Targeting of the mitochondrion by dinuclear thiolato-bridged arene ruthenium complexes in cancer cells and in the apicomplexan parasite Neospora caninum

A library of 18 dinuclear-thiolato bridged arene ruthenium complexes, some of which with demonstrated activity against cancer cells, was screened for activity against a transgenic Neospora caninum strain that constitutively expresses beta-galactosidase. Initial assessments were done at concentrations of 2500, 250, 25 and 2.5 nM, and 5 compounds were further evaluated with regard to their half maximal proliferation-inhibiting concentration (IC50). Among those, [(η6-p-MeC6H4Pri)2Ru2(μ2-SC6H4-p-CH3)3]Cl (1), [(η6-p-MeC6H4Pri)2Ru2(μ2-SC6H4-p-But)3]Cl (2) and [(η6-p-MeC6H4Pri)2Ru2(μ2-SCH2C6H4-p-But)2(μ2-SC6H4-p-OH)]BF4 (9) inhibited N. caninum proliferation with low C50 values of 15, 5 and 1 nM, respectively, while [(η6-p-MeC6H4Pri)2Ru2(μ2-SC6H4-p-OH)3]Cl (3) and [(η6-p-MeC6H4Pri)2Ru2(μ2-SC6H4-p-mco)3]Cl (5, mco = 4-methylcoumarinyl) were less active (IC50 = 280 and 108 nM, respectively). These compounds did not affect human foreskin fibroblast (HFF) host cells at dosages of 5 μM and above, but impaired proliferation of the human ovarian carcinoma cell line A2780 (IC50 values of 130 nM (1), 30 nM (2), 530 nM (3), 7730 nM (5), 130 nM (9)). A2780 cancer cells were treated with complexes 1, 2, and 5, and biodistribution analysis using inductively coupled plasma mass spectrometry (ICP-MS) showed that most of the drugs accumulated in the mitochondrial fractions. Transmission electron microscopy showed that the parasite mitochondrion is the primary target also in N. caninum tachyzoites, but these compounds, when applied at 200 nM for 15 days in vitro, did not act parasiticidal. Complexes 1, 2 and 9 applied orally at 2 and 10 mg kg−1 day−1 during 5 days in a neosporosis mouse model did not reduce parasite load and did not limit parasite dissemination to the central nervous system. In accordance with these results, ICP-MS carried out on different organs of mice orally administrated with complexes 1 and 9, demonstrated that the drugs were readily absorbed, and after 3 and 48 h, were mainly detected in liver and kidney, but were largely absent from the brain. Thus, dinuclear thiolato-bridged arene ruthenium complexes exhibit interesting activities against N. caninum in vitro, but further modifications of these promising molecules are required to improve their bioavailability and pharmacokinetic properties in order to exert a pronounced and selective effect against N. caninum in vivo

In vitro and in vivo antischistosomal activity of ferroquine derivatives

Schistosomiasis is a neglected tropical disease and drug-repurposing is a useful strategy to fill its exhausted drug development pipeline. The ferrocenyl analogue of chloroquine, ferroquine, is an antimalarial in late-stage drug development. The aim of the present work was to study the antischistosomal activity of ferroquine against Schistosoma mansoni adult worms and newly transformed schistosomula (NTS) in vitro and in vivo. Hydroxyl-ferroquine and ruthenoquine were included to study the potential role of reactive oxygen species in the antischistosomal activity. Chloroquine and mefloquine, the later described for its antischistosomal properties, served as comparators.; All metal complexes were shown to be moderately cytotoxic on human cervix HeLa cancer cells and human fetal lung fibroblasts MRC-5. 72 hours post-incubation NTS exposed to 33.3 µM ruthenoquine had died, while ferroquine and hydroxyl-ferroquine treated worms were strongly affected. No activity was observed treating NTS with chloroquine at 33.3 µM. Incubation of adult S. mansoni with 33.3 µM of the organometallic derivatives were highly affected in viability but were still alive 72 hours post-incubation. Mefloquine showed the highest activity against NTS and adult S. mansoni. Low total worm burden reductions of 0-36% were observed following oral administration of 200-800 mg/kg of the ferroquine derivatives to S. mansoni-infected mice.; The organometallic compounds evaluated in this study revealed moderate in vitro activity against both larval and adult stages of S. mansoni but low in vivo activity. No correlation can be drawn between the antimalarial and antischistosomal activity of chloroquine analogues and oxidative shock does not seem to play a role in the activity of these compounds against S. mansoni

Sedaxicenes: potential new antifungal ferrocene-based agents?

