A half sandwich Ru(II)-p-cymene nitrite complex selectively induces cell death in cisplatin-resistant malignant melanoma cells.

The Ru(II)-nitrite complex, Ru4, is explored to release nitric oxide (NO) under acidic conditions and selectively induce a cytotoxic effect towards SK-MEL-28 cisplatin-resistant malignant melanoma cells. These findings suggest that targeting the tumor-associated pHe level could be an effective strategy for the drug function of Ru(II)-nitrite compounds.

Steric and electronic influence on Cu-Cu short contacts in ß-thioketiminato tricopper(I) clusters.

A series of ß-thioketiminate copper(I) complex trimers [LCuI]3 were synthesized by modifying the ligand framework with electron-withdrawing groups (F and Cl) or electron-donating groups (iPr and Me) at the N-aryl ring as well as with CF3 groups on the chelating backbone. This ligand modification significantly impacts the enhancement of Cu⋯Cu short contacts, which can be rationalized by using steric and electronic factors of the chelated ligand. We observed that this intramolecular cuprophilicity among [LCuI]3 complexes is primarily governed by the size of N-aryl ortho-substituents. These findings were well supported by X-ray crystallography, Raman spectroscopy, and Mayer bond order analysis. The electronic effects induced by the ligand modification on the LCuI fragment were investigated using CO and 2,4,6-CNC6H2Me3 as probe molecules. Corroborated by the FTIR and CV measurements, our results reveal that the ß-thioketiminate SN chelators induce more pronounced changes in the electronic character of the LCuI fragment due to the presence of CF3 groups on the chelating backbone in comparison with the F or Cl substituents on the N-aryl ring.

Mechanical shear flow regulates the malignancy of colorectal cancer cells.

Colorectal cancer (CRC) is notable for its high mortality and high metastatic characteristics. The shear force generated by bloodstream provides mechanical signals regulating multiple responses of cells, including metastatic cancer cells, dispersing in blood vessels. We, therefore, studied the effect of shear flow on circulating CRC cells in the present study. The CRC cell line SW620 was subjected to shear flow of 12.5 dynes/cm2 for 1 and 2 h separately. Resulting elevated caspase-9 and -3 indicated that shear flow initiated the apoptosis of SW620. Enlarged cell size associated with a higher level of cyclin D1 was coincident with the flow cytometric results indicating that the cell cycle was arrested at the G1 phase. An elevated phosphor-eNOSS1177 increased the production of nitric oxide and led to reactive oxygen species-mediated oxidative stress. Shear flow also regulated epithelial-mesenchymal transition (EMT) by increasing E-cadherin and ZO-1 while decreasing Snail and Twist1. The migration and invasion of sheared SW620 were also substantially decreased. Further investigations showed that mitochondrial membrane potential was significantly decreased, whereas mitochondrial mass and ATP production were not changed. In addition to the shear flow of 12.5 dynes/cm2, the expressions of EMT were compared at lower (6.25 dynes/cm2) and at higher (25 dynes/cm2) shear flow. The results showed that lower shear flow increased mesenchymal characteristics and higher shear flow increased epithelial characteristics. Shear flow reduces the malignancy of CRC in their metastatic dispersal that opens up new ways to improve cancer therapies by applying a mechanical shear flow device.

One-Step Synthesis of 3-(Fmoc-amino acid)-3,4-diaminobenzoic Acids.

A one-step method for synthesizing 3-(Fmoc-amino acid)-3,4-diaminobenzoic acids was used to prepare preloaded diaminobenzoate resin. The coupling of free diaminobenzoic acid and Fmoc-amino acids gave pure products in 40-94% yield without any purification step in addition to precipitation except for histidine. For the proline residue, crude products were collected and used for solid-phase peptide synthesis to give a moderate yield of a pentapeptide. In addition, this method was used to prepare unusual amino acid derivatives, namely, (2-naphthyl) alanine and 6-aminohexanoic acid derivatives, in 50 and 65% yield, respectively.

Ligand Degradation Study of Unsymmetrical ß-Diketiminato Copper Dioxygen Adducts: The Length Chelating Arm Effect.

