Unusually Short Chalcogen Bonds Involving Organoselenium: Insights into the Se-N Bond Cleavage Mechanism of the Antioxidant Ebselen and Analogues

Structural studies on the polymorphs of the organoselenium antioxidant ebselen and its derivative show the potential of organic selenium to form unusually short Se center dot center dot center dot O chalcogen bonds that lead to conserved supramolecular recognition units. Se center dot center dot center dot O interactions observed in these polymorphs are the shortest such chalcogen bonds known for organoselenium compounds. The FTIR spectral evolution characteristics of this interaction from solution state to solid crystalline state further validates the robustness of this class of supramolecular recognition units. The strength and electronic nature of the Se center dot center dot center dot O chalcogen bonds were explored using high-resolution X-ray charge density analysis and atons-in-molecules (AIM) theoretical analysis. A charge density study unravels the strong electrostatic nature of Se center dot center dot center dot O chalcogen bonding and soft-metal-like behavior of organoselenium. An analysis of the charge density around Se-N and Se-C covalent bonds in conjunction with the Se center dot center dot center dot O chalcogen bonding modes in ebselen and its analogues provides insights into the mechanism of drug action in this class of organoselenium antioxidants. The potential role of the intermolecular Se center dot center dot center dot O chalcogen bonding in forming the intermediate supramolecular assembly that leads to the bond cleavage mechanism has been proposed in terms of electron density topological parameters in a series of molecular complexes of ebselen with reactive oxygen species (ROS).

Solid state structure of p-bromo phenyl 4,5,7-tri-O-benzyl-beta-D-glycero-D-talo-septanoside and an analysis of non-covalent interactions

The solid state structure of a new seven-membered sugar oxepane derivative, namely, p-bromo phenyl 4,5,7-tri-O-benzyl-beta-D-glycero-D-talo-septanoside is discussed, as determined through single crystal X-ray structural determination and in relation to their conformational features. The molecule adopts twist-chair as the preferred conformation, with conformational descriptor (TC2,3)-T-0,1. The solid state packing of molecules is governed by a rich network of non-covalent bonding originating from O-H center dot center dot center dot O, C-H center dot center dot center dot pi, C-H center dot center dot center dot Br and aromatic pi center dot center dot center dot pi interactions that stabilize the packing of molecules in the crystal. (C) 2015 Elsevier Ltd. All rights reserved.

Synthesis and evaluation of the biological activity of N `-2-oxo-1,2 dihydro-3H-indol-3-ylidene] benzohydrazides as potential anticancer agents

New N'-2-oxo-1,2-dihydro-3H-indol-3-ylidene]benzohydrazide derivatives were synthesized and evaluated for their cytotoxic properties against murine leukemia, L1210, human leukemia, REH and K562, human T-cell leukemia, CEM and human cervix carcinoma, HeLa cells. Among the tested compounds, the 3,4,5-trimethoxy-N'-5-methyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene]ben zohydrazide derivative (5t) emerged as the most potent inhibitor against all the tumor cell lines evaluated. To investigate the mechanism of action, 5t was further studied by cell cycle analysis, mitochondrial membrane potential analysis, DNA fragmentation and Annexin V-FITC flow cytometric analysis, which suggested that 5t was able to induce apoptosis at submicromolar range.

Methotrexate Promotes Platelet Apoptosis via JNK-Mediated Mitochondrial Damage: Alleviation by N-Acetylcysteine and N-Acetylcysteine Amide

Thrombocytopenia in methotrexate (MTX)-treated cancer and rheumatoid arthritis (RA) patients connotes the interference of MTX with platelets. Hence, it seemed appealing to appraise the effect of MTX on platelets. Thereby, the mechanism of action of MTX on platelets was dissected. MTX (10 mu M) induced activation of pro-apoptotic proteins Bid, Bax and Bad through JNK phosphorylation leading Delta psi m dissipation, cytochrome c release and caspase activation, culminating in apoptosis. The use of specific inhibitor for JNK abrogates the MTX-induced activation of pro-apoptotic proteins and downstream events confirming JNK phosphorylation by MTX as a key event. We also demonstrate that platelet mitochondria as prime sources of ROS which plays a central role in MTX-induced apoptosis. Further, MTX induces oxidative stress by altering the levels of ROS and glutathione cycle. In parallel, the clinically approved thiol antioxidant N-acetylcysteine (NAC) and its derivative N-acetylcysteine amide (NACA) proficiently alleviate MTX-induced platelet apoptosis and oxidative damage. These findings underpin the dearth of research on interference of therapeutic drugs with platelets, despite their importance in human health and disease. Therefore, the use of antioxidants as supplementary therapy seems to be a safe bet in pathologies associated with altered platelet functions.

