Organometallic compounds based on bioactive ligand systems have shown promising antiproliferative properties. The use of 8-hydroxyquinoline and its derivatives as bioactive ligands resulted in ...organometallic complexes with potent anticancer activity, but they lack aqueous solubility for further development. We report here the preparation of a series of MII/III(cym/Cp*)Cl complexes (η6-p-cymene (cym): M = Ru, Os; η5-pentamethylcyclopentadienyl (Cp*): M = Rh, Ir) with hydroxyquinoline-derived co-ligands and in a subsequent step the substitution of the chlorido ligands for amphiphilic 1,3,5-triaza-7-phosphatricyclo-3.3.1.1decane (PTA). Solubility studies indicated that the introduced PTA ligand significantly improved the aqueous solubility of all complexes. The complexes were shown to be stable in aqueous and DMSO solution over a period of at least 3 d. As would be expected for such modification of complexes, the higher solubility resulted in significantly decreased cytotoxicity in cancer cells. The antiproliferative activity was still more pronounced than that of RAPTA-C Ru(cym)(PTA)Cl which, however, has been demonstrated to have antimetastatic and antiangiogenic properties in vivo.
The introduction of a PTA ligand into organometallic hydroxyquinoline complexes significantly increases their aqueous solubility, and gives high stability but reduces their cytotoxic activity to an extent found for the prototype PTA anticancer agent RAPTA-C. Display omitted
•Preparation of organometallic anticancer agents•Substitution of chlorido ligands with an amphiphilic phosphine leads to high aqueous solubility.•The complexes showed high stability in aqueous solution.•Introduction of the PTA ligand decreased the anticancer activity of the complexes.
Ru(II) and Os(II) complexes of 2-pyridinecarbothioamide ligands were introduced as orally administrable anticancer agents (S.M. Meier, M. Hanif, Z. Adhireksan, V. Pichler, M. Novak, E. Jirkovsky, ...M.A. Jakupec, V.B. Arion, C.A. Davey, B.K. Keppler, C.G. Hartinger, Chem. Sci., 2013, 4, 1837–1846). In order to identify structure-activity relationships, a series of N-phenyl substituted pyridine-2-carbothiamides (PCAs) were obtained by systematically varying the substituents at the phenyl ring. The PCAs were then converted to their corresponding RuII(η6-p-cymene) complexes and characterized spectroscopically and by X-ray diffraction as well as in terms of stability in water and HCl. The cytotoxic activity of the PCA ligands and their respective organoruthenium compounds was evaluated in a panel of cell lines (HCT116, H460, SiHa and SW480). The lipophilic PCAs 1–4 showed cytotoxicity in the low micromolar range and 6 was the most potent compound of the series with an IC50 value of 1.1μM against HCT116 colon cancer cells. These observations were correlated with calculated octanol/water partition coefficient (clogP) data and quantitative estimated druglikeness. A similar trend as for the PCAs was found in their Ru complexes, where the complexes with more lipophilic ligands proved to be more cytotoxic in all tested cell lines. In general, the PCAs and their organoruthenium derivatives demonstrated excellent drug-likeness and cytotoxicity with IC50 values in the low micromolar range, making them interesting candidates for further development as orally active anticancer agents.
This paper aimed to develop structure-activity relationships for pyridine-2-carbothiamide-based organometallics that are orally active anticancer agents. The lipophilic nature of the ligands correlated well with the cytotoxicity of the complexes prepared. Display omitted
•Preparation of pyridine-2-carbothioamides and their organoruthenium complexes•Structural characterization of the ligands and complexes•Increased in vitro anticancer activity of the complexes as compared to the ligands•Lipophilicity correlates with anticancer activity•High stability under acidic conditions
Anticancer‐active RuII–η6‐p‐cymene complexes of bioactive 2‐pyridinecarbothioamide ligands have been shown to have high selectivity for plectin and can be administered orally. Reported herein is the ...functionalization of a 2‐pyridinecarbothioamide with a sulfonamide group and its conversion into M–η6‐p‐cymene complexes (M = Ru, Os). The presence of a sulfonamide moiety in many organic drugs and metal complexes endows these agents with interesting biological properties and can transform the latter into multi‐targeted agents. The compounds were characterized with standard methods and the in vitro anticancer activity data was compared with studies on the hydrolytic stability of the complexes and their reactivity to small biomolecules. A molecular modeling study revealed plausible modes of binding of the complexes in the catalytic pocket of carbonic anhydrase II.
A test of your metal: η6‐p‐Cymene–MII–2‐pyridinecarbothioamide (M=Ru, Os) complexes were functionalized with a sulfonamide group to obtain multi‐targeted, anticancer agents. In vitro anticancer activity studies revealed low activity, but it was demonstrated that the sulfonamide moiety can interact with a Zn2+ ion in the catalytic pocket of carbonic anhydrase II.
