Modulation of human platelet activation and in vivo vascular thrombosis by columbianadin: regulation by integrin αIIbß3 inside-out but not outside-in signals.

BACKGROUND: Columbianadin (CBN) is one of the main coumarin constituents isolated from Angelica pubescens. The pharmacological value of CBN is well demonstrated, especially in the prevention of several cancers and analgesic activity. A striking therapeutic target for arterial thrombosis is inhibition of platelet activation because platelet activation significantly contributes to these diseases. The current study examined the influence of CBN on human platelet activation in vitro and vascular thrombotic formation in vivo. METHODS: Aggregometry, immunoblotting, immunoprecipitation, confocal microscopic analysis, fibrin clot retraction, and thrombogenic animals were used in this study. RESULTS: CBN markedly inhibited platelet aggregation in washed human platelets stimulated only by collagen, but was not effective in platelets stimulated by other agonists such as thrombin, arachidonic acid, and U46619. CBN evidently inhibited ATP release, intracellular ([Ca2+]i) mobilization, and P-selectin expression. It also inhibited the phosphorylation of phospholipase C (PLC)γ2, protein kinase C (PKC), Akt (protein kinase B), and mitogen-activated protein kinases (MAPKs; extracellular signal-regulated kinase [ERK] 1/2 and c-Jun N-terminal kinase [JNK] 1/2, but not p38 MAPK) in collagen-activated platelets. Neither SQ22536, an adenylate cyclase inhibitor, nor ODQ, a guanylate cyclase inhibitor, reversed the CBN-mediated inhibition of platelet aggregation. CBN had no significant effect in triggering vasodilator-stimulated phosphoprotein phosphorylation. Moreover, it markedly hindered integrin αIIbß3 activation by interfering with the binding of PAC-1; nevertheless, it had no influences on integrin αIIbß3-mediated outside-in signaling such as adhesion number and spreading area of platelets on immobilized fibrinogen as well as thrombin-stimulated fibrin clot retraction. Additionally, CBN did not attenuate FITC-triflavin binding or phosphorylation of proteins, such as integrin ß3, Src, and focal adhesion kinase, in platelets spreading on immobilized fibrinogen. In experimental mice, CBN increased the occlusion time of thrombotic platelet plug formation. CONCLUSION: This study demonstrated that CBN exhibits an exceptional activity against platelet activation through inhibition of the PLCγ2-PKC cascade, subsequently suppressing the activation of Akt and ERKs/JNKs and influencing platelet aggregation. Consequently, this work provides solid evidence and considers that CBN has the potential to serve as a therapeutic agent for the treatment of thromboembolic disorders.

Benzene Hydroxylation by Bioinspired Copper(II) Complexes: Coordination Geometry versus Reactivity.

A series of bioinspired copper(II) complexes of N4-tripodal and sterically crowded diazepane-based ligands have been investigated as catalysts for functionalization of the aromatic C-H bond. The tripodal-ligand-based complexes exhibited distorted trigonal-bipyramidal (TBP) geometry (τ, 0.70) around the copper(II) center; however, diazepane-ligand-based complexes adopted square-pyramidal (SP) geometry (τ, 0.037). The Cu-NPy bonds (2.003-2.096 Å) are almost identical and shorter than Cu-Namine bonds (2.01-2.148 Å). Also, their Cu-O (Cu-Owater, 1.988 Å; Cu-Otriflate, 2.33 Å) bond distances are slightly varied. All of the complexes exhibited Cu2+ → Cu+ redox couples in acetonitrile, where the redox potentials of TBP-based complexes (-0.251 to -0.383 V) are higher than those of SP-based complexes (-0.450 to -0.527 V). The d-d bands around 582-757 nm and axial patterns of electron paramagnetic resonance spectra [g∥, 2.200-2.251; A∥, (146-166) × 10-4 cm-1] of the complexes suggest the existence of five-coordination geometry. The bonding parameters showed K∥ > K⊥ for all complexes, corresponding to out-of-plane π bonding. The complexes catalyzed direct hydroxylation of benzene using 30% H2O2 and afforded phenol exclusively. The complexes with TBP geometry exhibited the highest amount of phenol formation (37%) with selectivity (98%) superior to that of diazepane-based complexes (29%), which preferred to adopt SP-based geometry. Hydroxylation of benzene likely proceeded via a CuII-OOH key intermediate, and its formation has been established by electrospray ionization mass spectrometry, vibrational, and electronic spectra. Their formation constants have been calculated as (2.54-11.85) × 10-2 s-1 from the appearance of an O (π*σ) → Cu ligand-to-metal charge-transfer transition around 370-390 nm. The kinetic isotope effect (KIE) experiments showed values of 0.97-1.12 for all complexes, which further supports the crucial role of Cu-OOH in catalysis. The 18O-labeling studies using H218O2 showed a 92% incorporation of 18O into phenol, which confirms H2O2 as the key oxygen supplier. Overall, the coordination geometry of the complexes strongly influenced the catalytic efficiencies. The geometry of one of the CuII-OOH intermediates has been optimized by the density functional theory method, and its calculated electronic and vibrational spectra are almost similar to the experimentally observed values.

