Oxime@Zirconium-Metal-Organic Framework Hybrid Material as a Potential Antidote for Organophosphate Poisoning.

A novel material with dual activity toward organophosphate (OP) poisoning, based on Zr-MOF-808 and neutral oxime RS69N, has been prepared. The hybrid material has a significant drug payload (5.2 ± 0.9 oxime to MOF-808 molar ratio) and shows a sustained oxime release in simulated physiological media, leading to the successful reactivation of OP-inhibited acetylcholinesterase. At the same time, the hybrid system presents an efficient and moderately fast removal rate of a toxic organophosphorus model compound (diisopropylfluorophosphate) from simulated physiological media (t1/2 = 183 min; 95% removal rate after 24 h).

Zirconium Metal-Organic Polyhedra with Dual Behavior for Organophosphate Poisoning Treatment.

Organophosphate nerve agents and pesticides are extremely toxic compounds because they result in acetylcholinesterase (AChE) inhibition and concomitant nerve system damage. Herein, we report the synthesis, structural characterization, and proof-of-concept utility of zirconium metal-organic polyhedra (Zr-MOPs) for organophosphate poisoning treatment. The results show the formation of robust tetrahedral cages [((n-butylCpZr)3(OH)3O)4L6]Cl6 (Zr-MOP-1; L = benzene-1,4-dicarboxylate, n-butylCp = n-butylcyclopentadienyl, Zr-MOP-10, and L = 4,4'-biphenyldicarboxylate) decorated with lipophilic alkyl residues and possessing accessible cavities of ∼9.8 and ∼10.7 Šinner diameters, respectively. These systems are able to both capture the organophosphate model compound diisopropylfluorophosphate (DIFP) and host and release the AChE reactivator drug pralidoxime (2-PAM). The resulting 2-PAM@Zr-MOP-1(0) host-guest assemblies feature a sustained delivery of 2-PAM under simulated biological conditions, with a concomitant reactivation of DIFP-inhibited AChE. Finally, 2-PAM@Zr-MOP systems have been incorporated into biocompatible phosphatidylcholine liposomes with the resulting assemblies being non-neurotoxic, as proven using neuroblastoma cell viability assays.

Biomimetic 1-Aminocyclopropane-1-Carboxylic Acid Oxidase Ethylene Production by MIL-100(Fe)-Based Materials.

A novel core@shell hybrid material based on biocompatible hydroxyapatite nanoparticles (HA) and the well-known MIL-100(Fe) (Fe3O(H2O)2F(BTC)2·nH2O, BTC: 1,3,5-benzenetricarboxylate) has been prepared following a layer-by-layer strategy. The core@shell nature of the studied system has been confirmed by infrared, X-ray powder diffraction, N2 adsorption, transmission electron microscopy imaging, and EDS analyses revealing the homogeneous deposition of MIL-100(Fe) on HA, leading to HA@MIL-100(Fe) rod-shaped nanoparticles with a 7 nm shell thickness. Moreover, both MIL-100(Fe) and HA@MIL-100(Fe) have demonstrated to act as efficient heterogeneous catalysts toward the biomimetic oxidation of 1-aminocyclopropane-1-carboxylic acid into ethylene gas, a stimulator that regulates fruit ripening. Indeed, the hybrid material maintains the catalytic properties of pristine MIL-100(Fe) reaching 40% of conversion after only 20 min. Finally, the chemical stability of the catalyst in water has also been monitored for 21 days by inductively coupled plasma-mass spectrometry confirming that only ca. 3% of Ca is leached.

Coordination Modulation Method To Prepare New Metal-Organic Framework-Based CO-Releasing Materials.