Fungal infections are a group of diseases spread all over the world with an extremely high morbidity. Worryingly, although several pathogenic fungi were found to develop resistance towards traditional therapy, research towards the discovery of novel antimycotic agents is very limited. Considering the promising results obtained with the ferrocene-based drug candidates Ferroquine and Ferrocifen as antimalarial and anticancer drug candidates, respectively, we envisaged derivatizing the organic scaffold of a new broad-spectrum fungicide, namely sedaxane, with a ferrocenyl moiety in order to obtain new metal-based antifungal agents. The new ferrocenyl sedaxane derivatives called herein Sedaxicenes (1a, 2 and 3) were characterized using different analytical techniques and the structures were confirmed by X-ray crystallography. As expected for antimycotic agents, 1a, 2 and 3 were found to have a low or even no toxicity towards human cells (IC50 > 100 μM). Interestingly, while the parent drug did not display any mycotoxicity (EC50 > 100 μM), complex 1a was found to have some antifungal activity with an IC50 value of 43 μM under the same experimental conditions. In order to investigate the possible redox-mediated mode of action of 1a, we synthesized the ruthenocene analogue of 1a, namely 1b. Ruthenocene is known to have a completely different electrochemical behaviour from ferrocene although both the compounds are isostructural. As anticipated, complex 1a was found to induce an increase of the reactive oxygen species level in S. cerevisiae, contrary to its 1b analogue and to the parent compound sedaxane

Visible-light-induced annihilation of tumor cells with platinum-porphyrin conjugates

Despite the extensive use of porphyrins in photodynamic therapy (PDT), tetraplatinated porphyrins have so far not been studied for their anticancer properties. Herein, we report the synthesis of such novel platinum-porphyrin conjugates as well as their photophysical characterization and in vitro light-induced anticancer properties. These conjugates showed only minor cytotoxicity in the dark, but IC50 values down to 19 nm upon irradiation with light at 420 nm. These values correspond to an excellent phototoxic index (PI=IC50 in the dark/IC50 in light), which reached 5000 in a cisplatin-resistant cell line. After incubation with HeLa cells, nuclear Pt concentrations were 30 times higher than with cisplatin. All of these favorable characteristics imply that tetraplatinated porphyrin complexes are worthy of exploration as novel PDT anticancer agents in vivo

Enantioselective Total Syntheses of the Proposed Structures of Prevezol B and Evaluation of Anti-Cancer Activity

The first enantioselective total syntheses of the proposed structures of the natural product prevezol B are reported. The reported syntheses complement the previously-reported syntheses of the proposed structures of prevezol C, a stereoisomer of prevezol B. It was previously shown that the structure of the naturally occurring prevezol C had been incorrectly assigned. This work has led us to conclude that the proposed structures of prevezol B are also incorrect and major revision of both of the structures of the prevezols B and C is required. Cytotoxicity studies on the human cervical cancer cell line HeLa revealed that the synthesized prevezol B and C compounds were not active even at the highest concentration used (100 μM). However, one of the synthetic precursors was shown to have modest potency against HeLa cells (IC50 = 23.5 ± 1.8 μM)