Olefin metathesis is a valuable synthetic tool, widely used in several fields of science. Due to the importance of this transformation several contributions have been made in this field in order to ...understand mechanistic aspects, reactivity and applicability of this process. In this topic, ruthenium indenylidene complexes have shown great activity and stability in metathesis, making them very valuable pre-catalysts. However, several aspects of these pre-catalysts have not been evaluated yet. For example, even though reports of active second generation ruthenium indenylidene complexes bearing bulky N-heterocyclic carbenes are present in the literature, no studies have been done to understand how steric hindrance affects the process. For these reasons, RuCl₂(IPr*)(PPh₃)(3-phenylindenylidene) (IPr*-PPh₃) and RuCl₂(IPr*)(Py)(3-phenylindenylidene) (IPr*-Py), bearing the very bulky ligand, IPr* have been synthesised and compared with RuCl₂(IPr)(PPh₃)(3-phenylindenylidene) (IPr-PPh₃) and the new RuCl₂(IPr)(Py)(3-phenylindenylidene) (IPr-Py). Another important aspect, presented in this thesis, is the investigation of the stability of indenylidene pre-catalysts in alcohol solvents. Surprisingly, several different decomposition processes occur depending on the starting complex and the alcohol used. Mechanistic investigation into this decomposition, allowed us to develop a better understanding of this process, and to predict the decomposition product based on the environment. In particular, this study revealed that RuCl(η⁵-3-phenylindenyl)(PPh₃)₂ (Eta-5) is accessed from RuCl₂(3-phenylindenylidene)(PPh₃)₂ (M₁₀) via a novel indenylidene to η⁵-indenyl rearrangement. This formal decomposition product has been found to be active in at least 20 different catalytic transformations, rendering it a versatile catalytic tool.
This thesis reflects two main aims. Firstly, the synthesis and characterisation of a number of potential anion receptors was undertaken and their anion binding properties were assessed. In so doing, ...a second aim was fulfilled, namely a comparison of the various methods of detecting the bound anion, and quantifying the binding strength. Four techniques appear in this thesis; 1H nuclear magnetic resonance, UV-visible spectroscopy, electrochemistry and luminescent emission. Quantitative titrations were performed and, where possible, stability constants estimated. Chapter One provides an introduction to some of the themes of molecular recognition and provides a brief overview of the literature associated with anion recognition. A Prologue describes the design of the receptors studied; they all incorporate a metal centre and appended amide groups which provide sources of hydrogen bonding. The molecules are mostly cationic and a combination of positive charge and hydrogen bonding constitutes the binding interaction. Chapter Two is concerned with receptors based on cobalticinium, Cp2Co + . A number of receptors are presented and are found to bind anions with stability constants typically in the range of 500-1000 dm3mol-1 . Receptors involving more than one cobalticinium centre are found to bind much more strongly and, furthermore, variations in functional groups appended close to the proposed coordination site impart selectivity; dihydrogen phosphate is bound more strongly than chloride. It is also found that different techniques give different stability constants and comment is made on this phenomenon. Chapter Three examines the role of positive charge in anion binding and describes the synthesis and coordination properties of several neutral receptors. These molecules retain hydrogen bonding sites, and it is found that this is sufficient to bind anions, but the strength of the interaction is greatly reduced. Chapter Four introduces another system, based on RuL(bpy)22+ , where L is a 4,4'-amide disubstituted bpy. The strength of binding is an order of magnitude greater than the cobalticinium systems as detected by several methods including emission studies, which are very sensitive. Comparison with a neutral, rhenium-based receptor is made. A dihydrogen phosphate-selective luminescent sensor is also presented. The Epilogue identifies areas for future research. Specialised introductions and summaries are found at the beginning and end of each chapter.
This thesis describes the synthesis, chemistry and catalytic activity of several diruthenium complexes, in which two ruthenium centers are locked in close proximity by bridging ...bis(diphenylphosphino)methane, dppm, ligands. Ru2(μ-CO)(CO)4(μ-dppm)2 in acetone solution is an efficient catalyst for the reversible reaction between formic acid and hydrogen/carbon dioxide. The mechanism of the catalytic reactions is clearly elucidated and Ru2H(μ-H)(P-CO)(CO)2(μ-dppm) 2 is demonstrated to be the most active catalyst. Ru2(μ-CO)(CO)4(μ-dppm)2) in acetone solution is also a catalyst for the transfer hydrogenation of internal alkynes to give cis-alkynes using formic acid as the hydrogen source. The transfer hydrogenation of terminal alkynes is not successful. In the case of the alkyne PhCCH, it is shown that the alkyne reacts with Ru2(μ-CO)(μ-H)(CO) 4(μ-dppm)2+ to give the catalytically inactive complex Ru2(μ-CH=CHPh)(CO)4(μ-dppm) 2HCO2. Ru2(μ-CH2)(CO)4(μ-dppm) 2 is synthesized by the reaction of CH2N2 with Ru2(μ-CO)(CO)4(μ-dppm)2. The reactivity of this new methylene complex readily toward CO, HBF4, HCOOH, McOTf and CH3COOH are investigated. In the presence of HBF4, Ru2(μ-CH2)(CO)4(μ-dppm)2 is an efficient precatalyst for the ring-opening polymerization of norbornene. At 75°C, Ru2(μ-CH2)(CO)4(μ-dppm) 2 is also an efficient catalyst for the head to tail dimerization of terminal alkynes such as PhCCH and 1-hexyne. The active catalyst in the catalytic reactions is proposed to be a hydrido-alkynyl complex. In the presence of Et3N, Ru2(μ-H)(μ-CO)(CO) 3(μ-dppm)2OTf is an efficient catalyst precursor for the decomposition of HCOOH to CO2 and H2 at room temperature. The high catalytic efficiency of the system is shown to be due to the easy generation of Ru2H(μ-H)(μ-CO) (CO)2(μ-dppm) 2. Ru2(μ-H)(μ-CO)(CO)3 (μ-dPPM) 2OTf readily reacts with alkynes to afford either a μ-alkenyl complex or the σ-alkenyl complex, depending on the magnitude of steric effects between phenyl substituents. The first diruthenium diazoalkane complex Ru2(μ-NNCHCO 2Et)(CO)4(μ-dppm)2, in which the diazoalkane acts as a novel 2-electron ligand bridging a metal-metal bond, is synthesized by the reaction of Ru2(μ-CO)(CO)4(μ-dppm) 2 with N2CHCO2Et. This complex displays several novel reactivity patterns in its reactions with HBF4, PhCCH or HCOOH.