Aluminum-based metal-organic frameworks (MOFs), [Al(OH)(SDC)] n, (H2SDC: 4,4'-stilbenedicarboxylic acid), also known as CYCU-3, were prepared by means of the coordination modulation method to produce materials with different crystal size and morphology. In particular, we screened several reagent concentrations (20-60 mM) and modulator/ligand ratios (0-50), leading to 20 CYCU x_ y materials ( x: reagent concentration, y = modulator/ligand ratio) with different particle size and morphology. Noteworthy, the use of high modulator/ligand ratio gives rise to a new phase of CYCU-3 (CYCU-3' x_50 series), which was structurally analyzed. Afterward, to test the potential of these materials as CO-prodrug carriers, we selected three of them to adsorb the photo- and bioactive CO-releasing molecule (CORM) ALF794 [Mo(CNCMe2CO2H)3(CO)3] (CNCMe2CO2H = 2-isocyano-2-methyl propionic acid): (i) CYCU-3 20_0, particles in the nanometric range; (ii) CYCU-3 50_5, bar-type particles with heterogeneous size, and (iii) CYCU-3' 50_50, a new phase analogous to pristine CYCU-3. The corresponding hybrid materials were fully characterized, revealing that CYCU-3 20_0 with the smallest particle size was not stable under the drug loading conditions. Regarding the other two materials, similar ALF794 loadings were found (0.20 and 0.19 CORM/MOF molar ratios for ALF794@CYCU-3 50_5 and ALF794@CYCU-3' 50_50, respectively). In addition, these hybrid systems behave as CO-releasing materials (CORMAs), retaining the photoactive properties of the pristine CORM in both phosphate saline solution and solid state. Finally, the metal leaching studies in solution confirmed that ALF794@CYCU-3' 50_50 shows a good retention capacity toward the potentially toxic molybdenum fragments (75% of retention after 72 h), which is the lowest value reported for a MOF-based CORMA to date.

Silk fibroin nanoparticles as biocompatible nanocarriers of a novel light-responsive CO-prodrug.

[Mn(CO)3(2,2'-bipyridine)(PPh3)](ClO4) (1), a novel photoactive CO-releasing molecule, has been prepared and fully characterized. Besides, silk fibroin nanoparticles (SFNs) have been used, for the first time, as vehicles of 1 leading to the hybrid material 1@SFNs that shows an enhanced CO-delivery.

Silver(I)-Mediated Base Pairs in DNA Sequences Containing 7-Deazaguanine/Cytosine: towards DNA with Entirely Metallated Watson-Crick Base Pairs.

DNA sequences comprising noncanonical 7-deazaguanine (7C G) and canonical cytosine (C) are capable of forming Watson-Crick base pairs via hydrogen bonds as well as silver(I)-mediated base pairs by coordination to central silver(I) ions. Duplexes I and II containing 7C G and C have been synthesized and characterized. The incorporation of silver(I) ions into these duplexes has been studied by means of temperature-dependent UV spectroscopy, circular dichroism, and DFT calculations. The results suggest the formation of DNA molecules comprising contiguous metallated 7C G-AgI -C Watson-Crick base pairs that preserve the original B-type conformation. Furthermore, additional studies performed on duplex III indicated that, in the presence of AgI ions, 7C G-C and 7C A-T Watson-Crick base pairs (7C A, 7-deazadenine; T, thymine) can be converted to metallated 7C G-AgI -C and 7C A-AgI -T base pairs inside the same DNA molecule whilst maintaining its initial double helix conformation. These findings are very important for the development of customized silver-DNA nanostructures based on a Watson-Crick complementarity pattern.

Aluminum Doped MCM-41 Nanoparticles as Platforms for the Dual Encapsulation of a CO-Releasing Molecule and Cisplatin.

Mesoporous silica Al-MCM-41 nanoparticles have been used, for the first time, as vehicles for the single and dual encapsulation of the cationic CO-releasing molecule (CORM) [Mn(1,4,7-triazacyclononane)(CO)3]+ (ALF472+) and the well-known antineoplastic drug, cis-[PtCl2(NH3)2] (cisplatin). Thus, two new hybrid materials, namely, ALF472@Al-MCM-41 and ALF472-cisplatin@Al-MCM-41, have been isolated and fully characterized. The results reveal that the presence of CORM molecules enhances cisplatin loading 3-fold, yielding a cargo of 0.45 mmol g-1 of ALF472+ and 0.12 mmol g-1 of the platinum complex for ALF472-cisplatin@Al-MCM-41. It is worth noting that ALF472@Al-MCM-41 shows a good dispersion in phosphate buffered saline solution, while the dual hybrid material slightly aggregates in this simulated physiological medium (hydrodynamic size: 112 ± 23 and 336 ± 50 nm, respectively). In addition, both hybrid materials (ALF472@Al-MCM-41 and ALF472-cisplatin@Al-MCM-41) behave as photoactive CO-releasing materials, delivering 0.25 and 0.11 equiv of CO, respectively, after 24 h and exhibiting a more controlled CO delivery than that of the free CORM. Finally, metal leaching studies have confirmed the good retention capacity of Al-MCM-41 toward the potentially toxic manganese fragments (86% of retention after 72 h) as well as the low release of cisplatin (ca. 7% after 72 h).

