Palladium Complexes of N-Methylcorroles.

Alkylation of one of the inner-core nitrogen atoms is one possible approach to obtain dianionic corrole ligands, suitable for the coordination of divalent metal ions, such as PdII . Inner-core N-methylation can be obtained by treating the corrole with CH3 I, but the reaction conditions should be optimized to limit the formation of the dimethylated derivative. Two regioisomers, the N-21 and the N-22 methyl derivatives are obtained from the reaction, with the first product achieved in a higher amount. Structural characterization of the reaction products evidenced the distortion induced by the introduction of the methyl groups; the N-methylcorroles are chiral compounds, and the enantiomers were separated by chromatography, with their absolute configuration assigned by ECD computation. Palladium insertion was achieved in the case of monosubstituted corroles, but not with the dimethylated macrocycle; X-ray characterization of the complexes showed the distortion of the macrocycles. The Pd complexes do not show luminescence emission, but are able to produce singlet oxygen upon irradiation. The PdII complexes were also inserted in human serum albumin (HSA) and dispersed in water; in this case, the protein protects the corroles from photobleaching, and a switch from the type II to the type I mechanism in reactive oxygen species (ROS) production is observed.

Synthesis, substitution kinetics, DNA/BSA binding and cytotoxicity of tridentate N

The pincer complexes, [Pd(L1)Cl]BF4 (PdL1), [Pd(L2)Cl]BF4 (PdL2), [Pd(L3)Cl]BF4 (PdL3), [Pd(L4)Cl]BF4 (PdL4) were prepared by reacting the corresponding ligands, 2,6-bis[(1H-pyrazol-1-yl)methyl]pyridine (L1), bis[2-(1H-pyrazol-1-yl)ethyl]amine (L2), bis[2-(1H-pyrazol-1-yl)ethyl]ether (L3), and bis[2-(1H-prazol-1-yl)ethyl]sulphide (L4) with [PdCl2(NCMe)]2 in the presence NaBF4. The solid-state structures of complexes PdL1-PdL4 confirmed a tridentate coordination mode, with one chloro ligand completing the coordination sphere to afford square-planar complexes. Chemical behaviour of the complexes in solution confirms their stability in both aqueous and DMSO stock media. The electrochemical properties of the compounds showed irreversible two-electron reduction process. Kinetic reactivity of Pd complexes with the biological nucleophiles viz, thiourea (Tu), L-methionine (L-Met) and guanosine 5'-diphosphate disodium salt (5'-GMP) followed the order: PdL2 < PdL3 < PdL4, and PdL2 < PdL1. The kinetic reactivity is subject to the electronic effects of the spectator ligand(s), and the trend was supported by the DFT computed results. The palladium complexes PdL1-PdL4 bind to calf thymus (CT-DNA) via intercalation mode. In addition, the bovine serum albumin (BSA) showed good binding affinity to the complexes. The mode of quenching mechanism of the intrinsic fluorescence of CT-DNA and BSA by the complexes was found to be static. The order of interactions of the complexes with DNA and BSA was in tandem with the rate of substitution kinetics. The complexes, however, displayed relatively low cytotoxicity (IC50 > 100 µM) when tested against the human cervical adenocarcinoma (HeLa) cell line and the transformed human lung fibroblast cell line (MRC-5 SV2).

MOF-Stabilized Perfluorinated Palladium Cages Catalyze the Additive-Free Aerobic Oxidation of Aliphatic Alcohols to Acids.

Extremely high electrophilic metal complexes, composed by a metal cation and very electron poor σ-donor ancillary ligands, are expected to be privileged catalysts for oxidation reactions in organic chemistry. However, their low lifetime prevents any use in catalysis. Here we show the synthesis of fluorinated pyridine-Pd2+ coordinate cages within the channels of an anionic tridimensional metal-organic framework (MOF), and their use as efficient metal catalysts for the aerobic oxidation of aliphatic alcohols to carboxylic acids without any additive. Mechanistic studies strongly support that the MOF-stabilized coordination cage with perfluorinated ligands unleashes the full electrophilic potential of Pd2+ to dehydrogenate primary alcohols, without any base, and also to activate O2 for the radical oxidation to the aldehyde intermediate. This study opens the door to design catalytic perfluorinated complexes for challenging organic transformations, where an extremely high electrophilic metal site is required.

