness in the treatment of testicular cancer. A second generation analogue, carbo platin, offers reduced toxicity together with therapeutic activity, which gives it a place in the front-line therapy of genitourinary cancers. These and other successes have encouraged the search for novel metal-based drugs for cancer therapy. Research has shown that metal compounds have potential for activity not only as cytotoxic antitumour agents, but also in areas such as adjuvant therapy, diagnosis and immunotherapy. The aim of this book is to review and describe the major achievements and developments arising from this international research effort. The contributing authors come from labora tories throughout Europe and America and represent the many disci plines characteristic of this research, such as clinical research, pharmacology, tumour biology and inorganic medicinal chemistry.

Metal-based anticancer drugs are among the most successful therapeutic agents, as evidenced by the frequent prescription of selected platinum and arsenic compounds to patients. Metal-based Anticancer Agents covers the interdisciplinary world of inorganic drug discovery and development by introducing the most prominent compound classes based on different transition metals, discussing emerging concepts and enabling methods, as well as presenting key pre-clinical and clinical aspects. Recent progress on the unique features of next-generation targeted metal-based anticancer agents, including supramolecular coordination complexes used for both therapy and drug delivery, promise a bright future beyond the benefits of pure cytotoxic activity. With contributions from global leaders in the field, this book will serve as a useful reference to established researchers as well as a practical guide to those new to metallodrugs, and postgraduate students of medicinal chemistry and metallobiology.

This dissertation, "Anti-cancer N-heterocyclic Carbene Complexes of Gold(III), Gold(I) and Platinum(II): Thiol "switch-on" Fluorescent Probes, Thioredoxin Reductase Inhibitors and Endoplasmic Reticulum Targeting Agents" by Taotao, Zou, 邹滔滔, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled "Anti-Cancer N-Heterocyclic Carbene Complexes of Gold(III), Gold(I) and Platinum(II): Thiol "Switch-on" Fluorescent Probes, Thioredoxin Reductase Inhibitors and Endoplasmic Reticulum Targeting Agents" Submitted by ZOU TAOTAO for the degree of Doctor of Philosophy at The University of Hong Kong in Feb 2015 Despite the success of cisplatin in combating various cancers, the problems of resistance and side effects have limited its wide application in cancer treatment. Gold complexes have recently emerged as promising candidates for cancer treatment. Unlike cisplatin, gold complexes do not favor DNA binding, but instead preferentially bind SH/SeH-containing proteins/enzymes in cancer cells, giving hope that these compounds may overcome cisplatin's resistance problems. Since the side effects of cisplatin are, at least partially, caused by instability-associated, off-target binding interactions, the incorporation of N-heterocyclic carbene (NHC) ligands may be a useful strategy to improve the stability of metal-based chemotherapeutics due to the strong  donating ability of NHC to form strong M-C(NHC) bonds. Meanwhile, the ease of modification and steric effects of NHC ligands provide favorable lipophilicity, reactivity and binding specificity of metal complexes. Indeed, some Pt(II)-NHC complexes have been reported to specifically target proteins/organelles rather than DNA. 3+ + The reduction of 4-coordinated Au to 2-coordinated Au by thiols has been 3+ demonstrated. Meanwhile, owing to the low energy d 2 2 orbital of Au, most gold(III) x -y complexes are non-emissive in solutions. In Chapter 3, by taking advantage of these unique properties, the synthesis of a class of non-emissive Au(III) complexes containing highly fluorescent N DEGREESN DEGREESN ligands and NHC ligands is described. In these compounds, the NHC ligand prevented further reduction of Au(III) to Au(0) and increased the III + solubility of the Au(III) complexes. The [Au (N DEGREESN DEGREESN)(NHC)] complex was readily reduced by GSH to form [Au (NHC)(GS)], accompanied by the release of the fluorescent H N DEGREESN DEGREESN ligand, therefore acting as a fluorescent "switch-on" probe for thiols. In addition, the anti-cancer activity of Au(I) is owed to its ability to inhibit thiol-enzymes; thus, the Au(III) complexes could also serve as precursors/prodrugs, activated by metal reduction, to deliver anti-cancer active Au(I) species. The major problem of most Au(I) anti-cancer agents is the lack of in vivo anti-tumor activity due to their high thiol-reactivity which leads to many off-target binding interactions with blood thiols. In Chapter 4, the synthesis of a dinuclear gold(I) complex bearing a mixed diphosphine and bis(NHC) ligand is described. This dinuclear Au(I) complex displayed a favorable stability that conveys potent thioredoxin reductase inhibition without being attacked by blood thiols. This complex significantly inhibited tumor growth in two independent mouse models with no observable side effects. The dinuclear Au(I) complex also exhibited anti-angiogenesis activity in a tumor model and inhibited sphere formation of cancer stem cells in vitro. In toxicology studies, neither systemic anaphylaxis in guinea pigs nor localized irritation in rabbits was observed