An investigation on the reactivity of O2 binding to unsymmetrical ß-diketiminato copper(I) complexes by spectroscopic and titration analysis was performed. The length of chelating pyridyl arms (pyridylmethyl arm vs pyridylethyl arm) leads to the formation of mono- or di-nuclear copper-dioxygen species at -80 °C. The pyridylmethyl arm adduct (L1CuO2) forms mononuclear copper-oxygen species and shows ligand degradation, resulting in the formation of (2E,3Z)-N-(2,6-diisopropylphenyl)-4-(((E)-pyridin-2-ylmethylene)amino)pent-3-en-2-imine, which slowly converts to its cyclization isomer 1-(2,6-diisopropylphenyl)-4,6-dimethyl-2-(pyridin-2-yl)-1,2-dihydropyrimidine after addition of NH4OH at room temperature. On the other hand, the pyridylethyl arm adduct [(L2Cu)2(µ-O)2] forms dinuclear species at -80 °C and does not show any ligand degradation product. Instead, free ligand formation was observed after the addition of NH4OH. These experimental observations and product analysis results indicate that the chelating length of pyridyl arms governs the Cu/O2 binding ratio and the ligand degradation behavior.

Denticity governs the formation of ß-thioketiminato tri-copper(I) and mono-copper(I) complexes.

Two classes of ß-thioketiminate ligands, SN chelators (HL1 and HL2) and SNN chelators (HL3 and HL4), were prepared to understand their coordination behavior in copper(I) complex formation. The formation of these copper(I) complexes bearing ß-thioketiminate ligands and their corresponding adducts toward isocyanide, PPh3, and CO was investigated to address two important issues. First, whether the denticity governs the copper(I) thiolate species formation between SN chelators and SNN chelators. Second, how the length of the pendant pyridyl arm affects the coordination and reactivity behaviors of copper(I) complexes. Based on the characterization results, it was found that the denticity of SN chelators and SNN chelators led to different nuclearity of copper(I)-thiolate species. The coordination modes of the pendant pyridyl arm were confirmed by FTIR measurements, which allow us to conclude that the electron donating ability of the LCu fragment is in the order of SNN-chelator (SNN bound) > SNN-chelators (SN bound) > SN-chelator.

Glutamic acid-capped iron oxide quantum dots as fluorescent nanoprobe for tetracycline in urine.

The fabrication of iron oxide quantum dots (IO-QDs) modified with glutamic acid (Glu) under controllable conditions is reported. The IO-QDs have been characterized by transmission electron microscopy, spectrofluorometry, powder X-ray diffraction, vibrating sample magnetometry, UV-Vis spectroscopy, X-ray photoelectron spectroscopy, and Fourier-transform infrared spectroscopy. The IO-QDs exhibited good stability towards irradiation, temperature elevations, and ionic strength, and the quantum yield (QY) of IO-QDs was calculated to be 11.91 ± 0.09%. The IO-QDs were furtherly measured at an excitation wavelength of 330 nm with emission maxima at 402 nm, which were employed to detect tetracycline (TCy) antibiotics, including tetracycline (TCy), chlortetracycline (CTCy), demeclocycline (DmCy), and oxytetracycline (OTCy) in biological samples. The results indicated that TCy, CTCy, DmCy, and OTCy in urine samples show a dynamic working range between 0.01 and 80.0 µM; 0.01 and 1.0 µM; 0.01 and 10 µM; and 0.04 and 1.0 µM, respectively, with detection limits of 7.69 nM, 120.23 nM, 18.20 nM, and 67.74 nM, respectively. The detection was not interfered with by the auto-fluorescence from the matrices. In addition, the obtained recovery in real urine samples suggested that the developed method could be used in practical applications. Therefore, the current study has prospect to develop an easy, fast, eco-friendly, and efficient new sensing method for detecting tetracycline antibiotics in biological samples.

Antiangiogenic potential of Lepista nuda extract suppressing MAPK/p38 signaling-mediated developmental angiogenesis in zebrafish and HUVECs.