Water-Soluble Pd-Imidate Complexes as Versatile Catalysts for the Modification of Unprotected Halonucleosides.

Modification of unprotected nucleosides has been attracting continuous interest, since these building blocks themselves and their phosphate-upgraded corresponding nucleotides have shown a plethora of uses in fields like biochemistry or pharmacy. Pd-catalyzed cross-coupling reactions, conducted in water or its mixtures with polar organic solvents, have frequently been the researchers' choice for the functionalization of the purine/pyrimidine base of the unprotected nucleosides. In this scenario, the availability of hydrophilic ligands and its water-soluble palladium complexes has markedly set the pace of the advances. The approach of our group to the synthesis of such complexes, Pd-imidates specifically, has faced critical stages, namely the jump to synthesize water soluble complexes from our experience working in conventional solvents, the preparation of phosphine free complexes and the overall goal of getting catalytic systems able to work close to room temperature. The continuous feedback with Kapdi's group, experienced in the chemistry of nucleosides, has produced over the last decade the interesting results in both fields presented here.

DFT Calculations of 31P NMR Chemical Shifts in Palladium Complexes.

In this study, comparative analysis of calculated (GIAO method, DFT level) and experimental 31P NMR shifts for a wide range of model palladium complexes showed that, on the whole, the theory reproduces the experimental data well. The exceptions are the complexes with the P=O phosphorus, for which there is a systematic underestimation of shielding, the value of which depends on the flexibility of the basis sets, especially at the geometry optimization stage. The use of triple-ζ quality basis sets and additional polarization functions at this stage reduces the underestimation of shielding for such phosphorus atoms. To summarize, in practice, for the rapid assessment of 31P NMR shifts, with the exception of the P=O type, a simple PBE0/{6-311G(2d,2p); Pd(SDD)}//PBE0/{6-31+G(d); Pd(SDD)} approximation is quite acceptable (RMSE = 8.9 ppm). Optimal, from the point of view of "price-quality" ratio, is the PBE0/{6-311G(2d,2p); Pd(SDD)}//PBE0/{6-311+G(2d); Pd(SDD)} (RMSE = 8.0 ppm) and the PBE0/{def2-TZVP; Pd(SDD)}//PBE0/{6-311+G(2d); Pd(SDD)} (RMSE = 6.9 ppm) approaches. In all cases, a linear scaling procedure is necessary to minimize systematic errors.

Platinum and Palladium Complexes as Promising Sources for Antitumor Treatments.

There is a need for new, safer, and more effective agents to treat cancer. Cytostatics that have transition metals at their core have attracted renewed interest from scientists. Researchers are attempting to use chemotherapeutics, such as cisplatin, in combination therapy (i.e., in order to enhance their effectiveness). Moreover, studies are being carried out to modify molecules, by developing them into multinuclear structures, linking different compounds to commonly used drugs, or encapsulating them in nanoparticles to improve pharmacokinetic parameters, and increase the selectivity of these drugs. Therefore, we attempted to organize recent drug findings that contain palladium and platinum atoms in their structures.

Synthesis, Characterization, and Catalytic Application of Palladium Complexes Containing Indolyl-NNN-Type Ligands.

In this study, a series of N-heterocyclic indolyl ligand precursors 2-Py-Py-IndH, 2-Py-Pz-IndH, 2-Py-7-Py-IndH, 2-Py-7-Pz-IndH, and 2-Ox-7-Py-IndH (L1H-L5H) were prepared. The treatment of ligand precursors with 1 equivalent of palladium acetate affords palladium complexes 1-5. All ligand precursors and palladium complexes were characterized by NMR spectroscopy and elemental analysis. The molecular structures of complexes 3 and 5 were determined by single crystal X-ray diffraction techniques. The application of those palladium complexes 1-5 to the Suzuki reaction with aryl halide substrates was examined.

