Ruthenium(III) complexes entrapped in liposomes with enhanced cytotoxic and anti-metastatic properties

Metal-based anticancer drugs are pivotal in the fight against cancer pathologies. Since 1978 cis-platin was licensed for medical treatment of a wide number of tumor pathologies(1). However its chemiotherapic use is strongly limited by many and severe side effects and acquired tumor resistance. Since these limitations could be overcome by other metal complexes, in the last thirty years ruthenium compounds have been tested showing a remarkable antitumoral and antimetastatic activity associated with a lower toxicity. A hexacoordinate Ru(III) complex (NAMI-A) is currently undergoing advanced clinical evaluation (2). All data indicate that NAMI-A acts as a pro-drug, but the integrity of ruthenium complexes is essential to store the cytotoxic activity. In this scenario the condition of administration of ruthenium drugs are crucial to exploit their anticancer activity (3). In the last years innovative strategies have been produced to vehicle ruthenium ions in tumor cells like aggregates. This study aims to incorporate the ruthenium complexes in the inner aqueous compartment of liposomes and to test biological properties of two NAMI-A like pyridine derivatives. Specifically, we have investigated the pyridine derivatives of the sodium-compensated analogue of NAMI-A, Na[trans-RuCl4(pyridine)(DMSO)] (NAMI-Pyr) and Na[trans-RuCl4(Pytri)(DMSO)] (NAMI-Pytri). In thelatter complex the pyridine ligand is functionalized with a sugar moiety so as to increase biocompatibility and the ability to cross the cell membrane. The stability of the complexes was studied and compared in solution at different pH following UV-VIS spectra. Lipid formulations based on Egg PC were prepared adding Cholesterol, DSPE-PEG2000 joining molar ratio 57/38 /5% w/w respectively in MeOH/CHCl3 (50/50 v/v) mixture and hydrated with 0.9% w/w of NaCl. This composition was selected to reproduce analog supramolecular aggregates in clinical use to vehicle doxorubicin (Doxil). Ruthenium complexes were loaded into liposomes using the passive equilibration loading method. Full drug containing liposomes were structurally characterized by dynamic light scattering (DLS) measurements. Data indicate the formation of stable aggregates with size and shape in the right range for in vivo applications. The amount of encapsulated ruthenium complexes was quantified by means of ICP-AES. Stability and drug release properties of ruthenium containing liposomes were confirmed in buffer. The growth inhibitory effects of both liposomal and free complexes drug were tested on prostate cancer cells (PC3). Preliminary results show high cytotoxic effect of ruthenium complexes delivered by supramolecular aggregates with respect to free complexes drug

Sugar-Incorporated N-Heterocyclic-Carbene-Containing Gold(I) Complexes: Synthesis, Characterization, and Cytotoxic Evaluation

A series of neutral and cationic gold(I) complexes bearing a glucopyranoside-incorporated N-heterocyclic carbene (NHC) ligand are synthetized and structurally characterized. Different secondary ligands (chlorido, phosphane, or sugar–NHC) are employed to tune the properties of the complexes. The antiproliferative effects of the compounds are evaluated against PC-3 prostate cancer cells and a panel of human tumor cell lines. The activities of the phosphane complexes are comparable to that observed for cisplatin. The combined results provide further insights into the biological behavior of NHC–gold complexes

Novel Sugar-incorporated N-heterocyclic Carbene (NHC) Gold(I) Complexes as Potential Anticancer Agents

New metal complexes containing anticancer drugs are one of the major interests in bioinorganic or bioorganometallic medicinal chemistry. The development of novel metallodrugs is shifting to the use of non platinum central atoms coordinating different organic ligands in order to overcome the drawbacks (e.g. resistance, side effects) of the platinum antitumor agents. [1]. Gold(I) complexes show a very promising antiproliferative effects, but they are remarkable oxidizing properties. In order to reduce this character, in the last years, several studies have been reported based on gold(I) N-heterocyclic carbenes (NHCs) in vitro and in a few cases also in vivo [2]. Within this frame we have designed new gold(I) complexes based on sugar incorporated N-heterocyclic carbene. The presence of the sugar moiety allows to tune the lipophilicity behavior of the complexes. The complexes have been synthesized according to the scheme reported below. After the preparation of the NHC ligand, in the first step the corresponding Ag-complex (1AgBr) was prepared from Ag2O, to act as starting materials for transmetalation. The reaction of 1AgBr with gold(I) precursor, THTAuCl (THT = tetrahydrothiophene), in dichloromethane at room temperature overnight afford to gold complex. The compound was identified by NMR and RX. Starting from 1Cl, the cationic gold derivatives were prepared adding phosphorous and sulphur based neutral ligands, in the presence of silver tetrafluoroborate, as a chloride abstractor. The ligands have been selected in order to modulate electronic and hydrophilic complexes properties. The compounds will be investigated in screening on human cell line