The medicinal properties of natural/edible plant products and their use are popular in traditional practice owing to their nutritional contents with little to no side effects. Lepista nuda (L. nuda), an edible mushroom (Clitocybe nuda, commonly known as blewit), has attracted researchers to evaluate its contents and the mechanism of its activities. In the current study, we focused on evaluating the antiangiogenic effects of L. nuda water extract on zebrafish development and in vitro human umbilical vein endothelial cell (HUVEC) tube formation. Bioactive components such as ergothioneine, eritadenine, and adenosine were identified and quantified by HPLC analysis. The L. nuda extract showed antiangiogenic properties and inhibited intersegmental vessel (ISV), caudal vein plexus (CVP), hyaloid vessel (HV), and subintestinal vessel (SIV) development in Tg (fli1: EGFP) zebrafish embryos. The expression of angiogenesis-related genes (vegfaa, kdrl, vegfba, flt1, kdr) was affected following L. nuda extract treatment. L. nuda extract attenuated in vitro HUVEC tube formation, migration, and invasion. Furthermore, inhibition of MAPK/p38 signaling and depletion of proangiogenic genes, including growth factors (fgf, ang2, and vegfa); primary and accessory receptors (tie2, vegfr2, and eng); MMPs (mmp1 and mmp2); and cytokines (il-1α, il-1ß, il-6, and tnf-α) was observed in HUVECs following L. nuda treatment. An in vivo zebrafish xenograft assay showed that L. nuda extract inhibited HuCCT1 cell-induced SIV sprouting in HuCCT1-injected embryos. Collectively, the results suggest that L. nuda could be a potential inhibitor of angiogenesis limiting cancer progression.

An investigation on catalytic nitrite reduction reaction by bioinspired CuII complexes.

Catalytic nitrite reductions by CuII complexes containing anionic Me2Tp, neutral Me2Tpm, or neutral iPrTIC ligands in the presence of L-ascorbic acid, which served as an electron donor and proton source, were investigated. The results showed that auxiliary ligands are important for copper-mediated catalytic nitrite reduction. Furthermore, the electronic effects of the ligand govern the nitrite reduction efficiency, which should be considered at two control points: one is the susceptibility of the LCuI-nitrite species to protonation and the other is the susceptibility of LCuII to reduction giving LCuI. In addition, an external strong acid leads to the production of nitrous acid, which may suggest that the reactivity of nitrous acid toward the LCuI species is a third control point.

Bidentate acylthiourea ligand anchored Pd-PPh3 complexes with biomolecular binding, cytotoxic, antioxidant and antihemolytic properties.

Acylthiourea-based Pd(II) complexes (1-5) with a PPh3 moiety bearing the general formula [PdCl(PPh3)(L-R)] [L-R = monoanionic bidentate acylthiourea ligand, where R = C6H5 (L1), C6H4CH3(o) (L2), C6H4OCH2CH3(p) (L3), C10H7 (L4) or C6H4Cl (L5)] have been synthesized and characterized by spectroscopic and analytical tools. The single crystal X-ray structures (1-3) revealed that the acylthiourea ligands coordinated to Pd(II) ion in an uncommon bidentate fashion through S and N atoms, forming a four-member ring. The Pd(II) ion exhibited a square planar geometry fulfilled by the ligand (N, S), one Cl- and one triphenylphosphine (PPh3). Calf thymus (CT) DNA and bovine serum albumin (BSA) binding of the complexes have been analyzed by spectroscopic and molecular docking studies. The complexes were tested for their in vitro cytotoxicity on three cancer (cervical, breast and lung) and one normal (human embryo) cell lines. Complex 4 bearing the naphthalene substitution exhibited the highest activity against three cancer cells with the half-maximal inhibitory concentration (IC50) values of 8.6 (cervical), 8.8 (breast) and 9.4 µM (lung). The acridine orange/ethidium bromide (AO/EB) and 4',6-diamidino-2-phenylindole (DAPI) staining assays indicated that 4 induced cancer cell death through apoptosis. Among the complexes, 4 exhibited the highest 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity of 86.19%. All the complexes were subjected to the hemolysis assay which revealed their biocompatibility with red blood cells (RBCs) with a lysis rate of less than 5 %.

Nitric oxide generation study of unsymmetrical ß-diketiminato copper(II) nitrite complexes.