Novel thiazolinyl-picolinamide based palladium(II) complex-impregnated urinary catheters quench the virulence and disintegrate the biofilms of uropathogens.

Pseudomonas aeruginosa and Serratia marcescens are prominent members belonging to the group of ESKAPE pathogens responsible for Urinary Tract Infections (UTI) and nosocomial infections. Both the pathogens regulate several virulence factors, including biofilm formation through quorum sensing (QS), an intercellular communication mechanism. The present study describes the anti-biofilm and QS quenching effect of thiazolinyl-picolinamide based palladium(II) complexes against P. aeruginosa and S. marcescens. Palladium(II) complexes showed quorum sensing inhibitory potential in inhibiting swarming motility behaviour, pyocyanin production and other QS mediated virulence factors in both P. aeruginosa and S. marcescens. In addition, the establishment of biofilms was prevented on palladium (II) coated catheters. Overall, the present study demonstrates that thiazolinyl-picolinamide based palladium (II) complexes will be a promising strategy to combat device-mediated UTI infections.

Mononuclear Perfluoroalkyl-Heterocyclic Complexes of Pd(II): Synthesis, Structural Characterization and Antimicrobial Activity.

Two mononuclear Pd(II) complexes [PdCl2(pfptp)] (1) and [PdCl2(pfhtp)] (2), with ligands 2-(3-perfluoropropyl-1-methyl-1,2,4-triazole-5yl)-pyridine (pfptp) and 2-(3-perfluoroheptyl-1-methyl-1,2,4-triazole-5yl)-pyridine (pfhtp), were synthesized and structurally characterized. The two complexes showed a bidentate coordination of the ligand occurring through N atom of pyridine ring and N4 atom of 1,2,4-triazole. Both complexes showed antimicrobial activity when tested against both Gram-negative and Gram-positive bacterial strains.

Dynamic Complex-to-Complex Transformations of Heterobimetallic Systems Influence the Cage Structure or Spin State of Iron(II) Ions.

Two new heterobimetallic cages, a trigonal-bipyramidal and a cubic one, were assembled from the same mononuclear metalloligand by adopting the molecular library approach, using iron(II) and palladium(II) building blocks. The ligand system was designed to readily assemble through subcomponent self-assembly. It allowed the introduction of steric strain at the iron(II) centres, which stabilizes its paramagnetic high-spin state. This steric strain was utilized to drive dynamic complex-to-complex transformations with both the metalloligand and heterobimetallic cages. Addition of sterically less crowded subcomponents as a chemical stimulus transformed all complexes to their previously reported low-spin analogues. The metalloligand and bipyramid incorporated the new building block more readily than the cubic cage, probably because the geometric structure of the sterically crowded metalloligand favours the cube formation. Furthermore it was possible to provoke structural transformations upon addition of more favourable chelating ligands, converting the cubic structures into bipyramidal ones.

New platinum(II) and palladium(II) complexes with substituted terpyridine ligands: synthesis and characterization, cytotoxicity and reactivity towards biomolecules.

A series of palladium(II) (1-3) and platinum(II) chloride complexes (4 and 5) with 2,2':6',2″-terpyridine (terpy) derivatives substituted at the 4' position, was synthesized and fully characterized. Single crystal X-ray diffraction analysis of complexes 2, 3 and 5 showed tridentate coordination of the 4'-substituted terpyridine (terpy) ligands to the metal center. Moreover, in vitro cytotoxic activity of these complexes toward a panel of human cancer cell lines (lung cancer A549, colorectal cancer HCT116, ovarian cancer IGROV-1) and toward normal cell line HDF (dermal fibroblast) was determined by Trypan Blue exclusion assay. Overall, the tested compounds manifested a relevant cytotoxicity for the selected cancer cell lines with complex 4 also showing a modest cytotoxicity on the normal cell lines. To better understand the mode of action of these metal complexes, their reactivity with three model proteins, i.e. hen egg white lysozyme (HEWL), cytochrome c (cyt c) and ribonuclease A (RNase A) were comparatively investigated through ESI-MS analysis. The results highlighted a different behavior between the two series of complexes being platinum compounds more reactive toward RNase and cyt c than palladium compounds. Based on the obtained results, it is proposed that in presence of RNase A and cyt c, the platinum complexes undergo activation through release of labile ligands followed by binding to the protein. In contrast, palladium complexes revealed a far lower reactivity implying the likely occurrence of a different mechanism of action.

