Ruthenium phthalocyanine complexes : synethsis, properties and applications

University of Technology, Sydney. Faculty of Science.Ruthenium phthalocyanine and naphthalocyanine complexes are an extremely useful and adaptable class of inorganic complex that have been the focus of a large body of research. They are very stable and may be readily synthesised by a variety of routes. They are able to coordinate a large variety of functionalised ligands, and possess tuneable UV-vis absorbance and electrochemical processes, all of which makes them suitable for a wide variety of applications. Polypyridyl complexes of ruthenium, considered in the latter part of this thesis, also exhibit useful electronic and electrochemical properties that make them appropriate for many applications, particularly in the area of photovoltaic devices. In this thesis the syntheses of thirty new ruthenium phthalocyanine, ruthenium naphthalocyanine and ruthenium polypyridyl complexes are presented, and the properties and applications of these complexes are explored. Chapter 1 of this thesis reviews the synthesis, properties, and applications of previously reported ruthenium phthalocyanine and naphthalocyanine complexes. The synthesis section examines ring forming syntheses, incorporation of ruthenium into the phthalocyanine macrocycle, and axial ligand exchange reactions. The spectral properties (¹H NMR, UV-vis and infra-red) of ruthenium phthalocyanines are examined, as well as redox and conductivity properties. The application of ruthenium phthalocyanine complexes as thin films and catalysts is explored, together with their use as sensitising dyes in photodynamic therapy and photovoltaic devices. In Chapter 2 the optical and electrochemical properties of ruthenium phthalocyanine complexes bearing substituted pyridine axial ligands with varying electron withdrawing and donating abilities are discussed. The electron density at the phthalocyanine macrocycle may be adjusted using the axial ligands. Electrochemical data show that the axial pyridine ligands exert significant influence over the phthalocyanine ring-based redox processes. The axial ligands also influence the electronic absorption properties of the complexes with the influence also observed in the electrogenerated oxidised and reduced species. Chapter 3 explores the synthesis, electrochemistry and spectroscopic properties of the first examples of metal phthalocyanine and naphthalocyanine complexes with axially-coordinated arsine ligands. The AsPh₃ ligands readily dissociate in non-coordinating solvents with the naphthalocyanine showing more rapid dissociation than the phthalocyanine analog. In cyclic voltammetry experiments, the phthalocyanine analog displayed three macrocycle-centred redox processes; one reduction and two oxidation processes. One reduction and three oxidation processes were observed for naphthalocyanine analog. The reduction and first oxidation are assigned to macrocycle-centred processes. The UV-vis spectra of both complexes recorded over time showed macrocycle-centred oxidation. The rate of oxidation was slowed by removing dioxygen from the solvent or adding excess AsPh₃. In Chapter 4 the application of ruthenium phthalocyanine complexes as sensitising dyes in Dye-sensitised Solar Cells (DSCs) is explored. Solar energy conversion is emerging as an important area of research and DSCs offer a promising low cost alternative to conventional silicon-based solar cells. In addition to low cost, these cells may be flexible and semitransparent and therefore incorporated into building materials and other devices. A major hurdle to widespread use of DSCs is efficiency, with the best DSCs operating at approximately half the efficiency of silicon-based solar cells. Four monomeric ruthenium phthalocyanine complexes are reported that vary in peripheral substitution and axial ligand anchoring groups. Sensitising dyes that contain two ruthenium centres are also presented. These dyads, which contain phthalocyanine and bipyridyl chromophores, were prepared using a protection/deprotection strategy that allows for convenient purification. DSCs fabricated using the phthalocyanine complexes and dyads were less efficient than those incorporating a standard DSC dye. However, based on the number of molecules bound to the Ti0₂ electrode surfaces, several of the new complexes were more efficient at photocurrent generation. The results highlight the importance of molecular size, and thus the dye coverage of the electrode surface in the design of new sensitising dyes Literature procedures that describe syntheses of the landmark DSC dye [Bu₄N]₂[Ru(4-carboxy- 4-carboxylate-2,2'-bipyridine)₂(NCS)₂] (N719) either yield an impure product or are highly time consuming. In Chapter 5 a convenient synthesis of N719 is presented. Key to this synthetic procedure is the protection of the carboxyl functionalities with iso-butyl ester groups. This strategy allows the use of silica chromatography to remove the less efficient S- bound isomers and significantly reduces the time and difficulty of the synthesis. Chapter 6 investigates the absorption of ruthenium phthalocyanine complexes bearing functionalised axial ligands on gold surfaces. The surface chemistry of ruthenium phthalocyanines is fundamental to several topics explored in this thesis, and gold provides a smooth surface on which to conduct experiments. The chapter also introduces the novel application of Laser Ablation Inductively Coupled Plasma Mass Spectroscopy (LA ICP-MS) to the analysis of metal containing thin films. It was found that the peripheral substituents on the phthalocyanine ring affect the surface density of thin films. It was also discovered that thin films reach a maximum density after only one minute of immersion of the gold substrate in a solution of the complex. The final chapter of this thesis, Chapter 7, summarises the work presented in this thesis and highlights the key findings. It also outlines some directions for further possible research continuing from the work presented

Ruthenium phthalocyanine and naphthalocyanine complexes: Synthesis, properties and applications

This article reviews the synthesis of ruthenium phthalocyanine and naphthalocyanine complexes highlighting important advances, and examines their physical properties and applications. © 2006 Elsevier B.V. All rights reserved

Expansion of the structure-activity relationship of branched chain fatty acids: effect of unsaturation and branching group size on anticancer activity.