Square-planar vs. Trigonal bipyramidal geometry in Pt(II) complexes containing triazole-based glucose ligands as potential anticancer agents

This article describes the synthesis, characterization, and biological activity of novel square-planar cationic platinum(II) complexes containing glucoconjugated triazole ligands and a comparison with the results obtained from the corresponding five-coordinate complexes bearing the same triazole ligands. Stability in solution, reactivity with DNA and small molecules of the new compounds were evaluated by NMR, fluorescence, and UV–vis absorption spectroscopy, together with their cytotoxic action against pairs of immortalized and tumorigenic cell lines. The results show that the square-planar species exhibit greater stability than the corresponding five-coordinate ones. Furthermore, although the square-planar complexes are less cytotoxic than the latter ones, they exhibit a certain selectivity. These results simultaneously demonstrate that overall stability is a fundamental prerequisite for preserving the performance of the agents and that coordinative saturation constitutes a point in favor of their biological action

Impact of Hydrophobic Chains in Five-Coordinate Glucoconjugate Pt(II) Anticancer Agents

This study describes new platinum(II) cationic five-coordinate complexes (1-R,R’) of the formula [PtR(NHC)(dmphen)(ethene)]CF3SO3 (dmphen = 2,9-dimethyl-1,10-phenanthroline), containing in their axial positions an alkyl group R (methyl or octyl) and an imidazole-based NHC-carbene ligand with a substituent R’ of variable length (methyl or octyl) on one nitrogen atom. The Pt–carbene bond is stable both in DMSO and in aqueous solvents. In DMSO, a gradual substitution of dmphen and ethene is observed, with the formation of a square planar solvated species. Octanol/water partitioning studies have revealed the order of hydrophobicity of the complexes (1-Oct,Me > 1-Oct,Oct > 1-Me,Oct > 1-Me,Me). Their biological activity was investigated against two pairs of cancer and non-cancer cell lines. The tested drugs were internalized in cancer cells and able to activate the apoptotic pathway. The reactivity of 1-Me,Me with DNA and protein model systems was also studied using UV–vis absorption spectroscopy, fluorescence, and X-ray crystallography. The compound binds DNA and interacts in various ways with the model protein lysozyme. Remarkably, structural data revealed that the complex can bind lysozyme via non-covalent interactions, retaining its five-coordinate geometry

Pyridine Ruthenium(III) complexes entrapped in liposomes with enhanced cytotoxic properties in PC-3 prostate cancer cells

The first aim of the present study is the development of a new ruthenium(III) complex, belonging to NAMI-A class, with a potentially high cytotoxic ability. The presence of a fully protected sugar moiety as ruthenium ligand should increase the complex ability to cross cellular membranes. Furthermore, it sets this molecule in the area of biocompatible agents as tumor drug. The second, more relevant, purpose is to verify the ruthenium complexes activity after loading into liposomes. We reported the characterization and in vitro biological assays of pyridine derivatives of ruthenium complexes loaded into Egg L-α-phosphatidylcholine cholesterol/DSPE-PEG liposomes. Dynamic light scattering estimates that the sizes of all obtained liposomes are in the 100 nm range. This value is suitable for in vivo use. The loading ability and release kinetic allowed selecting the best ratio between the lipid fraction and metal to be tested in cellular experiments. The growth inhibitory effects of both liposomal and free complex in PC-3 prostate cancer cell lines demonstrate a high cytotoxic ability of the liposome entrapped ruthenium (III) complex suggesting additional role further the antimetastatic function

Asymmetric Oxidative Cation/Olefin Cyclization of Polyenes: Evidence for Reversible Cascade Cyclization

Ag und Pt arbeiten zusammen: Die Aktivierung von [(xylyl-phanephos)PtCl2] durch Silber erzeugt einen elektrophilen Katalysator, der enantio-, diastereo- und regioselektiv die stereospezifische oxidative Cyclisierung von Polyenolen vermittelt (siehe Schema; Tr=Trityl). Mechanistische Experimente lassen darauf schließen, dass der konfigurationsbestimmende Schritt nicht die einleitende Cyclisierung ist, sondern ein Folgeschritt der Reaktion

Mechanistic Studies of Ethylene Hydrophenylation Catalyzed by Bipyridyl Pt(II) Complexes

This article discusses mechanistic studies of ethylene hydrophenylation catalyzed by bipyridyl Pt(II) complexes