Exploiting NH···Cl Hydrogen Bonding Interactions in Cooperative Metallosupramolecular Polymerization.

The self-assembly features of hydrophobic bispyridyldichlorido Pd(II) complexes, equipped with an extended aromatic surface derived from oligophenyleneethynylene (OPE) and polarizable amide functional groups, are reported. The cooperative supramolecular polymerization of these complexes results in bundles of thin fibers in which the monomer units are arranged in a translationally displaced or slipped fashion. Spectroscopic and microscopy studies reveal that these assemblies are held together by simultaneous π-stacking of the OPE moieties and NH···ClPd hydrogen bonds. These unconventional forces are often observed in crystal engineering but remain largely unexploited in supramolecular polymers. Both steric and electronic effects (the presence of bulky and polarizable metal-bound Cl ligands as well as hydrogen bonding donor NH units) prevent the establishment of short Pd-Pd contacts and strongly condition the aggregation mode of the reported complexes, in close analogy to the previously reported amphiphilic Pd(II) complex 4. The results presented herein shed light on the subtle interplay between different noncovalent interactions and their impact on the self-assembly of metallosupramolecular systems.

Advances in Magnetic Nanoparticles-Supported Palladium Complexes for Coupling Reactions.

Carbon‒carbon (C‒C) and carbon‒heteroatom (C‒X) bonds that form via transition-metal-catalyzed processes have been extensively used in the organic synthesis and preparation of natural products and important compounds such as heterocycles, biologically active molecules, and dendrimers. Among the most significant catalysts, magnetic nanoparticles-supported palladium complexes are very effective, versatile, and heterogeneous catalysts for a wide range of C‒C and C‒X coupling reactions due to their reusability, thermal stability, and excellent catalytic performance. In this review, recent advances to develop magnetic nanoparticles supported palladium complexes, including their preparation, characterization, catalytic application, and reusability in the formation of both C‒C and C‒X bonds, by authors such as Sonogashira, Heck, Suzuki‒Miyaura, and Stille, and a few examples concerning N-arylation, S-arylation, and Csp2-P coupling reactions are discussed.

Structural, Luminescent and Thermal Properties of Heteronuclear PdII⁻LnIII⁻PdII Complexes of Hexadentate N2O4 Schiff Base Ligand.

New PdII⁻LnIII⁻PdII complexes of hexadentate N2O4 Schiff base ligand (H4L: N,N'-bis(2,3-dihydroxybenzylidene)-1,3-diamino-2,2-dimethylpropane) with Eu (1), Tb (2), Er (3) and Yb (4) ([Pd2Eu(H2L)2NO3](NO3)2∙2H2O∙2CH3OH 1, [Pd2Ln(H2L)2H2O](NO3)3∙3H2O, where Ln = Tb 2, Er 3, [Pd2Yb(H2L)2H2O](NO3)3∙5.5H2O 4) were synthesized and characterized structurally and physicochemically by thermogravimetry (TG), differential thermogravimetry (DTG), differential scanning calorimetry (DSC) and luminescence measurements. The compounds 1⁻4 are built of cationic heterometallic PdII⁻LnIII⁻PdII trinuclear units. The palladium(II) centers adopt a planar square geometry occupying the smaller N2O2 cavity of the Schiff base ligand. The lanthanide(III) is surrounded by two Schiff base ligands (eight oxygen atoms) and its coordination sphere is supplemented by a chelating bidentate nitrate ion in 1 or by a water molecule in 2⁻4. The complexes have a bent conformation along the PdII⁻LnIII⁻PdII line with valence angles in the ranges of 162⁻171°. The decomposition process of the complexes results in mixtures of: PdO, Pd and respective lanthanide oxides Eu2O3, Tb2O3, Tb4O7, Er2O3, Yb2O3. The luminescent measurements show low efficiency intramolecular energy transfer only in the complex of terbium(III) (2).