Ruthenium derivatives attenuate LPS-induced inflammatory responses and liver injury via suppressing NF-κB signaling and free radical production.

Ruthenium metal complex has been shown to exert several chemical and biological activities. A series of three novel ruthenium derivatives (TQ 1, 2 and 4) were synthesized to evaluate the anti-inflammatory and hepatoprotective activities in lipopolysaccharide (LPS)-stimulated macrophages and mice liver injury. The hydroxyl radical (OH°) scavenging activity of these derivatives has also been evaluated. The results revealed that among the tested compounds, TQ-4 effectively attenuated LPS-induced abnormal alteration in liver histoarchistructure via reducing alanine transaminase (ALT) and aspartate transaminase (AST). This compound exhibited significant inhibition of inflammatory cytokines (TNF-α and IL-1ß), inflammatory enzyme (iNOS), the component of NF-κB signaling pathway (p65) and JNK phosphorylation in LPS-induced mice liver tissues. In vitro results showed that TQ-4 had the best inhibition of NO production and iNOS expression in LPS-induced RAW 264.7 cells. Mechanistic approach indicated that TQ-4 inhibited the LPS-induced JNK phosphorylation, IκBα degradation, NF-κB p65 phosphorylation and its nuclear translocation, and hydroxyl radical (OH°) productions in RAW 264.7 cells. However, the compounds TQ-1 and 2 had no effects in this study. TQ-4 also inhibited LPS-induced OH° production. This study reveals the protective effect of TQ-4 against LPS-induced acute liver injury, inflammation, and oxidative reaction by destructing JNK/NF-κB signaling pathways. The result of this study may infer that TQ-4 might be a promising ruthenium metal derivative and/or therapeutic agent for treating liver injury.

Pyrene-Based Chemosensor for Picric Acid-Fundamentals to Smartphone Device Design.

Developing a fluorescent probe for the selective and sensitive detection of explosives is a topic of continuous research interest. Additionally, underlying the principles behind the detection mechanism is indeed providing substantial information about the design of an efficient fluorescence probe. In this context, a pyrene-tethered 1-(pyridin-2-yl)imidazo[1,5-a]pyridine-based fluorescent probe (TL18) was developed and employed as a fluorescent chemosensor for nitro explosives. The molecular structure of TL18 was well-characterized by NMR and EI-MS spectrometric techniques. UV-visible absorption, steady-state, and time-resolved fluorescence spectroscopic techniques have been employed to explicate the photophysical properties of TL18. The fluorescent nature of the TL18 probe was explored for detection of nitro explosives. Intriguingly, the TL18 probe was selectively responsive to picric acid over other explosives. The quantitative analysis of the fluorescence titration studies of TL18 with picric acid proved that the probe achieved a detection limit of 63 nM. Further, DFT and QTAIM studies were used to establish the nature of the sensing mechanism of TL18. The hydrogen-bonding interactions are the reason for the imperative sensing property of TL18 for picric acid. Thus, our experimental and theoretical studies provide an adequate and appropriate prerequisite for an efficient fluorescent probe. Furthermore, a smartphone-interfaced portable fluorimeter module is developed to facilitate sensitive and real-time sensing of picric acid. This portable module was capable of detecting picric acid down to 99 nM. Eventually, these studies will have a significant impact on development and application of a new class of chemosensors for detection of explosives.

Catalytic Conversion of Atmospheric CO2 into Organic Carbonates by Nickel(II) Complexes of Diazepane-Based N4 Ligands.