Engineering nanostructured polymer blends with controlled nanoparticle location for excellent microwave absorption: a compartmentalized approach

In order to obtain better materials, control over the precise location of nanoparticles is indispensable. It is shown here that ordered arrangements of nanoparticles, possessing different characteristics (electrical/ magnetic dipoles), in the blend structure can result in excellent microwave absorption. This is manifested from a high reflection loss of ca. -67 dB for the best blend structure designed here. To attenuate electromagnetic radiation, the key parameters of high electrical conductivity and large dielectric/magnetic loss are targeted here by including a conductive material multiwall carbon nanotubes, MWNTs], ferroelectric nanostructured material with associated relaxations in the GHz frequency barium titanate, BT] and lossy ferromagnetic nanoparticles nickel ferrite, NF]. In this study, bi-continuous structures were designed using 50/50 (by wt) blends of polycarbonate (PC) and polyvinylidene fluoride (PVDF). The MWNTs were modified using an electron acceptor molecule, a derivative of perylenediimide, which facilitates p-p stacking with the nanotubes and stimulates efficient charge transport in the blends. The nanoscopic materials have specific affinity towards the PVDF phase. Hence, by introducing surface-active groups, an ordered arrangement can be tailored. To accomplish this, both BT and NF were first hydroxylated followed by the introduction of amine-terminal groups on the surface. The latter facilitated nucleophilic substitution reactions with PC and resulted in their precise location. In this study, we have shown for the first time that by a compartmentalized approach, superior EM attenuation can be achieved. For instance, when the nanoparticles were localized exclusively in the PVDF phase or in both the phases, the minimum reflection losses were ca. -18 dB (for the MWNT/BT mixture) and -29 dB (for the MWNT/NF mixture), and the shielding occurred primarily through reflection. Interestingly, by adopting the compartmentalized approach wherein the lossy materials were in the PC phase and the conductive materials (MWNT) were in the PVDF phase, outstanding reflection losses of ca. -57 dB (for the BT and MWNT combination) and -67 dB (for the NF and MWNT combination) were noted and the shielding occurred primarily through absorption. Thus, the approach demonstrates that nanoscopic structuring in the blends can be achieved under macroscopic processing conditions and this strategy can further be explored to design microwave absorbers.

Synthesis of Novel Benzofuran-Gathered C-2,4,6-substituted Pyrimidine Derivatives Conjugated by Sulfonyl Chlorides: Orally Bioavailable, Selective, Effective Antioxidants and Antimicrobials Drug Candidates

In the present study, we have made an effort to develop the novel synthetic antioxidants and antimicrobials with improved potency. The novel benzofuran-gathered C-2,4,6-substituted pyrimidine derivatives 5a, 5b, 5c, 5d, 5e, 5f, 6a, 6b, 6c, 6d, 6e, 6f, 7a, 7b, 7c, 7d, 7e, 7f, 8a, 8b, 8c, 8d, 8e, 8f, 9a, 9b, 9c, 9d, 9e, 9f were synthesized by simple and efficient four-step reaction pathway. Initially, o-alkyl derivative of salicylaldehyde readily furnish corresponding 2-acetyl benzofuran 2 in good yield, upon the treatment with potassium tertiary butoxide in the presence of molecular sieves. Further, Claisen-Schmidt condensation with aromatic aldehydes via treatment with thiourea followed by coupling reaction with different sulfonyl chlorides afforded target compounds. The structures of newly synthesized compounds were confirmed by IR, H-1 NMR, C-13 NMR, mass, and elemental analysis and further screened for their antioxidant and antimicrobial activities. The results showed that the synthesized compounds 8b, 8e, 9b, and 9e produced significant antioxidant activity with 50% inhibitory concentration higher than that of reference, whereas compounds 7d and 7c produced dominant antimicrobial activity at concentrations 1.0 and 0.5mg/mL compared with standard Gentamicin and Nystatin, respectively.