A Rotaxane-like Cage-in-Ring Structural Motif for a Metallosupramolecular Pd6 L12 Aggregate.

A BODIPY-based bis(3-pyridyl) ligand undergoes self-assembly upon coordination to tetravalent palladium(II) cations to form a Pd6 L12 metallosupramolecular assembly with an unprecedented structural motif that resembles a rotaxane-like cage-in-ring arrangement. In this assembly the ligand adopts two different conformations-a C-shaped one to form a Pd2 L4 cage which is located in the center of a Pd4 L8 ring consisting of ligands in a W-shaped conformation. This assembly is not mechanically interlocked in the sense of catenation but it is stabilized only by attractive π-stacking between the peripheral BODIPY chromophores and the ligands' skeleton as well as attractive van der Waals interactions between the long alkoxy chains. As a result, the co-arrangement of the two components leads to a very efficient space filling. The overall structure can be described as a rotaxane-like assembly with a metallosupramolecular cage forming the axle in a metallosupramolecular ring. This unique structural motif could be characterized via ESI mass spectrometry, NMR spectroscopy, and X-ray crystallography.

Poly-MVA attenuates 7,12- dimethylbenz[a]anthracene initiated and croton oil promoted skin papilloma formation on mice skin.

OBJECTIVE: Chemopreventive agents which exhibit activities such as anti-inflammation, inhibition of carcinogen induced mutagenesis and scavenging of free radical might play a decisive role in the inhibition of chemical carcinogenesis either at the initiation or promotion stage. Many synthesized palladium (Pd) complexes tested experimentally for antitumor activity are found effective. Poly-MVA is a liquid blend preparation containing B complex vitamins, ruthenium with Pd complexed with alpha lipoic acid as the major ingredients. The antitumor effect of Poly-MVA was evaluated against 7,12-dimethylbenz[a] anthracene-initiated croton oil-promoted papilloma formation on mice skin. Skin tumor was initiated with a single application of 390 nmol of DMBA in 20 µl acetone. The effect of Poly-MVA against croton oil- induced inflammation and lipid peroxidation on the mice skin was also evaluated. Topical application of Poly-MVA (100 µl, twice weekly for 18 weeks) 30 minutes prior to each croton oil application, significantly decreased the tumor incidence (11%) and the average number of tumor per animals. Application of Poly-MVA (100 µl) before croton oil significantly (p &#60; 0.05) protected the mouse skin from inflammation (36%) and lipid peroxidation (14%) when compared to the croton oil alone treated group. Experimental results indicate that Poly-MVA attenuate the tumor promoting effects of croton oil and the effect may probably be due to its anti-inflammatory and antioxidant activity.

Novel Palladium(II) Complexes that Influence Prominin-1/CD133 Expression and Stem Cell Factor Release in Tumor Cells.

New Pd(II) complexes of 1,7-bis(2-methoxyphenyl)hepta-1,6-diene-3,5-dione were synthesized and structurally characterized. The complexes were tested in vitro on human colon and hepatic carcinoma cell lines, normal hepatic cells and hematopoietic progenitor cells. Biological tests proved that Pd(II) complexes 1 and 2 (containing a curcumin derivative) exhibit a strong in vitro antitumor effect against the cells derived from human colorectal carcinoma and the hepatic metastasis of a colorectal carcinoma. Complex 1 has an outstanding inhibitory effect against BRAF-mutant colon carcinoma and hepatocarcinoma cell growth; 1 and 2 are both more active than the free ligand and have the capacity to trigger early apoptotic processes. By flow cytometric measurements, an important decrease of prominin-1 (CD133) molecule expression on tumor cells membrane was identified in cell populations subjected to 1 and 2. Quantitative immune enzymatic assay proved restrictions in stem cell factor (SCF) release by treated tumor cells. Although less cytotoxic, the free ligand inhibits the surface marker CD133 expression in hepatocarcinoma cells, and in HT-29 colon carcinoma. The new synthesized Pd(II) complexes 1 and 2 exhibit an important potential through their selective cytotoxic activity and by targeting the stem-like tumor cell populations, which leads to the tumor growth arrest and prevention of metastasis.