This dissertation, "The Anti-cancer Properties of Cyclometalated Gold(III) Complexes and Organogold(III) Supramolecular Polymers" by Jingjing, Zhang, 张晶晶, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Prompted by the successful clinical application of cisplatin in cancer therapy, worldwide efforts have been devoted to develop new metal-based drugs for anticancer treatment. Gold(III) complexes at first received attention as anti-cancer drug candidates because of their square-planar geometry which resembles that of platinum(II) complexes. Subsequent studies revealed that various gold(III) complexes displayed promising anti-cancer activities with different biological mechanisms. Although some achievements have been obtained in the development of anti-cancer gold(III) complexes, challenges including the improvement of bioavailability, stability and selectivity, elucidation of the action mechanisms, and the development of novel delivery approaches of gold(III) complexes to reduce systematic toxicity, remain to be exploited. A panel of anti-cancer complexes [AuIII(R-C DEGREESN)(L)]n+ (wherein HC DEGREESN is 2-phenylpyridine, L is biguanide or biuret) have been identified and described in Chapter 3. Biguanide or biuret have been employed to improve the solubility of the complexes in aqueous solutions. Meanwhile, the lipophilicity could readily be adjusted by varying the R group to obtain a balance between lipophilicity and aqueous solubility. Among the synthesized complexes, the cationic complexes, [AuIII(butyl-C DEGREESN)biguanide]Cl (3.1) and [AuIII(C DEGREESN)biguanide]Cl (3.2) are soluble in aqueous solutions with solubility over 5 mg/mL. Besides, introduction of butyl groups to 3.1 and [AuIII(butyl-C DEGREESN)biuret] (3.3) resulted in higher cellular uptake of gold, which might enhance their cytotoxic activities (IC50 values: 1.5-17 μM) compared with 3.2 and [AuIII(C DEGREESN)biuret] (3.4) (IC50 values: 9.4-47.3 μM). Moreover, 3.1 was also found to induce cell cycle arrest in S-phase and endoplasmic reticulum (ER) damage in human cervical epithelial carcinoma (HeLa) cells, and display significant anti-angiogenic activity at its sub-cytotoxic concentrations. In Chapter 4, a series of gold(III) complexes with dithiocarbamate and 2-phenylpyridine ligands to target deubiquitinases (DUBs), have been designed. These complexes achieved significant inhibition on purified DUBs. Notably, [AuIII(2-(4-nbutylphenyl) pyridyl)(diethyldithiocarbamate)]PF6 (4.1) inhibited both the purified (IC50 values: 46-223 nM) and cell-based DUBs activities with high efficiency. Its interaction with DUB UCHL1 and peptides which are present in several types of DUBs and contain active cysteine residue were confirmed by mass spectrometric analysis. All complexes displayed significant cytotoxicities, and those containing diethyldithiocarbamate ligand displayed specific cytotoxicity on breast cancer cells. Accumulation of a tumor suppressor p53, cell-cycle arrest, and apoptotic cell death were induced in breast cancer cells by 4.1. Besides, 4.1 also showed anti-angiogenic effects. These biological activities might be related with DUBs inhibition. In Chapter 5, a cytotoxic complex [AuIII(C DEGREESN DEGREESC)(4-dpt)](CF3SO3) (5.1, HC DEGREESN DEGREESCH = 2,6-diphenylpyridine; 4-dpt = 2,4-diamino-6-(4-pyridyl)-1,3,5-triazine) has been designed to self-assemble into supramolecular polymers (5.1-SP) in acetonitrile. In physiologically relevant solutions, 5.1-SP displayed a sustained-release property of the anti-angiogenic ligand 4-dpt, and in the presence of glutathione (GSH), [AuIII(C DEGREESN D

When this book was first conceived as a project the expanding interest in the clinical use of platinum and gold complexes made a survey of the relevant biological properties of metal complexes timely and appropriate. This timeliness has not diminished during the gestation and final publica tion of the manuscript. The introduction contains an explanation of the layout and approach to the book, which I wrote as an overall survey of the wide variety of biological properties of metal complexes. Hopefully, the reader will see the parallels in mechanisms and behavior, even in different organisms. The writing was considerably helped by the enthusiasm and confidence (totally unearned on my part) in the project of Professor Brian James and lowe him my special thanks. I also owe a great debt of gratitude to my colleagues, and especially to Eucler Paniago, of the Universidade Federal de Minas Gerais, for their comprehension and for the initial leave of absence which allowed me to begin the project. To those who read some or all of the manuscript and made suggestions, Bernhard Lippert, Kirsten Skov, and Tom Tritton, as well as the editor's reviewer I am also grateful. As usual, the final responsibility for errors or otherwise rests with the author.