Spectral characterizations and photophysical properties of one-step synthesized blue fluorescent 4 `-aryl substituted 2,2 `:6 `,2 `'-terpyridine for OLEDs application

We have synthesized a series of 4'-aryl substituted 2,2':6',2 `'-terpyridine (terpy) derivatives, namely 4'-(4-methylphenyl)-2,2':6',2 `'-terpyridine (C-1), 4'-(2-furyl)-2,2':6'2 `'-terpyridine (C-2), and 4'-(3,4,5-trimethoxyphenyl)-2,2':6',2 `'-terpyridine (C-3). The synthesized terpy compounds were characterized by elemental analyses, FTIR, NMR (H-1 and C-13), and ESI-Mass spectrometry. Photophysical, electrochemical and thermal properties of terpy compounds were systematically studied. Maximum excitation band was observed between 240 and 330 nm using UV-visible spectra, and maximum emission peaks from PL spectra were observed at 385, 405 and 440 nm for C-1, C-2 and C-3 respectively. Fluorescence lifetime (tau) of the fluorophores was found to be 035 and 1.55 ns at the excitation wavelength of 406 nm for C-1 and C-2 respectively, and tau value for C-3 was found to be 0.29 ns at the excitation wavelength of 468 nm. We noticed that the calculated values of HOMO energy levels were increased from 5.96 (C-1) to 6.08 (C-3) eV, which confirms that C-3 derivative is more electrons donating in nature. The calculated electrochemical band gaps were 2.95, 2.82 and 3.02 eV for C-1, C-2 and C-3 respectively. These blue fluorescent emitter derivatives can be used as an electron transport and electroluminescent material to design the blue fluorescent organic light emitting diode (OLED) applications. (C) 2015 Elsevier B.V: All rights reserved.

Catalytic Aldol-Cyclization Cascade of 3-Isothiocyanato Oxindoles with alpha-Ketophosphonates for the Enantioselective Synthesis of beta-Amino-alpha-hydroxyphosphonates

A cascade aldol cyclization reaction between 3-isothiocyanato oxindoles and alpha-ketophosphonates has been developed for the synthesis of beta-amino-alpha-hydroxyphosphonate derivatives. Catalyzed by a quinine-based tertiary amino-thiourea derivative, this reaction delivers 2-thioxooxazolidinyl phosphonates based on a spirooxindole scaffold bearing two contiguous quaternary stereogenic centers in high yields with excellent diastereo- (up to >20:1 dr) and enantioselectivities (up to >99:1 er).

Ac2PIM-responsive miR-150 and miR-143 Target Receptor-interacting Protein Kinase 2 and Transforming Growth Factor Beta-activated Kinase 1 to Suppress NOD2-induced Immunomodulators

Specific and coordinated regulation of innate immune receptor-driven signaling networks often determines the net outcome of the immune responses. Here, we investigated the cross-regulation of toll-like receptor (TLR)2 and nucleotide-binding oligomerization domain (NOD)2 pathways mediated by Ac2PIM, a tetra-acylated form of mycobacterial cell wall component and muramyl dipeptide (MDP), a peptidoglycan derivative respectively. While Ac2PIM treatment of macrophages compromised their ability to induce NOD2-dependent immunomodulators like cyclooxygenase (COX)-2, suppressor of cytokine signaling (SOCS)-3, and matrix metalloproteinase (MMP)-9, no change in the NOD2-responsive NO, TNF-alpha, VEGF-A, and IL-12 levels was observed. Further, genome-wide microRNA expression profiling identified Ac2PIM-responsive miR-150 and miR-143 to target NOD2 signaling adaptors, RIP2 and TAK1, respectively. Interestingly, Ac2PIM was found to activate the SRC-FAK-PYK2-CREB cascade via TLR2 to recruit CBP/P300 at the promoters of miR-150 and miR-143 and epigenetically induce their expression. Loss-of-function studies utilizing specific miRNA inhibitors establish that Ac2PIM, via the miRNAs, abrogate NOD2-induced PI3K-PKC delta-MAPK pathway to suppress beta-catenin-mediated expression of COX-2, SOCS-3, and MMP-9. Our investigation has thus underscored the negative regulatory role of Ac2PIM-TLR2 signaling on NOD2 pathway which could broaden our understanding on vaccine potential or adjuvant utilities of Ac2PIM and/or MDP.

