Ruthenium(II) polypyridyl complexes continue to raise increasing interest for the encouraging results in several biomedical areas. Considering their vast chemical-physical repertoire, in particular the possibility to switch from the sensitization of reactive oxygen species (ROS) to ROS-scavenging abilities by tuning the nature of their ligands, it is therefore surprising that their potential as antioxidants has not been largely investigated so far. Herein, we explored the antioxidant behaviour of the novel ruthenium compound [Ru(dbpy)(2,3-DAN)Cl]PF6 (Ru1), featuring a benzoxazole derivative (dpby = 2,6-bis(4-methyl-2-ossazolyl)pyridine) and the non-innocent 2,3-diamminonaftalene (2,3 DAN) ligand, along with the reference tpy-containing analogue [Ru(tpy)(2,3-DAN)Cl]PF6 (Ru2) (tpy = 2,2':6',2''-terpyridine). Following the synthesis and the electrochemical characterization, chemical antioxidant assays highlighted the beneficial role of dpby for the ROS-scavenging properties of Ru1. These data have been corroborated by the highest protective effect of Ru1 against the oxidative stress induced in SH-SY5Y human neuroblastoma, which exerts pro-survival and anti-inflammatory actions. The results herein reported highlight the potential of Ru1 as pharmacological tool in neurodegenerative diseases and specially prove that the antioxidant properties of such compounds are likely the result of a non-trivial synergetic action involving the bioactive ligands in their chemical architectures.
The covalent modification of Ru(II) polypyridyl complexes (RPCs) with organic chromophores is a powerful strategy to obtain metal-based photosensitizer agents (PSs) with improved performance for application in photodynamic therapy (PDT). In this respect, perylene-imides are of particular interest due to their rich chemical-physical repertoire, and it is therefore quite surprising that their combination with RPCs has been poorly considered so far. Herein, we report on the photophysical behavior of two newly synthesized RPCs bearing a perylene monoimide appendant (PMI-Ad). Differently from the majority of RPCs-perylene-imides dyads, these chromophores are dissymmetric and are tethered to the metal centers through a single C-C bond in the 3- or 5-position of 1,10-phenanthroline (Ru-3PMI-Ad and Ru-5PMI-Ad). Both compounds show excellent singlet oxygen photosensitizing activity, with quantum yields reaching >90% in the case of Ru-3PMI-Ad. A combined spectroscopic and theoretical analysis, also involving transient absorption and luminescence lifetime measurements, demonstrates that both compounds undergo intersystem crossing on a very fast time scale (tens of picoseconds) and with high efficiency. Our results further demonstrate that the increased electron delocalization between the metal center and the PMI-Ad chromophore observed for Ru-3PMI-Ad additionally contributes to increase the singlet oxygen quantum yields by prolonging the lifetime of the triplet state.
Ruthenium(II) polypyridyl complexes (RPCs) are gaining momentum in photoactivated chemotherapy (PACT), thanks to the possibility of overcoming the classical reliance on molecular oxygen of photodynamic therapy while preserving the selective drug activation by using light. However, notwithstanding the intriguing perspectives, the translation of such an approach in the development of new antimicrobials has been only barely considered. Herein, MTZH-1 and MTZH-2, two novel analogues of metronidazole (MTZ), a mainstay drug in the treatment of anaerobic bacterial infections, were designed and inserted in the strained ruthenium complexes [Ru(tpy)(dmp)(MTZ-1)]PF6 (Ru2) and [Ru(tpy)(dmp)(MTZ-2)]PF6 (Ru3) (tpy = terpyridine, dmp = 2,9-dimethyl-1,10-phenanthroline) (Chart 1). Analogously to the parental compound [Ru(tpy)(dmp)(5NIM)]PF6 (Ru1) (5-nitroimidazolate), the Ru(II)-imidazolate coordination of MTZ derivatives resulted in promising Ru(II) photocages, capable to easily unleash the bioactive ligands upon light irradiation and increase the antibacterial activity against Bacillus subtilis, which was chosen as a model of Gram-positive bacteria. The photoreleased 5-nitroimidazole-based ligands led to remarkable phototoxicities under hypoxic conditions (<1% O2), with the lead compound Ru3 that exhibited the highest potency across the series, being comparable to the one of the clinical drug MTZ. Besides, the chemical architectures of MTZ derivatives made their interaction with NimAunfavorable, being NimA a model of reductases responsible for bacterial resistance against 5-nitroimidazole-based antibiotics, thus hinting at their possible use to combat antimicrobial resistance. This work may therefore provide fundamental knowledge in the design of novel photoresponsive tools to be used in the fight against infectious diseases. For the first time, the effectiveness of the "photorelease antimicrobial therapy" under therapeutically relevant hypoxic conditions was demonstrated.