Inorganic mesoporous silicas as vehicles of two novel anthracene-based ruthenium metalloarenes.

Two novel anthracene-based half-sandwich organometallic Ru(II) compounds, namely, [Ru(p-cymene)(L1)Cl2] (1) and [Ru(p-cymene)(L2)Cl2] (2) (L1=1-(anthracen-9-yl)-N-(pyridin-3-ylmethyl)methanamine; L2=1-(anthracen-9-yl)-N-(pyridin-4-ylmethyl)methanamine) have been synthesized and characterized. We demonstrate that the fluorescence properties of these complexes are highly affected by the linking position of the anthracene unit, as only 2 shows fluorescence emission in the blue region. Regarding their biological activity, both ruthenium metallodrugs show interaction with different biological targets such as S-donor amino acids (cysteine) and proteases (cysteine cathepsin B). Moreover, 1 and 2 show in vitro cytotoxicity against HL-60 cancer cell line (IC50=84.5 and 87.0µM for 1 and 2, respectively), with cell death occurring via apoptosis. Further studies have shown that diffusion into cells is the main mechanism of metallodrug uptake. Finally, as a proof of concept, these ruthenium complexes have been successfully encapsulated into MCM-41 and SBA-15 mesoporous silicas using two different incorporation strategies (impregnation and grinding).

A combined experimental and DFT investigation on the structure and CO-releasing properties of mono and binuclear fac-ReI(CO)3 complexes with 5-pyridin-2-ylmethylene-amino uracils.

The synthesis, structure and CO-releasing properties of a number of new tricarbonyl rhenium(i) complexes with 5-substituted-6-amino-1,3-dimethyluracils are reported and their structural features discussed on the basis of both spectral and X-ray crystallographic analyses. The 5-substituent library includes -N[double bond, length as m-dash]CH-2py (DAAUPic) and -CH[double bond, length as m-dash]N-N[double bond, length as m-dash]CH-2py (FDUHzPic) as additional metal binding components and chloride, acetonitrile or pyridine acting as ancillary ligands. The compounds have been identified by elemental analysis, NMR, MS and IR spectroscopy. In addition, [ReCl(CO)3(DAAUPic)], [Re(CO)3(FDUHzPic)py]ClO4, [Re(CO)3(FDUHzPic)py]PF6, [Re2Cl2(CO)6(FDUHzPic)] and [Re2Cl(CO)6(FDUHzPicH-1)(H2O)] structures have been solved by X-ray diffraction methods. These studies have clearly shown that the preferred coordination mode to rhenium takes place through the (N1F,N52)-pyridin-2-yl-methyleneamine moiety, the uracil coordinative availability (O4-N51 or N6-N51) being used only to bind the second metal center. The CO-releasing ability of these rhenium compounds has been investigated by the reaction with myoglobin; the corresponding studies have revealed that two of the mononuclear complexes and their related binuclear analogues are able to release CO to a moderate extent. This ability has also been theoretically assessed through a QTAIM analysis. The results, although non-conclusive, may explain somehow possible different preferences in CO releasing power after a comparison between the nature of Re-CO links in mononuclear and binuclear compounds.

Cation Exchange Strategy for the Encapsulation of a Photoactive CO-Releasing Organometallic Molecule into Anionic Porous Frameworks.