Relative stabilities of condensed face sharing mono- and di-carboranes: CB20H18 and C2B19H18+

The relative energies of triangular face sharing condensed macro polyhedral carboranes: CB20H18 and C2B19H18+ derived from mono- and di-substitution of carbons in (4) B21H18- is calculated at B3LYP/6-31G* level. The relative energies, H center dot center dot center dot H non-bonding distances, NICS values, topological charge analysis and orbital overlap compatibility connotes the face sharing condensed macro polyhedral mono-carboranes, 8 (4-CB20H18) to be the lowest energy isomer. The di-carba- derivative, (36) 4,4'a-C2B19H18+ with carbons substituted in a different B-12 cage in (4) B21H18- in anti-fashion is the most stable isomer among 28 possibilities. This structure has less non-bonding H center dot center dot center dot H interaction and is in agreement with orbital-overlap compatibility, and these two have the pivotal role in deciding the stability of these clusters. An estimate of the inherent stability of these carboranes is made using near-isodesmic equations which show that CB20H18 (8) is in the realm of the possible. (C) 2015 Elsevier B.V. All rights reserved.

Amine Functionalized polyaniline grafted to exfoliated graphite oxide: Synthesis, characterization and multi-element sensor studies

An amine functionalized polyaniline (AMPANI) derivative has been grafted onto exfoliated graphite oxide (EGO). The synthesis involved the in-situ chemical oxidative polymerization of functionalized aniline monomer in the presence of EGO with diaminobenzene acting as a bridging ligand to yield EGAMPANI. The synthesized compound was characterized by FT-IR and FT-Raman spectroscopy as well as thermogravimetric and X-ray diffraction analysis. The EGAMPANI was then used to modify a carbon paste electrode (CPE), which was applied for multi-elemental sensing of Pb2+, Cd2+ and Hg2+ ions using differential pulse anodic stripping voltammetty. The limits of detection achieved using the EGAMPANI modified CPE were 22 x 10(-6) M for Hg2+ ion, 1.2 x 10(-6) M for Cd2+ ion and 9.8 x 10(-7) M for Pb2+ ion. (C) 2015 Elsevier B.V. All rights reserved.

Vesicular Nanostructure Formation by Self-Assembly of Anisotropic Penta-phenol-Substituted Fullerene in Water

A study on self-assembly of anisotropically substituted penta-aryl fullerenes in water has been reported. The penta-phenol-substituted amphiphilic fullerene derivative C60Ph5(OH)(5)],exhibited self-assembled vesicular nanostructures in water under the experimental conditions. The size of the vesicles Was observed to depend upon the kinetics of self-assembly and could be varied from similar to 300 to similar to 70 nm. Our mechanistic study indicated that the self-assembly of C60Ph5(OH)(5) is driven by extensive intermolecular as well as water-mediated hydrogen :bonding along with fullerene-fullerene hydrophobic interaction in water. The cumulative effect of these interactions is responsible for the stability of vesicular structures even on the removal of solvent. The substitution of phenol with anisole resulted in different packing and interaction of the fullerene derivative, as Indicated in the molecular dynamics studies, thus resulting in different self-assembled nanostructures. The hollow vesicles were further encapsulated with a hydrophobic conjugated polymer and water-soluble dye as guest molecules. Such confinement of pi-conjugated polymers in fullerene has significance in bulk heterojunction devices for efficient exciton diffusion.

A fluorescent molecularly-imprinted polymer gate with temperature and pH as inputs for detection of alpha-fetoprotein

In this work, we have reported a new approach on the use of stimuli-responsive molecularly imprinted polymer (MIP) for trace level sensing of alpha-fetoprotein (AFP), which is a well know cancer biomarker. The stimuli-responsive MIP is composed of three components, a thermo-responsive monomer, a pH responsive component (tyrosine derivative) and a highly fluorescent vinyl silane modified carbon dot. The synthesized AFP-imprinted polymer possesses excellent selectivity towards their template molecule and dual-stimuli responsive behavior. Along with this, the imprinted polymer was also explored as `OR' logic gate with two stimuli (pH and temperature) as inputs. However, the non-imprinted polymers did not have such `OR' gate property, which confirms the role of template binding. The imprinted polymer was also used for estimation of AFP in the concentration range of 3.96-80.0 ng mL(-1), with limit of detection (LOD) 0.42 ng mL(-1). The role of proposed sensor was successfully exploited for analysis of AFP in real human blood plasma, serum and urine sample. (C) 2015 Elsevier B.V. All rights reserved.