Rational Design of a Robust Fluorescent Probe for the Detection of Endogenous Carbon Monoxide in Living Zebrafish Embryos and Mouse Tissue.

Carbon monoxide (CO) is one of the most important gaseous signal molecules in biological systems. However, the investigation of the functions of CO in living organisms is restricted by the lack of functional molecular tools. To address this critical challenge, we present herein the rational design, synthesis, and in vivo imaging studies of a powerful two-photon excited near-infrared fluorescent probe (1-Ac) for endogenous CO monitoring. The advantageous features of the new probe include high stability, low background fluorescence, large fluorescence enhancement, high sensitivity, and two-photon excitation with emission in the near-infrared region. Significantly, these merits of the probe enable the tracking of endogenous CO in zebrafish embryos and mouse tissues for the first time.

Activity of phosphino palladium(II) and platinum(II) complexes against HIV-1 and Mycobacterium tuberculosis.

Treatment of human immunodeficiency virus (HIV) is currently complicated by increased prevalence of co-infection with Mycobacterium tuberculosis. The development of drug candidates that offer the simultaneous management of HIV and tuberculosis (TB) would be of great benefit in the holistic treatment of HIV/AIDS, especially in sub-Saharan Africa which has the highest global prevalence of HIV-TB coinfection. Bis(diphenylphosphino)-2-pyridylpalladium(II) chloride (1), bis(diphenylphosphino)-2-pyridylplatinum(II) chloride (2), bis(diphenylphosphino)-2-ethylpyridylpalladium(II) chloride (3) and bis(diphenylphosphino)-2-ethylpyridylplatinum(II) (4) were investigated for the inhibition of HIV-1 through interactions with the viral protease. The complexes were subsequently assessed for biological potency against Mycobacterium tuberculosis H37Rv by determining the minimal inhibitory concentration (MIC) using broth microdilution. Complex (3) showed the most significant and competitive inhibition of HIV-1 protease (p = 0.014 at 100 µM). Further studies on its in vitro effects on whole virus showed reduced viral infectivity by over 80 % at 63 µM (p < 0.05). In addition, the complex inhibited the growth of Mycobacterium tuberculosis at an MIC of 5 µM and was non-toxic to host cells at all active concentrations (assessed by tetrazolium dye and real time cell electronic sensing). In vitro evidence is provided here for the possibility of utilizing a single metal-based compound for the treatment of HIV/AIDS and TB.

Sugar-Annulated Oxazoline Ligands: A Novel Pd(II) Complex and Its Application in Allylic Substitution.

Two novel carbohydrate-derived pyridyl (PYOX)- and cyclopropyl (CYBOX)-substituted oxazoline ligands were prepared from d-glucosamine hydrochloride and 1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-ß-d-glucopyranose hydrochloride in two steps, respectively. The sugar-annulated PYOX ligand formed a stable metal complex with Pd(II), which was fully characterized by NMR spectroscopy and X-ray crystallography. NMR and X-ray analysis revealed a change of the conformation in the sugar moiety upon complexation with the palladium(II) species. Both glycosylated ligands resulted in high asymmetric induction (up to 98% ee) upon application as chiral ligands in the Pd-catalyzed allylic alkylation of rac-1,3-diphenylallyl acetate with dimethyl malonate (Tsuji-Trost reaction). Both ligands provided mainly the (R)-enantiomer of the alkylation product.