ß-Diketiminato copper(II) L1CuCl-L4CuCl and their nitrite complexes L1Cu(O2N) and L2Cu(O2N) have been synthesized and characterized. X-ray analysis of the L1CuCl-L4CuCl complexes clearly reveals their mononuclear structure with a four-coordinated Cu(II) center bound by one chloride and three nitrogen atoms of unsymmetrical ß-diketiminato ligands. Cyclic voltametric analysis of the Cu(II) complexes shows that the length of the pyridyl arm controls the Cu(II)/Cu(I) redox process. DFT and EPR results confirm that the geometry of the Cu(II) complexes is also controlled by the length of the chelating pyridyl arm. The oxygen atom transfer nitrite reduction of the Cu(II) nitrite complexes leads to the formation of copper(I)-PPh3 and OPPh3 which were confirmed by 1H and 31P NMR. The length of the pyridyl arm of the copper(II) nitrite complexes governs the NO-releasing ability. These findings illustrate the important bioinspired behaviour and NO generation from nitrite via oxygen atom transfer of the unsymmetrical ß-diketiminato copper(II) complexes as compared to symmetrical ß-diketiminato copper(II) complexes.

Tris-(2-pyridyl)-pyrazolyl Borate Zinc(II) Complexes: Synthesis, DNA/Protein Binding and In Vitro Cytotoxicity Studies.

Zn(II) complexes bearing tris[3-(2-pyridyl)-pyrazolyl] borate (Tppy) ligand (1-3) was synthesized and examined by spectroscopic and analytical tools. Mononuclear [TppyZnCl] (1) has a Zn(II) centre with one arm (pyrazolyl-pyridyl) dangling outside the coordination sphere which is a novel finding in TppyZn(II) chemistry. In complex [TppyZn(H2O)][BF4] (2) hydrogen bonding interaction of aqua moiety stabilizes the dangling arm. In addition, solution state behaviour of complex 1 confirms the tridentate binding mode and reactivity studies show the exogenous axial substituents used to form the [TppyZnN3] (3). The complexes (1-3) were tested for their ability to bind with Calf thymus (CT) DNA and Bovine serum albumin (BSA) wherein they revealed to exhibit good binding constant values with both the biomolecules in the order of 104-105 M-1. The intercalative binding mode with CT DNA was confirmed from the UV-Visible absorption, viscosity, and ethidium bromide (EB) DNA displacement studies. Further, the complexes were tested for in vitro cytotoxic ability on four triple-negative breast cancer (TNBC) cell lines (MDA-MB-231, MDA-MB-468, HCC1937, and Hs 578T). All three complexes (1-3) exhibited good IC50 values (6.81 to 16.87 µM for 24 h as seen from the MTS assay) results which indicated that these complexes were found to be potential anticancer agents against the TNBC cells.

Binding mode transformation and biological activity on the Ru(II)-DMSO complexes bearing heterocyclic pyrazolyl ligands.

Three Ru(II)-DMSO complexes (1-3) containing 2-(3-pyrazolyl)pyridine (PzPy), 2-pyrazol-3-ylfuran (PzO), or 2-pyrazol-3-ylthiophene (PzS) ligand, were synthesized and characterized. The monodentate coordination of the heterocyclic pyrazolyl ligand (PzPy) with Ru(II) ion via N atom was confirmed by single crystal X-ray diffraction. Complex 1 could be converted to the known η2-bidentate PzPy complex cis(Cl), cis(S)-[RuCl2(PzPy)(DMSO)2] (4) under reflux conditions. The mechanism underlying binding mode transformation was studied by 1H NMR spectroscopy and density functional theory (DFT) calculations. The binding abilities of the complexes (1-4) with calf-thymus (CT) DNA and bovine serum albumin (BSA) were investigated using spectroscopic and molecular docking techniques. Among the four Ru(II) complexes, complexes 1 and 3 inhibited the long-term proliferation of human breast cancer cells, whereas complexes 2 and 4 did not inhibit their proliferation to a considerable extent. Interestingly, complexes 1 and 3 did not induce significant cell death but rather attenuated the clonogenicity of breast cancer cells by upregulating reactive oxygen species (ROS), endoplasmic reticulum (ER) and autophagic stress.

Half-sandwich Ru(η6-p-cymene) complexes featuring pyrazole appended ligands: Synthesis, DNA binding and in vitro cytotoxicity.