Activation of CO2 and conversion into value-added products is an effective option to mitigate CO2 emission. The nickel(II) complexes [Ni(L1)](ClO4)2 1, [Ni(L2)](ClO4)2 2, and [Ni(L3)(CH3CN)2](Ph4B)2 3 of diazepane-based ligands [1,4-bis[(pyridin-2-yl-methyl)]-1,4-diazepane (L1), 1,4-bis[2-(pyridin-2-yl)ethyl]-1,4-diazepane (L2), and 4-bis[2-(quinoline-2-yl)-methyl]-1,4-diazepane (L3)] have been synthesized and structurally characterized. The complexes were employed as the catalysts for the conversion of atmospheric CO2 into organic carbonates in the absence of cocatalyst at 1 atm pressure. The single-crystal X-ray structures of 1 and 2 exhibit distorted square-planar geometry with almost identical Ni-N bond distances (1.891-1.946 Å). The geometry of the complexes rearranged into octahedral in acetonitrile, which was studied by paramagnetic 1H NMR and electronic spectra. The complexes selectively captured CO2 from the atmospheric air and readily converted epoxides into cyclic carbonates without any cocatalyst. They showed a maximum yield of 25% (TON, 500) using 1 atm air, which is drastically enhanced up to 89% (TON, 1780) using 1 atm pure CO2 gas. This is the highest catalytic efficiency reported for CO2 fixation using nickel-based catalysts to date. The CO2 fixation reaction without organic substrate showed the formation of carbonate-bridged dinuclear nickel(II) complexes. They showed characteristic absorption bands around 571-612 nm and were further confirmed by electrospray ionization mass spectrometry, IR, and single-crystal X-ray structures. The molecular structure of carbonate-bridged intermediates exhibited two Ni2+-centers with distorted square pyramidal geometries for 2a and 3a but distorted octahedral and square pyramidal geometries for 1a. The CO2 fixation reactions possibly proceeded via the formation of CO2-bound nickel species.

Suppression of Human Platelet Activation via Integrin αIIbß3 Outside-In Independent Signal and Reduction of the Mortality in Pulmonary Thrombosis by Auraptene.

Auraptene is the most abundant coumarin derivative from plants. The pharmacological value of this compound has been well demonstrated, especially in the prevention of cancer and neurodegenerative diseases. Platelet activation is a major factor contributing to arterial thrombosis. Thus, this study evaluated the influence of auraptene in platelet aggregation and thrombotic formation. Auraptene inhibited platelet aggregation in human platelets stimulated with collagen only. However, auraptene was not effective in inhibiting platelet aggregation stimulated with thrombin, arachidonic acid, and U46619. Auraptene also repressed ATP release, [Ca2+]i mobilization, and P-selectin expression. Moreover, it markedly blocked PAC-1 binding to integrin αIIbß3. However, it had no influence on properties related to integrin αIIbß3-mediated outside-in signaling, such as the adhesion number, spreading area of platelets, and fibrin clot retraction. Auraptene inhibited the phosphorylation of Lyn-Fyn-Syk, phospholipase Cγ2 (PLCγ2), protein kinase C (PKC), Akt, and mitogen-activated protein kinases (MAPKs; extracellular-signal-regulated kinase (ERK1/2), and c-Jun N-terminal kinase (JNK1/2), but not p38 MAPK). Neither SQ22536, an adenylate cyclase inhibitor, nor ODQ, a guanylate cyclase inhibitor, reversed the auraptene-mediated inhibition of platelet aggregation. Auraptene reduced mortality caused by adenosine diphosphate (ADP)-induced pulmonary thromboembolism. In conclusion, this study provides definite evidence that auraptene signifies a potential therapeutic agent for preventing thromboembolic disorders.

Esculetin, a Coumarin Derivative, Prevents Thrombosis: Inhibitory Signaling on PLCγ2-PKC-AKT Activation in Human Platelets.

Esculetin, a bioactive 6,7-dihydroxy derivative of coumarin, possesses pharmacological activities against obesity, diabetes, renal failure, and cardiovascular disorders (CVDs). Platelet activation plays a major role in CVDs. Thus, disrupting platelet activation represents an attractive therapeutic target. We examined the effect of esculetin in human platelet activation and experimental mouse models. At 10-80 µM, esculetin inhibited collagen- and arachidonic acid-induced platelet aggregation in washed human platelets. However, it had no effects on other agonists such as thrombin and U46619. Esculetin inhibited adenosine triphosphate release, P-selectin expression, hydroxyl radical (OH·) formation, Akt activation, and phospholipase C (PLC)γ2/protein kinase C (PKC) phosphorylation, but did not diminish mitogen-activated protein kinase phosphorylation in collagen-activated human platelets. Platelet function analysis indicated that esculetin substantially prolonged the closure time of whole blood. In experimental mice, esculetin significantly increased the occlusion time in thrombotic platelet plug formation and reduced mortality associated with acute pulmonary thromboembolism. However, it did not prolong the bleeding time. This study demonstrates that esculetin inhibits human platelet activation via hindering the PLCγ2-PKC cascade, hydroxyl radical formation, Akt activation, and ultimately suppressing platelet activation. Therefore, esculetin may act as an essential therapeutic agent for preventing thromboembolic diseases.