A glucose-centric perspective of hyperglycemia

Digestion of food in the intestines converts the compacted storage carbohydrates, starch and glycogen, to glucose. After each meal, a flux of glucose (>200 g) passes through the blood pool (4-6 g) in a short period of 2 h, keeping its concentration ideally in the range of 80-120 mg/100 mL. Tissue-specific glucose transporters (GLUTs) aid in the distribution of glucose to all tissues. The balance glucose after meeting the immediate energy needs is converted into glycogen and stored in liver (up to 100 g) and skeletal muscle (up to 300 g) for later use. High blood glucose gives the signal for increased release of insulin from pancreas. Insulin binds to insulin receptor on the plasma membrane and activates its autophosphorylation. This initiates the post-insulin-receptor signal cascade that accelerates synthesis of glycogen and triglyceride. Parallel control by phos-dephos and redox regulation of proteins exists for some of these steps. A major action of insulin is to inhibit gluconeogensis in the liver decreasing glucose output into blood. Cases with failed control of blood glucose have alarmingly increased since 1960 coinciding with changed life-styles and large scale food processing. Many of these turned out to be resistant to insulin, usually accompanied by dysfunctional glycogen storage. Glucose has an extended stay in blood at 8 mM and above and then indiscriminately adds on to surface protein-amino groups. Fructose in common sugar is 10-fold more active. This random glycation process interferes with the functions of many proteins (e.g., hemoglobin, eye lens proteins) and causes progressive damage to heart, kidneys, eyes and nerves. Some compounds are known to act as insulin mimics. Vanadium-peroxide complexes act at post-receptor level but are toxic. The fungus-derived 2,5-dihydroxybenzoquinone derivative is the first one known to act on the insulin receptor. The safe herbal products in use for centuries for glucose control have multiple active principles and targets. Some are effective in slowing formation of glucose in intestines by inhibiting alpha-glucosidases (e.g., salacia/saptarangi). Knowledge gained from French lilac on active guanidine group helped developing Metformin (1,1-dimethylbiguanide) one of the popular drugs in use. One strategy of keeping sugar content in diets in check is to use artificial sweeteners with no calories, no glucose or fructose and no effect on blood glucose (e.g., steviol, erythrytol). However, the three commonly used non-caloric artificial sweetener's, saccharin, sucralose and aspartame later developed glucose intolerance, the very condition they are expected to evade. Ideal way of keeping blood glucose under 6 mM and HbAlc, the glycation marker of hemoglobin, under 7% in blood is to correct the defects in signals that allow glucose flow into glycogen, still a difficult task with drugs and diets.

Targeting human telomeric G-quadruplex DNA with curcumin and its synthesized analogues under molecular crowding conditions

The formation of telomeric G-quadruplexes has been shown to inhibit telomerase activity. Indeed, a number of small molecules capable of p-stacking with G-tetrads have shown the ability to inhibit telomerase activity through the stabilization of G-quadruplexes. Curcumin displays a wide spectrum of medicinal properties ranging from anti-bacterial, anti-viral, anti-protozoal, anti-fungal and anti-inflammatory to anti-cancer activity. We have investigated the interactions of curcumin and its structural analogues with the human telomeric sequence AG(3)(T(2)AG(3))(3) under molecular crowding conditions. Experimental studies indicated the existence of a AG(3)(T(2)AG(3))(3)/curcumin complex with binding affinity of 0.72 x 10(6) M-1 under molecular crowding conditions. The results from UV-visible absorption spectroscopy, a fluorescent TO displacement assay, circular dichroism and molecular docking studies, imply that curcumin and their analogues interact with G-quadruplex DNA via groove binding. While other analogs of curcumin studied here bind to G-quadruplexes in a qualitatively similar manner their affinities are relatively lower in comparison to curcumin. The Knoevenagel condensate, a methoxy-benzylidene derivative of curcumin, also exhibited significant binding to G-quadruplex DNA, although with two times decreased affinity. Our study establishes the potential of curcumin as a promising natural product for G-quadruplex specific ligands.