Organometallic Ru(II)-arene complexes have emerged as potential alternatives to platinum appended agents due to their wide range of interesting features such as stability in solution and solid, significant activity, less toxicity and hydrophobic property of arene moiety, etc. Hence, a series of Ru(II)-p-cymene complexes, [(η6-p-cymene)Ru(η2-N,N-L1)Cl]Cl (1), [(η6-p-cymene)Ru(η1-N-L2)Cl2] (2) and [(η6-p-cymene)Ru(η1-N-L3)Cl2] (3) were prepared from pyrazole based ligands [2-(1H-pyrazol-3-yl)pyridine (L1), 3-(furan-2-yl)-1H-pyrazole (L2) and 3-(thiophen-2-yl)-1H-pyrazole (L3)], and [RuCl2-(η6-p-cymene)] dimer. The new Ru(II)-p-cymene complexes were well characterized by elemental analysis, and spectroscopic (FT-IR, UV-Visible, 1H NMR, 13C NMR and mass) and crystallographic methods. The Ru(II)-p-cymene complexes (1-3) were found to adopt their characteristic piano stool geometry around Ru(II) ion. The calf thymus DNA (CT-DNA) binding ability of the new complexes was investigated by electronic absorption spectroscopic titration and viscosity methods. The molecular docking study results showed that complex 1 strongly bound with targeted biomolecules than 2 and 3. Docked poses of bidentate pyrazole based Ru(II)-p-cymene complex 1 revealed that the complex formed a crucial guanine N7 position hydrogen bond with DNA receptor. Complexes 1-3 might hydrolyze under physiological conditions and form aqua complexes 4-8, and docking calculations showed that the aqua complexes bound strongly with the receptors than original complexes. The in vitro cytotoxicity of the Ru(II)-p-cymene complexes and cisplatin was evaluated against triple negative breast cancer (TNBC) MDA-MB-231 cells. Our results showed that the inhibitory effect of bidentate pyrazole based Ru(II)-p-cymene complex 1 on the growth of breast cancer cells was superior to other tested complexes.

Importance of Binding Affinity for the Activity of a Metallodendritic Chemical Nuclease.

A family of bis(2-pyridyl)amino-modified poly(amidoamine) dendrimer Cu complexes was prepared, and their chemical nuclease activities and binding affinity (Kb) levels for DNA plasmid were investigated. The Kb values of the G2 to G6 apodendrimers for DNA plasmid were found to be 7.4, 23, 48, 70, and 280 µM-1, respectively, using ethidium bromide (EtBr) displacement experiments. The chemical nuclease activities of the corresponding complexes were determined by gel electrophoresis, and a clear positive dendritic effect was observed. Further analysis indicated a linear correlation between the Kb values of the G2 to G5 apodendrimers and the nuclease activity of the corresponding complexes. This observation indicated the importance of substrate binding affinity for macromolecular nuclease activity. In addition, an experiment using 3'-(p-hydroxyphenyl) fluorescein suggested that hydroxyl radicals formed under the tested conditions. Subsequently performed inhibition studies indicated that the hydroxyl radical was the active species responsible for the plasmid cleavage.

Nitric oxide-release study of a bio-inspired copper(i)-nitrito complex under chemical and biological conditions.

The selective and efficient nitrite reduction process is ubiquitous in biological systems. To understand copper-mediated nitrite reduction, we developed a bio-inspired model system to investigate the mechanism of copper-containing nitrite reductase. A well-characterized copper(i)-nitrate complex with amino functionalized 2-(diphenylphosphino)aniline ligands, [(Ph2PC6H4(o-NH2))2Cu(ONO)], demonstrated the aniline protonation will cause NO release in an acidic environment. To further understand NO releasing ability, we also performed pH-dependency experiments and confocal imaging to release NO under physiological buffer conditions. According to titration and spectroscopic studies on the protonation reaction of complex [(Ph2PC6H4(o-NH2))2Cu(ONO)], we proposed a mechanistic pathway for proton transfer and NO release. Furthermore, DFT calculations predicted that the release of NO takes place via aniline in both organic and aqueous media. These results highlight the importance of the proton-rich microenvironment around the copper(i)-nitrite core to induce nitrate reduction in a chemical and biological environment.

Structure and nitrite reduction reactivity study of bio-inspired copper(i)-nitro complexes in steric and electronic considerations of tridentate nitrogen ligands.