A combined experimental and computational investigation on pyrene based D-π-A dyes.

The geometry (twist vs. planar) of a dye is one of the most pivotal factors for determining intramolecular charge transfer (ICT), light harvesting and photovoltaic properties of dye-sensitized solar cells. In order to comprehend the role of dye geometry on the above properties, we have devised the pyrene based D-π-A dyes namely 2-cyano-3-(5-pyren-1-yl-furan-2-yl)-acrylic acid (PFCC) and 2-cyano-3-(5-pyren-1-ylethynyl-furan-2-yl)-acrylic acid (PEFCC). The synthesized pyrene dyes were well characterized by NMR and EI-MS spectrometry. In both the dyes, the donor (pyrene) and acceptor (cyanoacrylic acid) segments remained the same. The varied π-spacers were furan and ethynyl furan. The influences of the ethynyl spacer on the energy levels, light absorption, dynamics of excited states and photovoltaic properties of the DSCs were systematically investigated via theoretical calculations and spectroscopic measurements. UV-visible absorption spectral measurements indicated that the introduction of the ethynyl spacer enhances the molar absorptivity of a dye (PEFCC) in the order of 2, but does not shift the absorption range, which is consistent with the results obtained from density functional theory (DFT) calculations. The theoretical analysis indicated that the charge transfer transition is mainly constituted of the HOMO to the LUMO that were found to be located on donor and acceptor segments, respectively, which is supportive for efficient charge separation and electron injection processes. TDDFT calculations highlighted that the LUMO of the PEFCC dye is more stabilized by the incorporation of the ethynyl group between the pyrene and furan moieties that aid to inject electrons efficiently into TiO2 thereby resulting in an enhanced power conversion efficiency of 2.47% when compared to the PFCC dye. Notably, the overall conversion efficiency of the PEFCC dye reached 60% with respect to that of an N719-based device (4.12%) fabricated under similar conditions. Transient absorption kinetic studies demonstrated that a slower charge recombination rate is an essential factor behind enhanced efficiencies in PEFCC based cells.

Novel Therapeutic Agent against Platelet Activation In Vitro and Arterial Thrombosis In Vivo by Morin Hydrate.

Morin hydrate, a bioactive flavonoid, has been proven to prevent inflammation and apoptosis of cells. Flavonoids can reduce the risk of cardiovascular diseases, in which platelet activation plays a major role. This study investigated the effect of morin hydrate on platelet activation in vitro and in vivo. Morin hydrate markedly inhibited platelet aggregation stimulated by collagen in human platelets but not that stimulated by other agonists. In collagen-activated platelets, morin hydrate inhibited adenosine triphosphate (ATP) release; intracellular Ca2+ mobilization; P-selectin expression; and phosphorylation of phospholipase Cγ2 (PLCγ2), protein kinase C (PKC), and Akt. In mitogen-activated protein kinase (MAPK) activation, morin hydrate evidently diminished ERK2 or JNK1 activation, except for p38 MAPK. Additionally, morin hydrate markedly reduced the OH· signals in platelet suspensions but not in the cell-free system (Fenton reaction solution). Moreover, morin hydrate substantially increased the occlusion time of thrombotic platelet plug formation but had no effect on bleeding time in mice. In conclusion, morin hydrate crucially inhibits platelet activation through inhibition of the PLCγ2⁻PKC cascade and subsequent suppression of Akt and MAPK activation, thereby ultimately inhibiting platelet aggregation. Therefore, this paper suggests that morin hydrate constitutes a novel and potential natural therapeutic product for preventing or treating thromboembolic disorders.

Structure-Antiplatelet Activity Relationships of Novel Ruthenium (II) Complexes: Investigation of Its Molecular Targets.

The regulation of platelet function by pharmacological agents that modulate platelet signaling has proven to be a positive approach to the prevention of thrombosis. Ruthenium complexes are fascinating for the development of new drugs, as they possess numerous chemical and biological properties. The present study aims to evaluate the structure-activity relationship (SAR) of newly synthesized ruthenium (II) complexes, TQ-1, TQ-2 and TQ-3 in agonists-induced washed human platelets. Silica gel column chromatography, aggregometry, immunoblotting, NMR, and X-ray analyses were performed in this study. Of the three tested compounds, TQ-3 showed a concentration (1-5 µM) dependent inhibitory effect on platelet aggregation induced by collagen (1 µg/mL) and thrombin (0.01 U/mL) in washed human platelets; however, TQ-1 and TQ-2 had no response even at 250 µM of collagen and thrombin-induced aggregation. TQ-3 was effective with inhibiting collagen-induced ATP release, calcium mobilization ([Ca2+]i) and P-selectin expression without cytotoxicity. Moreover, TQ-3 significantly abolished collagen-induced Lyn-Fyn-Syk, Akt-JNK and p38 mitogen-activated protein kinases (p38 MAPKs) phosphorylation. The compound TQ-3 containing an electron donating amino group with two phenyl groups of the quinoline core could be accounted for by its hydrophobicity and this nature might be the reason for the noted antiplatelet effects of TQ-3. The present results provide a molecular basis for the inhibition by TQ-3 in collagen-induced platelet aggregation, through the suppression of multiple machineries of the signaling pathway. These results may suggest that TQ-3 can be considered a potential agent for the treatment of vascular diseases.

