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

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

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

Naphthalene-1,8-diamine–2-(pyrimidin-2-yl)-1H-perimidine (2/1)

In the title adduct the pyrimidine ring is nearly co-planar with the heteroatomic perimidine ring. The perimidine and diaminonaphthalene molecules are linked by N—H••••N hydrogen bonds across an inversion center. In the crystal, alternating layers of the perimidine and the aminonaphthalene molecules are formed along [100]. In the perimidine layer the molecules are stacked along the c axis direction with an interplane separation of approximately 3.4 A ˚

Emerging catalysis in biomass valorisation: simple Zn(II) catalysts for fatty acids esterification and transesterification

The growing concern about global warming and the consumption of fossil fuels has driven in recent decades the use of biomass as a renewable feedstock. In this context, vegetable oils, the corresponding fatty acids (FAs) and esters (FAEs) have primary importance: their esterification and transesterification lead to innovative products, that find application in several sectors, from biofuels to solvents, from surfactants to cosmetic ingredients and plasticizers. Lewis acid catalysis represents the most accredited methodology for developing processes of esterification and transesterification in line with sustainability requirements. The results available so far reveal the prevalent catalytic role of Zn(II) salts and coordination compounds, due to their beneficial eco-toxicological profile, combined with an appropriate acidity, finely tunable through selective functionalization. This review provides a picture of the state of the art in this important sector of biomass valorization