Patrick Gamez

Four cyclometalated Rh(iii) and Ir(iii) piano-stool complexes were synthesized and fully characterized, including single-crystal X-ray structural analysis. Their potential anticancer properties were evaluated using cancer stem-cell mammospheres.

Half-sandwich arene osmium(ii) complex 2 can inhibit the amyloid-β aggregation in vitro and in vivo using a Caenorhabditis elegans animal model of Alzheimer's disease.

A new tetradentate ligand, namely 3,3′‐((1E,1′E)‐(ethane‐1,2‐diylbis(azaneylylidene))bis(methaneylylidene))bis(pyridin‐2‐amine) (en2ampy) was prepared and two copper(II) complexes, viz. [Cu(en2ampy)]Cl₂ (1) and [Cu(en2ampy)](NO₃)₂ (2), were obtained through its reaction with copper(II) chloride and copper(II) nitrate, respectively. The single‐crystal X‐ray structure of the compounds showed that the metal centre was coordinated in a square‐planar fashion by a doubly deprotonated en2ampy acting as a tetradentate / ‐donor ligand. DNA‐binding studies revealed that 1 and 2 were electrostatically binding to DNA, probably in the grooves and cytotoxicity assays showed that the complexes were clearly more efficient than cisplatin against ovarian carcinoma (A2780) cells and the cisplatin‐resistant (A2780Cis) ones.

The cytotoxicity behaviour of 10 piano-stool Os( ii ) complexes and their isostructural Ru( ii ) analogues was comparatively investigated.

Two ruthenium(II) polypyridyl complexes were prepared with the {Ru(phen)₂}²⁺ moiety and a third sterically non-hindering bidentate ligand, namely 2,2′-dipyridylamine (dpa) and N-benzyl-2,2′-dipyridylamine (Bndpa). Hence, complexes [Ru(phen)₂(dpa)](PF₆)₂ (1) and [Ru(phen)₂(Bndpa)](PF₆)₂ (2) were characterized and their photochemical behaviour in solution (acetonitrile and water) was subsequently investigated. Compounds 1 and 2, which do not exhibit notably distorted octahedral coordination environments, contrarily to the homoleptic “parent” compound [Ru(phen)₃](PF₆)₂, experience two-step photoejection of the dpa and Bndpa ligand upon irradiation (1050–430 nm) for several hours. DNA-binding studies revealed that compounds 1 and 2 affect the biomolecule differently upon irradiation; while 2 solely modifies its electrophoretic mobility, complex 1 is also capable of cleaving it. In vitro cytotoxicity studies with two cancer-cell lines, namely A549 (lung adenocarcinoma) and A375 (melanoma), showed that both 1 and 2 are not toxic in the dark, while only 1 is significantly cytotoxic if irradiated, 2 remaining non-toxic under these conditions. Graphical abstract Light irradiation of the complex cation [Ru(phen)₂(dpa)]²⁺ leads to the generation of transient Ru species that is present in the solution medium for several hours, and that is significantly cytotoxic, ultimately producing non-toxic free dpa and [Ru(phen)(OH₂)₂]²⁺.

Photodynamic therapy (PDT) uses a combination of molecular oxygen, light and a photosensitizer (PS) to generate singlet oxygen or reactive oxygen species (ROS), which can eradicate tumoral cells. All currently approved PSs for cancer treatment are molecular PSs. To date, no nanoparticlebased PSs are used clinically although it has widely been shown that nanotechnology may help to improve the properties of molecular PSs; for instance, molecular PSs suffer from some intrinsic limitations that undermine their therapeutic efficacy. In the present minireview, the most critical weaknesses exhibited by molecular PSs are described, and the potential use of nanoparticles (NPs) to address them and to reach the clinics is discussed.

One of the pathological hallmarks of Alzheimer’s disease (AD) is the formation of amyloid-β plaques. Since acetylcholinesterase (AChE) promotes the formation of such plaques, the inhibition of this enzyme could slow down the progression of amyloid-β aggregation, hence being complementary to the palliative treatment of cholinergic decline. Antiaggregation assays performed for apigenin and quercetin, which are polyphenolic compounds that exhibit inhibitory properties against the formation of amyloid plaques, reveal distinct inhibitory effects of these compounds on Aβ40 aggregation in the presence and absence of AChE. Furthermore, the analysis of the amyloid fibers formed in the presence of these flavonoids suggests that the Aβ40 aggregates present different quaternary structures, viz., smaller molecular assemblies are generated. In agreement with a noncompetitive inhibition of AChE, molecular modeling studies indicate that these effects may be due to the binding of apigenin and quercetin at the peripheral binding site of AChE. Since apigenin and quercetin can also reduce the generation of reactive oxygen species, the data achieved suggest that multitarget catechol-type compounds may be used for the simultaneous treatment of various biological hallmarks of AD.