Pyrene based D-π-A architectures: synthesis, density functional theory, photophysics and electron transfer dynamics.

Pyrene derivatives show immense potential as sensitizers for dye-sensitized solar cells (DSCs). Therefore, this work focuses on the impact of π-spacers on the photophysical, electrochemical and photovoltaic properties of pyrene based D-π-A dyes, since the insertion of π-spacers is one of the doable strategies to improve the light harvesting properties of the dye. In this respect, three new pyrene based D-π-A dyes have been synthesized and characterized by 1H, 13C NMR, and elemental analyses and EI-MS spectrometry. The selected π-spacers are benzene, thiophene and furan. Compared with a benzene spacer, the introduction of a heterocyclic ring spacer reduces the band gap of the dye and brings about the broadening of the absorption spectra to the longer wavelength region through intramolecular charge-transfer (ICT). Combined experimental and theoretical studies were performed to investigate the ICT process involved in the pyrene derivatives. The profound solvatochromism with increased nonradiative rate constants (knr) has been construed in terms of ICT from the pyrene core to rhodanine-3-acetic acid via conjugated π-spacers. Electrochemical data also reveal that the HOMO and LUMO energy levels are fine-tuned by incorporating different π-spacers between pyrene and rhodanine-3-acetic acid. On the basis of the optimized DSC test conditions, the best performance was found for PBRA, in which a benzene group is the conjugated π-spacer. The divergence in the photovoltaic behaviors of these dyes was further explicated by femtosecond fluorescence and electrochemical impedance spectroscopy.

Antiplatelet Activity of a Newly Synthesized Novel Ruthenium (II): A Potential Role for Akt/JNK Signaling.

In oncotherapy, ruthenium complexes are considered as potential alternatives for platinum compounds, and have been proved as promising anticancer drugs with high efficacy and lesser side effects. Platelet activation plays a major role in cancer metastasis and progression. Hence, this study explored the effect of a newly synthesized ruthenium complex, [Ru(η6-cymene)(L)Cl]BF4(TQ5), where L = 4-phenyl-2-pyridin-2-yl-quinazoline), on human platelet activation. TQ5 (3-5 µM) inhibited concentration-dependent collagen-induced platelet aggregation in washed human platelets. However, this compound only inhibited platelet aggregation at a maximum concentration of 500 and 100 µM against thrombin and 9,11-dideoxy-11α, 9α-epoxymethanoprostaglandin (U46619)-induced stimulation, respectively. TQ5 inhibited collagen-induced ATP release and calcium mobilization ([Ca2+]i), without inducing cell cytotoxicity. In addition, neither SQ22536, an adenylate cyclase inhibitor, nor 1H-[1,2,4] oxadiazolo [4,3-a]quinoxalin-1-one (ODQ), a guanylate cyclase inhibitor, significantly reversed the TQ5-mediated inhibition of platelet aggregation. TQ5 inhibited the collagen-induced phosphorylation of protein kinase B (Akt) and c-Jun N-terminal kinase (JNK), but did not effectively inhibit extracellular signal-regulated kinase 1/2 (ERK1/2) and p38-mitogen-activated protein kinase (p38-MAPK) in human platelets. Additionally, TQ5 significantly prolonged the closure time in whole blood and increased the occlusion time of thrombotic platelet plug formation in mice. This study demonstrates, for the first time, that a newly synthesized ruthenium complex, TQ5, exhibits potent antiplatelet activity by hindering ATP release and [Ca2+]i, and by decreasing the activation of Akt/JNK signals. Together, these results suggest that TQ5 could be developed as a therapeutic agent that helps prevent or treat thromboembolic disorders, since it is found to be potently more effective than a well-established antithrombotic aspirin.

New Therapeutic Agent against Arterial Thrombosis: An Iridium(III)-Derived Organometallic Compound.