Anti-Infective Agents , Coordination Complexes , Ruthenium , Anti-Bacterial Agents/pharmacology , Coordination Complexes/chemistry , Metronidazole/pharmacology , Ruthenium/pharmacology , Ruthenium/chemistry , Ligands
In this study, the ligands 23,24-dihydroxy-3,6,9,12-tetraazatricyclo[17.3.1.1(14,18)]eicosatetra-1(23),14,16,18(24),19,21-hexaene, L1, and 26,27-dihidroxy-3,6,9,12,15-pentaazatricyclo[20.3.1.1(17,21)]eicosaepta-1(26),17,19,21(27),22,24-hexaene, L2, were synthesized: they represent a new class of molecules containing a biphenol unit inserted into a macrocyclic polyamine fragment. The previously synthesized L2 is obtained herein with a more advantageous procedure. The acid-base and Zn(II)-binding properties of L1 and L2 were investigated through potentiometric, UV-Vis, and fluorescence studies, revealing their possible use as chemosensors of H+ and Zn(II). The new peculiar design of L1 and L2 afforded the formation in an aqueous solution of stable Zn(II) mono (LogK 12.14 and 12.98 for L1 and L2, respectively) and dinuclear (LogK 10.16 for L2) complexes, which can be in turn exploited as metallo-receptors for the binding of external guests, such as the popular herbicide glyphosate (N-(phosphonomethyl)glycine, PMG) and its primary metabolite, the aminomethylphosphonic acid (AMPA). Potentiometric studies revealed that PMG forms more stable complexes than AMPA with both L1- and L2-Zn(II) complexes, moreover PMG showed higher affinity for L2 than for L1. Fluorescence studies showed instead that the L1-Zn(II) complex could signal the presence of AMPA through a partial quenching of the fluorescence emission. These studies unveiled therefore the utility of polyamino-phenolic ligands in the design of promising metallo-receptors for elusive environmental targets.
A water-soluble ruthenium(II) complex (L), capable of producing singlet oxygen (1O2) when irradiated with visible light, was used to modify the surface of an indium-tin oxide (ITO) electrode decorated with a nanostructured layer of TiO2 (TiO2/ITO). Singlet oxygen triggers the appearance of a cathodic photocurrent when the electrode is illuminated and biased at a proper reduction potential value. The L/TiO2/ITO electrode was first characterized with cyclic voltammetry, impedance spectroscopy, NMR, and Raman spectroscopy. The rate constant of singlet oxygen production was evaluated by spectrophotometric measurements. Taking advantage of the oxidative process initiated by 1O2, the analysis of phenolic compounds was accomplished. Particularly, the 1O2-driven oxidation of hydroquinone (HQ) produced quinone moieties, which could be reduced back at the electrode surface, biased at -0.3 V vs Ag/AgCl. Such a light-actuated redox cycle produced a photocurrent dependent on the concentration of HQ in solution, exhibiting a limit of detection (LOD) of 0.3 µmol dm-3. The L/TiO2/ITO platform was also evaluated for the analysis of p-aminophenol, a commonly used reagent in affinity sensing based on alkaline phosphatase.