Branched chain fatty acids (BCFAs) are a class of fatty acid with promising anticancer activity. The BCFA 13-methyltetradecanoic acid (13-MTD) inhibits tumour growth in vivo without toxicity but efficacy is limited by moderate potency, a property shared by all known BCFAs. The mechanism of action of BCFAs has not been fully elucidated, and in the absence of a clearly defined target optimisation of BCFA potency must rely on structure-activity relationships. Our current understanding of the structural features that promote BCFA anticancer activity is limited by the low structural diversity of reported BCFAs. The aim of this study was to examine the effects of two new structural modifications- unsaturation and branching group size- on BCFA activity. Thus, homologous series of saturated and cis-Δ9 unsaturated BCFAs were synthesised bearing methyl, ethyl, propyl and butyl branching groups, and were screened in vitro for activity against three human cancer cell lines. Potencies of the new BCFAs were compared to 13-MTD and an unbranched monounstaurated fatty acid (MUFA) bearing a cis-Δ9 double bond. The principal findings to emerge were that the anticancer activity of BCFAs was adversly affected by larger branching groups but significantly improved by incorporation of a cis-Δ9 double bond into the BCFA alkyl chain. This study provides new structure-activity relationship insights that may be used to develop BCFAs with improved potency and therapeutic potential

The O(3P) and N(4S) density measurement at 225 km by ultraviolet absorption and fluorescence in the Apollo-Soyuz test project

The densities of O(3P) and N(4S) at 225 km were determined during the Apollo Soyuz Test Project by a resonance absorption/fluorescence technique in which OI and NI line radiation produced and collimated on board the Apollo was reflected from the Soyuz back to the Apollo for spectral analysis. The two spacecraft maneuvered so that a range of observation angles of plus or minus 15 deg with respect to the normal to the orbital velocity vector was scanned. The measurements were made at night on two consecutive orbits at spacecraft separations of 150 and 500 m. The resulting relative counting rates as function of observation angle were compared to calculated values to determine the oxygen value. This value agrees with mass spectrometric measurements made under similar conditions. The nitrogen value is in good agreement with other measurements and suggests a smaller diurnal variation than is predicted by present models

Convenient synthesis and purification of [Bu<inf>4</inf>N] <inf>2</inf>[Ru(4-carboxy-4-carboxylate-2,2′-bipyridine) <inf>2</inf>(NCS)<inf>2</inf>]: A landmark DSC Dye

We present here a convenient synthesis of the landmark dye-sensitized solar cell dye [Bu4N]2[Ru(4-carboxy-4-carboxylate-2,2?- bipyridine)2(NCS)2] (N719). Key to this synthetic procedure is the protection of the carboxyl functionalities with iso-butyl ester groups. This strategy allows the use of silica chromatography to remove the less efficient S-bound isomers and significantly reduces the time and difficulty of the synthesis. © CSIRO 2008

Alkaloid-like Molecules for Drug Discovery

The alkaloid class of natural compounds is extensively known for their variety of biological activities. A high percentage of currently employed chemotherapeutic drugs - more than 60% for cancer are of plant origin, and many are alkaloids.[1] Synthetic compounds that display similar structures to alkaloids are known as alkaloid-like molecules. Alkaloids are commonly documented to poses pharmacological properties such as antineoplasticity and acetylcholinesterase (AChE) inhibition. The Aristotelia alkaloids (1 and 2) have a broad spectrum of biological activities,[2] several of which contain the same 3-aza-bicyclo[3.3.1]nonane core structure architecture, seen in blue in Figure 2. Figure 1: Aristotelia alkaloids, 1 and 2. As these Alkaloids are both rare and require complex isolation, it is more resourceful to generate libraries of molecules with the same core scaffold through synthetic pathways, such as the Bridging Ritter reaction.[3] Through the use of the Bridging Ritter reaction with (-)-β-pinene (3) and various nitriles, a small library of alkaloid-like molecules has been synthesized. Figure 2: The bridging Ritter reaction of (-)-β-pinene with various nitriles. AChE inhibitors are currently the front line of drugs used for relieving the symptoms of Alzheimer’s disease (AD) by restoring natural levels neurotransmitter acetylcholine, found to be low in the synapse of AD suffers.[4] All of the currently approved AChE inhibitors have severe undesirable side-effects and with the diseases mortality rate expected to increase greatly, it is imperative that more suitable drug candidates be developed. Therefore, these alkaloid-like compounds were screened for AChE inhibitory activity using The TLC bioautographic method[5] and Ellman Assay[6]. A library of 27 alkaloid-like molecules has been synthesised. The library is currently undergoing in-house anticancer testing using the MTS assay[7] against the MDA-MB-231 breast cancer cell line. External screening has revealed one series of compounds to show potent inhibition properties against MCF-7 and one inparticular to be inactive against healthy mammalian (Vero cell line) and human oral cavity carcinoma (KB) respectively. Screening against AChE showed that the current library act only as weak inhibitors but combined with molecular modeling, has provided useful SAR data to guide the synthesis of more potent hits. Of significant interest is the importance the alkene functionality plays in providing activity. The recent finding of our work will be presented in details in this presentation