Platelet activation plays a major role in cardio and cerebrovascular diseases, and cancer progression. Disruption of platelet activation represents an attractive therapeutic target for reducing the bidirectional cross talk between platelets and tumor cells. Platinum (Pt) compounds have been used for treating cancer. Hence, replacing Pt with iridium (Ir) is considered a potential alternative. We recently developed an Ir(III)-derived complex, [Ir(Cp*)1-(2-pyridyl)-3-(2-hydroxyphenyl)imidazo[1,5-a]pyridine Cl]BF4 (Ir-11), which exhibited strong antiplatelet activity; hence, we assessed the therapeutic potential of Ir-11 against arterial thrombosis. In collagen-activated platelets, Ir-11 inhibited platelet aggregation, adenosine triphosphate (ATP) release, intracellular Ca2+ mobilization, P-selectin expression, and OH· formation, as well as the phosphorylation of phospholipase Cγ2 (PLCγ2), protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), and Akt. Neither the adenylate cyclase inhibitor nor the guanylate cyclase inhibitor reversed the Ir-11-mediated antiplatelet effects. In experimental mice, Ir-11 prolonged the bleeding time and reduced mortality associated with acute pulmonary thromboembolism. Ir-11 plays a crucial role by inhibiting platelet activation through the inhibition of the PLCγ2-PKC cascade, and the subsequent suppression of Akt and MAPK activation, ultimately inhibiting platelet aggregation. Therefore, Ir-11 can be considered a new therapeutic agent against either arterial thrombosis or the bidirectional cross talk between platelets and tumor cells.

Time-resolved neutron reflectometry and photovoltaic device studies on sequentially deposited PCDTBT-fullerene layers.

We have used steady-state and time-resolved neutron reflectometry to study the diffusion of fullerene derivatives into the narrow optical gap polymer poly[N-9″-hepta-decanyl-2,7-carbazole-alt-5,5-(4',7'-di-2-thienyl-2',1',3'-benzothiadiazole)] (PCDTBT) to explore the sequential processing of the donor and acceptor for the preparation of efficient organic solar cells. It was found that when [6,6]-phenyl-C61-butyric-acid-methyl-ester (60-PCBM) was deposited onto a thin film of PCDTBT from dichloromethane (DCM), a three-layer structure was formed that was stable below the glass-transition temperature of the polymer. When good solvents for the polymer were used in conjunction with DCM, both 60-PCBM and [6,6]-phenyl-C71-butyric-acid-methyl-ester (70-PCBM) were seen to form films that had a thick fullerene layer containing little polymer and a PCDTBT-rich layer near the interface with the substrate. Devices composed of films prepared by sequential deposition of the polymer and fullerene had efficiencies of up to 5.3%, with those based on 60-PCBM close to optimized bulk heterojunction (BHJ) cells processed in the conventional manner. Sequential deposition of pure components to form the active layer is attractive for large-area device fabrication, and the results demonstrate that this processing method can give efficient solar cells.

Determination of fullerene scattering length density: a critical parameter for understanding the fullerene distribution in bulk heterojunction organic photovoltaic devices.

Fullerene derivatives are commonly used as electron acceptors in combination with (macro)molecular electron donors in bulk heterojunction (BHJ) organic photovoltaic (OPV) devices. Understanding the BHJ structure at different electron donor/acceptor ratios is critical to the continued improvement and development of OPVs. The high neutron scattering length densities (SLDs) of the fullerenes provide effective contrast for probing the distribution of the fullerene within the blend in a nondestructive way. However, recent neutron scattering studies on BHJ films have reported a wide range of SLDs ((3.6-4.4) × 10(-6) Å(-2)) for the fullerenes 60-PCBM and 70-PCBM, leading to differing interpretations of their distribution in thin films. In this article, we describe an approach for determining more precisely the scattering length densities of the fullerenes within a polymer matrix in order to accurately quantify their distribution within the active layers of OPV devices by neutron scattering techniques.

Design of an anticancer organoruthenium complex as the guest and polydiacetylene-coated fluorogenic nanocarrier as the host: engineering nanocarrier using ene-yne conjugation for sustained guest release, enhanced anticancer activity and reduced in vivo toxicity.