Two square-planar coordination compounds, namely [Cu(CPYA)Cl₂] (1) and [Pd(CPYA)Cl₂] (2), were prepared from the ligand 4-chloro-N-(pyridin-2-ylmethyl)aniline (CPYA) and two chloride salts, and were fully characterized, including by X-ray diffraction. Spectroscopic, electrophoretic and AFM studies revealed that the two isostructural compounds were interacting differently with DNA. In both cases, the initial interaction involves electrostatic contacts of the CPYA ligand in the minor groove (as suggested by molecular docking), but subsequent strong binding occurs with the palladium(II) complex2, whereas the binding with the copper complex1is weaker and concentration dependent. The strong binding of2eventually leads to the cleavage of the double strand and the redox activity of1allows to oxidatively cleave the biomolecule.Graphic abstract

We have recently reported a series of piano-stool ruthenium(II) complexes of the general formula [RuCl₂(η⁶-arene)(P(1-pyrenyl)R²R³)] showing excellent cytotoxic activities (particularly when R² = R³ = methyl). In the present study, new members of this family of compounds have been prepared with the objective to investigate the effect of the steric hindrance of a bulky phosphane ligand, namely diisopropyl(1-pyrenyl)phosphane (L), on exchange reactions involving the coordinated halides (X = Cl, I). Two η⁶-arene rings were used, i.e. η⁶-methyl benzoate (mba) and η⁶-p-cymene (p-cym), and four complexes were synthesized, namely [RuCl₂(mba)(L)] (1 Cl₂^iPr), [RuI₂(mba)(L)] (1 I₂^iPr), [RuCl₂(p-cym)(L)] (2 Cl₂^iPr), and [RuI₂(p-cym)(L)] (2 I₂^iPr). Unexpectedly, all of the complexes exhibited poor cytotoxic activities after 24 h of incubation with cells, in contrast to the related compounds previously reported. However, it was observed that aged DMSO solutions of 2 I₂^iPr (from 2 to 7 days) exhibited better activities in comparison to freshly prepared solutions and that the activity improved over “aging” time. Thorough studies were therefore performed to uncover the origin of this lag time in the cytotoxicity efficiency. The data achieved clearly demonstrated that compounds 2 I₂^iPr and 2 Cl₂^iPr were undergoing a series of transformation reactions in DMSO (with higher rates for the iodido complex 2 I₂^iPr), ultimately generating cyclometalated species through a mechanism involving DMSO as a coordinated proton abstractor. The cyclometalated complexes detected in solution were subsequently prepared; hence, pure [RuCl(p-cym)(κ²C-diisopropyl(1-pyrenyl)phosphane)] (3_Cl^iPr), [RuI(p-cym)(κ²C-diisopropyl(1-pyrenyl)phosphane)] (3_I^iPr), and [Ru(p-cym)(κS-dmso)(κ²C-diisopropyl(1-pyrenyl)phosphane)]PF₆ (3_dmso^iPr) were synthesized and fully characterized. Remarkably, 3_Cl^iPr, 3_I^iPr, and 3_dmso^iPr are all very efficient cytotoxic agents, exhibiting slightly better activities in comparison to the chlorido noncyclometalated complexes [RuCl₂(η⁶-arene)(P(1-pyrenyl)R²R³)] described in an earlier report. For comparison purposes, the iodido compounds [RuI₂(mba)(dimethyl(1-pyrenyl)phosphane)] (1 I₂^Me) and [RuI₂(p-cym)(dimethyl(1-pyrenyl)phosphane)] (2 I₂^Me), bearing the less hindered dimethyl(1-pyrenyl)phosphane ligand, have also been prepared. The cytotoxic and chemical behaviors of 1 I₂^Me and 1 I₂^Me were comparable to those of their chlorido counterparts reported previously.

Alzheimer’s disease (AD), affecting almost 50 million individuals worldwide, is currently the first cause of dementia. Despite the tremendous research efforts in the last decade, only four supportive or palliative drugs, namely, acetylcholinesterase (AChE) inhibitors donepezil, galantamine, and rivastigmine and the glutamate NMDA receptor antagonist memantine, are currently available. New therapeutic strategies are becoming prominent, such as the direct inhibition of amyloid formation or the regulation of metal homeostasis. In the present report, the potential use of Prussian blue (PB), a drug that is in the World Health Organization Model List of Essential Medicines, in AD treatment is demonstrated. Both in vitro and in cellulo studies indeed suggest that PB nanoparticles (PBNPs) are capable of reducing the formation of typical amyloid-β fibers (detected by thioflavin T fluorescence) and restoring the usual amyloid fibrillation pathway via chelation/sequestration of copper, which is found in high concentrations in senile plaques.