Ruthenium , Singlet Oxygen , Light , Oxidation-Reduction , Electrodes
Ovarian cancer recurrence is frequent and associated with chemoresistance, leading to extremely poor prognosis. Herein, we explored the potential anti-cancer effect of a series of highly charged Ru(II)-polypyridyl complexes as photosensitizers in photodynamic therapy (PDT), which were able to efficiently sensitize the formation of singlet oxygen upon irradiation (Ru12+ and Ru22+) and to produce reactive oxygen species (ROS) in their corresponding dinuclear metal complexes with the Fenton active Cu(II) ion/s ([CuRu1]4+ and [Cu2Ru2]6+). Their cytotoxic and anti-tumor effects were evaluated on human ovarian cancer A2780 cells both in the absence or presence of photoirradiation, respectively. All the compounds tested were well tolerated under dark conditions, whereas they switched to exert anti-tumor activity following photoirradiation. The specific effect was mediated by the onset of programed cell death, but only in the case of Ru12+ and Ru22+ was preceded by the loss of mitochondrial membrane potential soon after photoactivation and ROS production, thus supporting the occurrence of apoptosis via type II photochemical reactions. Thus, Ru(II)-polypyridyl-based photosensitizers represent challenging tools to be further investigated in the identification of new therapeutic approaches to overcome the innate chemoresistance to platinum derivatives of some ovarian epithelial cancers and to find innovative drugs for recurrent ovarian cancer.
Antineoplastic Agents , Coordination Complexes , Ovarian Neoplasms , Photochemotherapy , Ruthenium , Humans , Female , Photosensitizing Agents/pharmacology , Photosensitizing Agents/chemistry , Ruthenium/pharmacology , Ruthenium/chemistry , Carcinoma, Ovarian Epithelial/drug therapy , Cell Line, Tumor , Reactive Oxygen Species , HeLa Cells , Ovarian Neoplasms/drug therapy , Neoplasm Recurrence, Local , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry
5-Nitroimidazole (5NIMH), chosen as a molecular model of nitroimidazole derivatives, which represent a broad-spectrum class of antimicrobials, was incorporated into the ruthenium complexes [Ru(tpy)(phen)(5NIM)]PF6 (1) and [Ru(tpy)(dmp)(5NIM)]PF6 (2) (tpy = terpyridine, phen = phenanthroline, dmp = 2,9-dimethyl-1,10-phenanthroline). Besides the uncommon metal coordination of 5-nitroimidazole in its imidazolate form (5NIM), the different architectures of the spectator ligands (phen and dmp) were exploited to tune the "mode of action" of the resulting complexes, passing from a photostable compound where the redox properties of 5NIMH are preserved (1) to one suitable for the nitroimidazole phototriggered release (2) and whose antibacterial activity against B. subtilis, chosen as cellular model, is effectively improved upon light exposure. This study may provide a fundamental knowledge on the use of Ru(II)-polypyridyl complexes to incorporate and/or photorelease biologically relevant nitroimidazole derivatives in the design of a novel class of antimicrobials.
Coordination Complexes , Nitroimidazoles , Ruthenium , Anti-Bacterial Agents/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Ligands , Nitroimidazoles/pharmacology , Ruthenium/chemistry , Ruthenium/pharmacology
The antimicrobial potential of two ruthenium(II) polypyridyl complexes, [Ru(phen)2L1]2+ and [Ru(phen)2L2]2+ (phen = 1,10-phenanthroline) containing the 4,4'-(2,5,8,11,14-pentaaza[15])-2,2'-bipyridilophane (L1) and the 4,4'-bis-[methylen-(1,4,7,10-tetraazacyclododecane)]-2,2' bipyridine (L2) units, is herein investigated. These peculiar polyamine frameworks afford the formation of highly charged species in solution, influence the DNA-binding and cleavage properties of compounds, but they do not undermine their singlet oxygen sensitizing capacities, thus making these complexes attractive 1O2 generators in aqueous solution. L1 and L2 also permit to stably host Fenton -active Cu2+ ion/s, leading to the formation of mixed Ru2+/Cu2+ forms capable to further strengthen the oxidative damages to biological targets. Herein, following a characterization of the Cu2+ binding ability by [Ru(phen)2L2]2+, the water-octanol distribution coefficients, the DNA binding, cleavage and 1O2 sensitizing properties of [Ru(phen)2L2]2+ and [Cu2Ru(phen)2L2]6+ were analysed and compared with those of [Ru(phen)2L1]2+ and [CuRu(phen)2L1]4+. The antimicrobial activity of all compounds was evaluated against B. subtilis, chosen as a model for gram-positive bacteria, both under dark and upon light-activation. Our results unveil a notable phototoxicity of [Ru(phen)2L2]2+ and [Cu2Ru(phen)2L2]6+, with MIC (minimal inhibitory concentrations) values of 3.12 µM. This study highlights that the structural characteristics of polyamine ligands gathered on highly charged Ru(II)-polypyridyl complexes are versatile tools that can be exploited to achieve enhanced antibacterial strategies.