Despite the enormous efforts made over the past two decades to develop metallodrugs and nanocarriers for metallodrug delivery, there are still few precise strategies that aim to optimize the design of both metallodrugs and metallodrug carriers jointly in a concerted effort. In this work, three half-sandwich ruthenium(II) complexes with pyridylimidazo[1,5-a]pyridine ligand functionalized with polycyclic aromatic moiety (Ru(nap), Ru(ant), Ru(pyr)) are evaluated as possible anticancer candidates and polydiacetylene (PDA)-coated amino-functionalized mesoporous silica nanoparticles (AMSNs) are designed as a functional nanocarrier for drug delivery. Ru(pyr) exhibits higher cytotoxicity in HT-29 colorectal cancer cells compared to other complexes and cis-platin, but it does not exhibit better cellular uptake. Ru(pyr) is found to be preferentially accumulated in plasma, mitochondria, and ER-Golgi membrane. The complex induces cell cycle arrest in the G0/G1 phase, while higher concentrations cause programmed cell death via apoptosis. Ru(pyr) influences cancer cell adhesion property and acts as an antioxidant in HT-29 cells. In order to modulate the anticancer potency of Ru(pyr), AMSNs are used to encapsulate the complex, and then diacetylene self-assembly is allowed to deposit on the surface of the nanoparticles. Subsequently, the nanoparticles undergo topopolymerization, which results in π-conjugated PDA-Ru(pyr)@AMSNs. Owing to the ene-yne polymeric skeleton in the backbone, the non-fluorescent AMSNs turn into red-emissive particles, which are exploited for cell imaging applications. The release profile analysis reveals that such a π-conjugated polymer prevents the premature release of the complex from porous silica nanoparticles with the accelerated release of the complex in an acidic medium compared to physiological conditions. The PDA gatekeepers have also been proven to enhance the cellular internalization of Ru(pyr) with slow continuous release from the nanoformulation. Zebrafish embryo toxicity analysis suggests that the PDA-coated nanocarriers could be suitable candidates for in vivo investigations.

Nickel(II) Complexes of Tripodal Ligands as Catalysts for Fixation of Atmospheric CO2 as Organic Carbonates.

The fixation of atmospheric CO2 into value-added products is a promising methodology. A series of novel nickel(II) complexes of the type [Ni(L)(CH3 CN)2 ](BPh4 )2 1-5, where L=N,N-bis(2-pyridylmethyl)-N', N'-dimethylpropane-1,3-diamine (L1), N,N-dimethyl-N'-(2-(pyridin-2-yl)ethyl)-N'-(pyridin-2-ylmethyl) propane-1,3-diamine (L2), N,N-bis((4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-N',N'-dimethylpropane-1,3-diamine (L3), N-(2-(dimethylamino) benzyl)-N',N'-dimethyl-N-(pyridin-2-ylmethyl) propane-1,3-diamine (L4) and N,N-bis(2-(dimethylamino)benzyl)-N', N'-dimethylpropane-1,3-diamine (L5) have been synthesized and characterized as the catalysts for the conversion of atmospheric CO2 into organic cyclic carbonates. The single-crystal X-ray structure of 2 was determined and exhibited distorted octahedral coordination geometry with cis-α configuration. The complexes have been used as a catalyst for converting CO2 and epoxides into five-membered cyclic carbonates under 1 atmospheric (atm) pressure at room temperature in the presence of Bu4 NBr. The catalyst containing electron-releasing -Me and -OMe groups afforded the maximum yield of cyclic carbonates, 34% (TON, 680) under 1 atm air. It was drastically enhanced to 89% (TON, 1780) under pure CO2 gas at 1 atm. It is the highest catalytic efficiency known for CO2 fixation using nickel-based catalysts at room temperature and 1 atm pressure. The electronic and steric factors of the ligands strongly influence the catalytic efficiency. Furthermore, all the catalysts can convert a wide range of epoxides (ten examples) into corresponding cyclic carbonate with excellent selectivity (>99%) under this mild condition.

Crystal structure of [2-({[2-(dimethylamino-κN)ethyl]imino-κN}methyl)phenolato-κO](1,10-phen-anthroline-κ2 N,N')copper(II) perchlorate.

The title compound, [Cu(C11H15N2O)(C12H8N2)]ClO4 or [Cu(L)(phen)](ClO4) {where L refers to the deprotonated form of 2-[(2-di-methyl-amino-ethyl-imino)-meth-yl]phenol} and phen is 1,10-phenanthroline) is a mononuclear mixed ligand copper(II) complex. The CuII atom is coordinated by two N and one O atoms of the tridentate Schiff base ligand (HL) and two N atoms of the 1,10-phenanthroline ligand, resulting in a five-coordinate complex. The asymmetric unit of the title complex contains two crystallographically independent complex cations (a and b) with a slightly different geometry around the CuII ion. The value of the trigonality index τ, indicates that in both cations a and b, the CuII atoms display a square-pyramidal distorted trigonal-bipyramidal (SPDTBP) geometry, although the distortion is greater for cation a.

Mixed ligand copper(II)-diimine complexes of 2-formylpyridine-N4-phenylthiosemicarbazone: diimine co-ligands tune the in vitro nanomolar cytotoxicity.