The encapsulation of the photoactive, nontoxic, water-soluble, and air-stable cationic CORM [Mn(tacn)(CO)3]Br (tacn = 1,4,7-triazacyclononane) in different inorganic porous matrixes, namely, the metalorganic framework bio-MOF-1, (NH2(CH3)2)2[Zn8(adeninate)4(BPDC)6]·8DMF·11H2O (BPDC = 4,4'-biphenyldicarboxylate), and the functionalized mesoporous silicas MCM-41-SO3H and SBA-15-SO3H, is achieved by a cation exchange strategy. The CO release from these loaded materials, under simulated physiological conditions, is triggered by visible light. The results show that the silica matrixes, which are unaltered under physiological conditions, slow the kinetics of CO release, allowing a more controlled CO supply. In contrast, bio-MOF-1 instability leads to the complete leaching of the CORM. Nevertheless, the degradation of the MOF matrix gives rise to an enhanced CO release rate, which is related to the presence of free adenine in the solution.

Nanoscaled Zinc Pyrazolate Metal-Organic Frameworks as Drug-Delivery Systems.

This work describes synthesis at the nanoscale of the isoreticular metal-organic framework (MOF) series ZnBDP_X, based on the assembly of Zn(II) metal ions and the functionalized organic spacers 1,4-bis(1H-pyrazol-4-yl)-2-X-benzene (H2BDP_X; X = H, NO2, NH2, OH). The colloidal stability of these systems was evaluated under different relevant intravenous and oral-simulated physiological conditions, showing that ZnBDP_OH nanoparticles exhibit good structural and colloidal stability probably because of the formation of a protein corona on their surface that prevents their aggregation. Furthermore, two antitumor drugs (mitroxantrone and [Ru(p-cymene)Cl2(pta)] (RAPTA-C) where pta = 1,3,5-triaza-7-phospaadamantane) were encapsulated within the pores of the ZnBDP_X series in order to investigate the effect of the framework functionalization on the incorporation/delivery of bioactive molecules. Thus, the loading capacity of both drugs within the ZnBDP_X series seems to directly depend on the surface area of the solids. Moreover, ligand functionalization significantly affects both the delivery kinetics and the total amount of released drug. In particular, ZnBDP_OH and ZnBDP_NH2 matrixes show a slower rate of delivery and higher percentage of release than ZnBDP_NO2 and ZnBDP_H systems. Additionally, RAPTA-C delivery from ZnBDP_OH is accompanied by a concomitant and progressive matrix degradation due to the higher polarity of the BPD_OH ligand, highlighting the impact of functionalization of the MOF cavities over the kinetics of delivery.

QD-filled micelles which combine SPECT and optical imaging with light-induced activation of a platinum(IV) prodrug for anticancer applications.

The fac-[(99m)Tc(OH2)3(CO)3](+) complex reacts with QD-filled micelles to create a bimodal SPECT-optical imaging probe which upon visible light irradiation generates cisplatin from an inert Pt(IV) prodrug.

H-bonds superstructures built by aquacomplexes and an azapurine derivative: a case of molecular recognition.

The crystal structures of six compounds involving the divalent cations of Mn, Zn and Cd, the anionic form of the heterocycle 4,6-dimethyl-1,2,3-triazolo[4,5-d]pyrimidin-5,7-dione (Hdmax) and bipyridyl based spacer ligands are reported. The most important feature of these structures is the presence, in all cases, of a topologically identical 1-D polymeric superstructure (tape), involving tetra- or hexaaqua complex cations and triazolopyrimidine anions, built through hydrogen bonds. Adding these results to others previously published, we may consider these tapes as robust supramolecular synthons where a defined/clear case of molecular recognition between these two moieties takes place.

In vitro anti-leishmania evaluation of nickel complexes with a triazolopyrimidine derivative against Leishmania infantum and Leishmania braziliensis.

Studies on the anti-proliferative activity in vitro of seven ternary nickel (II) complexes with a triazolopyrimidine derivative and different aliphatic or aromatic amines as auxiliary ligands against promastigote and amastigote forms of Leishmania infantum and Leishmania braziliensis have been carried out. These compounds are not toxic for the host cells and two of them are effective at lower concentrations than the reference drug used in the present study (Glucantime). In general, the in vitro growth rate of Leishmania spp. was reduced, its capacity to infect cells was negatively affected and the multiplication of the amastigotes decreased. Ultrastructural analysis and metabolism excretion studies were executed in order to propose a possible mechanism for the action of the assayed compounds. Our results show that the potential mechanism is at the level of organelles membranes, either by direct action on the microtubules or by their disorganization, leading to vacuolization, degradation and ultimately cell death.