Towards cancer cell-specific phototoxic organometallic rhenium(I) complexes

Over the recent years, several Re(i) organometallic compounds have been shown to be toxic to various cancer cell lines. However, these compounds lacked sufficient selectivity towards cancer tissues to be used as novel chemotherapeutic agents. In this study, we probe the potential of two known N,N-bis(quinolinoyl) Re(i) tricarbonyl complex derivatives, namely Re(i) tricarbonyl [N,N-bis(quinolin-2-ylmethyl)amino]-4-butane-1-amine () and Re(i) tricarbonyl [N,N-bis(quinolin-2-ylmethyl)amino]-5-valeric acid (), as photodynamic therapy (PDT) photosensitizers. and proved to be excellent singlet oxygen generators in a lipophilic environment with quantum yields of about 75%. Furthermore, we envisaged to improve the selectivity of via conjugation to two types of peptides, namely a nuclear localization signal (NLS) and a derivative of the neuropeptide bombesin, to form and , respectively. Fluorescent microscopy on cervical cancer cells (HeLa) showed that the conjugation of to significantly enhanced the compound's accumulation into the cell nucleus and more specifically into its nucleoli. Importantly, in view of PDT applications, the cytotoxicity of the Re complexes and their bioconjugates increased significantly upon light irradiation. In particular, was found to be at least 20-fold more toxic after light irradiation. DNA photo-cleavage studies demonstrated that all compounds damaged DNA via singlet oxygen and, to a minor extent, superoxide production

Cytotoxic gold(I) N-heterocyclic carbene complexes with phosphane ligands as potent enzyme inhibitors

Organometallic gold complexes with N-heterocyclic carbene (NHC) ligands have been demonstrating promising properties as novel anticancer agents. Gold(I) NHC complexes containing different phosphanes as secondary ligands were shown to trigger strong cytotoxic effects in cancer cells, and their effective uptake into the cells was quantified by atomic absorption spectroscopy. Moreover, the new compounds strongly inhibited the activity of the seleno-enzyme thioredoxin reductase (TrxR) and of the zinc-finger enzyme poly(ADP-ribose) polymerase 1 (PARP-1). In the case of TrxR inhibition, their activity depended clearly on the size of the alkyl/aryl residues of phosphorus atoms. Density functional theory (DFT) calculations showed that the Au[BOND]P bond of the triphenylphosphane complex [AuI(NHC)(PPh3)]I had a lower bond dissociation energy compared to trialkylphosphane complexes [AuI(NHC)(PR3)]I, indicating a higher kinetic reactivity of this particular compound. In fact, [AuI(NHC)(PPh3)]I triggered an enhanced inhibitory activity against PARP-1

Towards the Synthesis of New Tumor Targeting Photosensitizers for Photodynamic Therapy and Imaging Applications

The synthesis of three complexes, which bear tumor-targeting peptide and which are suitable for imaging applications might act at the same time, is reported. Their structure contain a PS (a porphyrin or a fulleropyrrolidine derivative), a [1,4,7]-triazacyclononane (TACN) chelator suitable for coordination, and a bombesin BN[7-14] as a targeting peptide. Overall, this work paves the way for the preparation of theranostic complexes although the yields will need to be seriously improved and the synthetic process optimized. Targeting peptides are very promising molecules to increase tumor selectivity of anticancer drugs. Herein, we report the synthesis of three complexes, which might act at the same time as photosensitizers (PSs) for cancer photodynamic therapy (PDT), as delivery systems of Re(I)/99mTc(I) fragments into tumor cells as well as targeting agents for prostate cancer cells. To this aim, we designed a structure containing a PS such as a water soluble +3-charged tris-methylpyridinium porphyrin or a fulleropyrrolidine derivative, a [1,4,7]-triazacyclononane (TACN) chelator suitable for coordination, and a bombesin BN[7-14] as a targeting peptide. Their syntheses were performed using two different approaches: the first one was based on a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC, \u201cclick reaction\u201d) in solution, that led to compound 1, and the second one based on coupling reactions on the solid phase, that led to compounds 2 and 3. We could successfully prepare molecules bearing tumor-targeting PSs and which are suitable for imaging applications. Overall, this work paves the way for the synthesis of theranostic complexes although the yields will need to be seriously improved and the synthetic process optimized