Recently, mixed-ligand copper(II) complexes have received much attention in searching for alternative metallodrugs to cisplatin. A series of mixed ligand Cu(II) complexes of the type [Cu(L)(diimine)](ClO4) 1-6, where the HL is 2-formylpyridine-N4-phenylthiosemicarbazone and the diimine is 2,2'-bipyridine (1), 4,4'-dimethyl-2,2'-bipyridine (2), 1,10-phenanthroline (3), 5,6-dimethyl-1,10-phenanathroline (4), 3,4,7,8-tetramethyl-1,10-phenanthroline (5) and dipyrido-[3,2-f:2',3'-h]quinoxaline (6), has been synthesized and their cytotoxicity in HeLa cervical cancer cells examined. In the molecular structures of 2 and 4, as determined by single-crystal X-ray studies, Cu(II) assumes a trigonal bipyramidal distorted square-based pyramidal (TBDSBP) coordination geometry. DFT studies reveal that the axial Cu-N4diimine bond length, interestingly, varies linearly with the experimental CuII/CuI reduction potential as well as the trigonality index τ of the five-coordinate complexes, and that methyl substitution on diimine co-ligands tunes the extent of the Jahn-Teller distortion at the Cu(II). While 4 is involved in strong DNA groove binding with a hydrophobic interaction of methyl substituents, 6 is involved in stronger binding through partial intercalation of dpq with DNA. Complexes 3, 4, 5, and 6 efficiently cleave supercoiled DNA into NC form in ascorbic acid by generating hydroxyl radicals. Interestingly, 4 exhibits higher DNA cleavage in hypoxic than at normoxic conditions. Notably, except for [CuL]+, all the complexes were stable in 0.5% DMSO-RPMI (without phenol red) cell culture medium up to 48 h at 37 °C. Remarkably, all the complexes show time-dependent cytotoxicity at nanomolar concentrations (IC50, 7.0-182 nM) in HeLa cervical cancer cells compared with uncoordinated ligand HL (IC50 > 10 000 nM). Except for 2 and 3, all the complexes exhibit higher cytotoxicity than [CuL]+ at 48 h. 4 shows (57.2 nM) higher cytotoxicity than 1 (181.5 nM) at 24 h incubation; however, notably, 1 demonstrates phenomenal cytotoxicity (7.0 nM) higher than 4 (13.6 nM) at 48 h incubation. The selectivity index (SI) reveals that complexes 1 and 4 are 53.5 and 37.3, respectively, times less toxic to HEK293 normal cells than to cancerous cells. Except for [CuL]+, all the complexes generate ROS to different extents at 24 h, with 1 producing the highest amount, which is consistent with their redox properties. Also, 1 and 4 exhibit, respectively, sub-G1 and G2-M phase cell arrest in the cell cycle. Therefore, complexes 1 and 4 have the potential to emerge as promising anticancer agents.

Integrated Approach to Interaction Studies of Pyrene Derivatives with Bovine Serum Albumin: Insights from Theory and Experiment.

This work aimed to investigate the interaction of bovine serum albumin with newly synthesized potent new pyrene derivatives (PS1 and PS2), which might prove useful to have a better antibacterial character as found for similar compounds in the previous report [Low et al. Bioconjugate Chemistry 2014, 12, 2269-2284]. However, to date, binding studies with plasma protein are still unknown. Steady-state fluorescence spectroscopy and lifetime fluorescence studies show that the static interaction binding mode and binding constants of PS1 and PS2 are 7.39 and 7.81 [Kb × 105 (M-1)], respectively. The experimental results suggest that hydrophobic forces play a crucial role in interacting pyrene derivatives with BSA protein. To verify this, molecular docking and molecular dynamics simulations were performed to predict the nature of the interaction and the dynamic behavior of the two compounds in the BSA complex, PS1 and PS2, under physiological conditions of pH = 7.1. In addition, the free energies of binding for the BSA-PS1 and BSA-PS2 complexes were estimated at 300 K based on the molecular mechanics of the Poisson-Boltzmann surface (MMPBSA) with the Gromacs package. PS2 was found to have a higher binding affinity than PS1. To determine the behavior of the orbital transitions in the ground state geometry, we found that both compounds have similar orbital transitions from HOMO-LUMO via π → π* and HOMO-1-LUMO+1 via n → π*, which was included in the FMO analysis. A cytotoxicity study was performed to determine the toxicity of the compounds. Based on the MD study, the stability of the compounds with BSA and the dynamic binding modes were further revealed, as well as the nature of the binding force components involved and the important residues involved in the binding process. From the binding energy analysis, it can be assumed that PS2 may be more active than PS1.