Iron oxide-filled micelles as ligands for fac-[M(CO)3]+ (M = (99m)Tc, Re).

Magnetite-filled micelles capture fac-[M(OH(2))(3)(CO)(3)](+) complexes (M = (99m)Tc, Re), creating versatile self-assembled constructs for multimodal SPECT/MR/optical imaging and radiopharmaceutical guided delivery.

A turn-on fluorescence sensor for cyanide from mechanochemical reactions between quantum dots and copper complexes.

Manual grinding of CuCl(2), 2,2'-bipyridine and hydrophobic CdSe QDs creates a selective and fast turn-on fluorescence sensor for detection of nanogram quantities of solid cyanide salts by the naked-eye. Using a fluorescence detector this simple sensor detects 100 ppm of NaCN in sand.

Synergy between quantum dots and 1,10-phenanthroline-copper(II) complex towards cleaving DNA.

We have found that the DNA cleaving activity of quantum dots and 1,10-phenanthroline-Cu(II) complex is significantly enhanced when they are combined.

In vitro and in vivo trypanocidal evaluation of nickel complexes with an azapurine derivative against Trypanosoma cruzi.

Seven ternary nickel(II) complexes (three previously described and four firstly described here) with an azapurine derivative (the anionic form of 4,6-dimethyl-1,2,3-triazolo[4,5-d]pyrimidin-5,7-dione) have been synthesized and spectroscopically characterized, and the crystal structures of three of them have been solved by X-ray diffraction. Studies in vitro and in vivo on the antiproliferative activity of these complexes against Trypanosoma cruzi (epimastigote, amastigote, and trypomastigote forms) have been carried out, displaying in some cases significantly higher antitrypanosomatid activity and lower toxicity than the reference drug for Chagas' disease, benznidazole (N-benzyl-2-(2-nitro-1H-imidazol-1-yl)acetamide). Ultrastructural analysis and metabolism excretion studies were also executed in order to propose a possible mechanism of action for the assayed drugs.

Versatile binding behaviour of 4,6-dimethyl-1,2,3-triazolo[4,5-d]-pyrimidin-5,7-dionato in the presence of bipyrimidine. Supramolecular H-bond architectures.

Complexes with the ligand 4,6-dimethyl-1,2,3-triazolo-[4,5-d]-pyrimidin-5,7-dionato (dmax(-)) and the auxiliary chelating-bridging ligand bipyrimidine (bpym) have been synthesized and structurally characterized for the divalent cations of Zn, Cd and Cu. For Zn and Cd, dinuclear complexes with the formulae [Zn(2)(dmax)(4)(H(2)O)(2)(bpym)].2H(2)O and [Cd(2)(dmax)(4)(H(2)O)(4)(bpym)].6H(2)O have been isolated whereas for Cu, the one-dimensional polymer {[Cu(2)(dmax)(4)(bpym)].5H(2)O}(n) has been obtained. Bpym acts as a chelating-bridging ligand in the three compounds, joining couples of metal ions. Two crystallographically and chemically different dmax(-) ligands are present in each of these complexes, one monodentately linked via the triazole N atom furthest from the pyrimidine ring (N2) and the other either monodentately linked via the triazole N atom closer to a carbonyl group (N1, Zn and Cd compounds) or in bridging N1-N2 mode (Cu compound), in the latter case generating an one-dimensional polymer with alternating bpym and (dmax)(2) bridges. The magnetic interaction across the bpym bridge gives rise to a strong antiferromagnetic interaction (2J = -201 cm(-1)), whereas that across the (dmax)(2) bridge is negligible and cannot be reliably determined (obscured by the strong one). The hydrogen bonds between water molecules and the triazolopyrimidine derivative build the 3-D structure of the compounds.

Effective photoreduction of a Pt(IV) complex with quantum dots: a feasible new light-induced method of releasing anticancer Pt(II) drugs.

Irradiation of CdSe-ZnS quantum dots (QDs) with visible light in the presence of [PtCl(4)(bpy)] (1) (bpy = 2,2'-bipyridine) produced with high efficiency [PtCl(2)(bpy)] (2) by photoinduced electron transfer; a reaction and strategy which opens up new opportunities for cancer therapy.