Thin films of a dimeric ruthenium phthalocyanine complex on gold

Thin films of a new dimeric ruthenium phthalocyanine complex bearing a thioester-functionalized axial ligand were formed on gold surfaces. Characterization of the thin films by laser ablation-inductively coupled-mass spectrometry and scanning tunneling microscopy revealed that the films do not have any long-range order. © 2009 Elsevier B.V. All rights reserved

Perylene dye photodegradation due to ketones and singlet oxygen

The photodegradation rate of a perylene dye (Lumogen F Yellow 083) in methyl isobutyrate was found to increase with ketone concentration for two different ketones. Of the ketones employed, methyl pyruvate, an impurity in methyl methacrylate, was found to be particularly deleterious to dye stability. In agreement with other published studies, the addition of the anti-oxidant DABCO (1,4-diazabicyclo-[2.2.2] octane) to the dye matrix was found to increase dye stability; however when ketones were present, DABCO lead to increased photodegradation. These results highlight the importance of removing ketone impurities from dye matrices during production of Luminescent Solar Concentrators (LSCs). © 2009 Elsevier Ltd. All rights reserved

Anti-tumor activities of lipids and lipid analogues and their development as potential anticancer drugs

© 2015 Elsevier Inc. All rights reserved. Lipids have the potential for development as anticancer agents. Endogenous membrane lipids, such as ceramides and certain saturated fatty acids, have been found to modulate the viability of tumor cells. In addition, many tumors over-express cyclooxygenase, lipoxygenase or cytochrome P450 enzymes that mediate the biotransformation of ω-6 polyunsaturated fatty acids (PUFAs) to potent eicosanoid regulators of tumor cell proliferation and cell death. In contrast, several analogous products from the biotransformation of ω-3 PUFAs impair particular tumorigenic pathways. For example, the ω-3 17,18-epoxide of eicosapentaenoic acid activates anti-proliferative and proapoptotic signaling cascades in tumor cells and the lipoxygenase-derived resolvins are effective inhibitors of inflammatory pathways that may drive tumor expansion. However, the development of potential anti-cancer drugs based on these molecules is complex, with in vivo stability a major issue. Nevertheless, recent successes with the antitumor alkyl phospholipids, which are synthetic analogues of naturally-occurring membrane phospholipid esters, have provided the impetus for development of further molecules. The alkyl phospholipids have been tested against a range of cancers and show considerable activity against skin cancers and certain leukemias. Very recently, it has been shown that combination strategies, in which alkyl phospholipids are used in conjunction with established anticancer agents, are promising new therapeutic approaches. In future, the evaluation of new lipid-based molecules in single-agent and combination treatments may also be assessed. This could provide a range of important treatment options in the management of advanced and metastatic cancer

Differential effects of hepatic cirrhosis on the intrinsic clearances of sorafenib and imatinib by CYPs in human liver

© 2017 Elsevier B.V. The tyrosine kinase inhibitors sorafenib and imatinib are important in the treatment of a range of cancers but adverse effects in some patients necessitate dosage modifications. CYP3A4 has a major role in the oxidation of sorafenib to its N-oxide and N-hydroxymethyl metabolites and also acts in concert with CYP2C8 to mediate imatinib N-demethylation. CYP3A4 expression and function are impaired in patients with advanced liver disease, whereas the functions of CYP2C enzymes are relatively preserved. We evaluated the biotransformation of sorafenib and imatinib in well-characterized microsomal fractions from 17 control subjects and 19 individuals with hepatic cirrhosis of varying severity. The principal findings were that liver disease impaired the microsomal oxidation of sorafenib to its major metabolites to 40–44% of control (P < 0.01), whereas the N-demethylation of imatinib was relatively unimpaired. The impairments in sorafenib biotransformation were correlated with decreased serum albumin concentrations and increased serum bilirubin concentrations in patients with liver disease, but not with the overall grade of liver disease according to the Child-Pugh system. In contrast, there was no relationship between imatinib N-demethylation and clinicopathologic factors in liver disease patients. These findings were accounted for in terms of the differential roles of CYPs 3A4 and 2C8 in the intrinsic clearance of the drugs. CYP3A4 has the major role in the intrinsic clearance of sorafenib but plays a secondary role to CYP2C8 in the intrinsic clearance of imatinib. In agreement with these findings CYP2C protein expression and CYP2C8-mediated paclitaxel 6α-hydroxylation were unimpaired in cirrhotic livers. This information could be adapted in individualized approaches such as in vivo CYP3A4 phenotyping to optimize sorafenib safety and efficacy in cancer patients with liver dysfunction