Anti-Bacterial Agents/pharmacology , Coordination Complexes/pharmacology , Pyridines/pharmacology , Animals , Anti-Bacterial Agents/radiation effects , Bacillus subtilis/drug effects , Cattle , Coordination Complexes/radiation effects , Copper/chemistry , Copper/radiation effects , DNA/drug effects , DNA Cleavage/drug effects , Ligands , Microbial Sensitivity Tests , Pyridines/radiation effects , Ruthenium/chemistry , Ruthenium/radiation effects , Singlet Oxygen/metabolism
The synthesis of a new RuII complex, in which the metal is coordinated by two 1,10-phenanthroline ligands and a 2,2'-bipyridyl unit linked, via methylene bridges in its 4 and 4' positions, to two 1,4,7,10-tetraazacyclododecane (cyclen) macrocycles ([Ru(phen)2 L]2+) is reported. Protonation and ZnII binding by [Ru(phen)2 L]2+ have been analyzed by potentiometric titration, evidencing the formation of mixed hetero-binuclear and hetero-trinuclear ZnII/RuII complexes. These complexes were tested as bis-phenol A (BPA) binders. Only the dizinc complex with [Ru(phen)2 L]2+ is able to bind BPA in aqueous solution, affording a remarkably stable {Zn2[Ru(phen)2 L]BPA(H-2)}4+ adduct at neutral pH, in which BPA is bound in its doubly deprotonated form to the two ZnII ions. BPA binding was found to quench the luminescence emission of the RuII(phen)2bipy core. Although the quenching effect is modest, this study demonstrates that appropriately designed dizinc complexes can be used for binding and optical sensing of BPA in water.
Benzhydryl Compounds/isolation & purification , Phenols/isolation & purification , Water/chemistry , 2,2'-Dipyridyl/chemistry , Anions/chemistry , Benzhydryl Compounds/chemistry , Ligands , Luminescence , Metals/chemistry , Molecular Structure , Phenols/chemistry , Ruthenium/chemistry
Mechanochemistry is an emerging and reliable alternative to conventional solution (batch) synthesis of complex molecules under green and solvent-free conditions. In this regard, we report here on the conjugation of a dextran polysaccharide with a fluorescent probe, a phenylboronic acid (PBA)-functionalized boron dipyrromethene (BODIPY) applying the ball milling approach. The ball milling formation of boron esters between PBA BODIPY and dextran proved to be more efficient in terms of reaction time, amount of reactants, and labelling degree compared to the corresponding solution-based synthetic route. PBA-BODIPY dextran assembles into nanoparticles of around 200 nm by hydrophobic interactions. The resulting PBA-BODIPY dextran nanoparticles retain an apolar interior as proved by pyrene fluorescence, suitable for the encapsulation of hydrophobic drugs with high biocompatibility while remaining fluorescent.
We report here on the efficient and straightforward synthesis of a series of modular and functional PBA-BODIPY dyes 1-4. They are an outstanding example of the efficient merge of the versatility of the 3,5-dichloro-BODIPY derivatives and the receptor-like ability of the PBA moiety. The potential bioanalytical applicability of these tools was assessed by measuring the binding to glycan chains of antibodies by a Quartz Crystal Microbalance (QCM).