Two copper(i)-nitro complexes [Tpm3-tBuCu(NO2)] (1) and [(Ph3P)2N][Tp3-tBuCu(NO2)] (2), containing steric bulky neutral tris(3-tert-butylpyrazolyl)methane and anionic hydrotris(3-tert-butylpyrazolyl)borate ligands, have been synthesized and characterized. Complex 2 adopts a unique κ2-binding mode of Tp3-tBu around the copper(i)-nitro environment in the solid state and shows a four-coordinated tetrahedral geometry surrounded by a nitro and three pz3-tBu groups in solution. Both complexes 1 and 2 allow for the stoichiometric reduction of NO2- to NO with H+ addition. The results of this effort show that increasing steric bulk and electron donation properties on the nitrogen ancillary ligand will improve the nitrite reduction ability of the copper(i)-nitro model complexes.

Enhanced Catalytic Activity of Aluminum Complexes for the Ring-Opening Polymerization of ε-Caprolactone.

A series of dinuclear aluminum (Al2Pyr2) complexes bridged by two pyrazole ligands were synthesized, and their catalytic activity toward ring-opening polymerization of ε-caprolactone (CL) was investigated. Different types of the Al-N-N-Al-N-N skeletal ring were found among these Al2Pyr2 complexes. The butterfly form, LThio2Al2Me4, exerted the highest catalytic activity for CL polymerization. κ2-CL coordination with both Al centers within the butterfly form LThio2Al2Me4 facilitates the initiation process. Generally speaking, the Al2Pyr2 complexes exhibited substantially higher catalytic activity for CL polymerization than literature examples such as ß-diketiminate- or traiaza-bearing aluminum complexes. In fact, the Al2Pyr2 complexes can even carry out CL polymerization at room temperature.

Reactivity Study of Unsymmetrical ß-Diketiminato Copper(I) Complexes: Effect of the Chelating Ring.

ß-Diketiminato copper(I) complexes play important roles in bioinspired catalytic chemistry and in applications to the materials industry. However, it has been observed that these complexes are very susceptible to disproportionation. Coordinating solvents or Lewis bases are typically used to prevent disproportionation and to block the coordination sites of the copper(I) center from further decomposition. Here, we incorporate this coordination protection directly into the molecule in order to increase the stability and reactivity of these complexes and to discover new copper(I) binding motifs. Here we describe the synthesis, structural characterization, and reactivity of a series of unsymmetrical N-aryl-N'-alkylpyridyl ß-diketiminato copper(I) complexes and discuss the structures and reactivity of these complexes with respect to the length of the pyridyl arm. All of the aforementioned unsymmetrical ß-diketiminato copper(I) complexes bind CO reversibly and are stable to disproportionation. The binding ability of CO and the rate of pyridyl ligand decoordination of these copper(I) complexes are directly related to the competition between the degree of puckering of the chelate system and the steric demands of the N-aryl substituent.

Interaction of electrons with cisplatin and the subsequent effect on DNA damage: a density functional theory study.

Cisplatin, Pt(NH3)2Cl2, is a leading chemotherapeutic agent that has been widely used for various cancers. Recent experiments show that combining cisplatin and electron sources can dramatically enhance DNA damage and the cell-killing rate and, therefore, is a promising way to overcome the side effects and the resistance of cisplatin. However, the molecular mechanisms underlying this phenomenon are not clear yet. By using density functional theory calculations, we confirm that cisplatin can efficiently capture the prehydrated electrons and then undergo dissociation. The first electron attachment triggers a spontaneous departure of the chloride ion, forming a T-shaped [Pt(NH3)2Cl]˙ neutral radical, whereas the second electron attachment leads to a spontaneous departure of ammine, forming a linear [Pt(NH3)Cl](-) anion. We further recognize that the one-electron reduced product [Pt(NH3)2Cl]˙ is extremely harmful to DNA. It can abstract hydrogen atoms from the C-H bonds of the ribose moiety and the methyl group of thymine, which in turn leads to DNA strand breaks and cross-link lesions. The activation energies of these hydrogen abstraction reactions are relatively small compared to the hydrolysis of cisplatin, a prerequisite step in the normal mechanism of action of cisplatin. These results rationalize the improved cytotoxicity of cisplatin by supplying electrons. Although the biological effects of the two-electron reduced product [Pt(NH3)Cl](-) are not clear at this stage, our calculations indicate that it might be protonated by the surrounding water.