Radical Cascade Cyclization of Unactivated Alkene-Tethered Indoles with Aryldiazonium Salt and Sodium Metabisulfite to Access Azo- and Sulfonylated-2,3-Dihyro-1H-pyrrolo[1,2-a]indoles.

A method for the construction of heterocyclic scaffold 2,3-dihyro-1H-pyrrolo[1,2-a]indoles via arylsulfonyl radical-triggered cascade cyclization of unactivated alkene-tethered indoles in the absence of any external photocatalyst has been developed. This protocol features easily accessible starting materials such as sodium metabisulfite and aryldiazonium tetrafluoroborates at room temperature and offers good functional group compatibility, enabling the introduction of various functionalized sulfonyl and azo groups into pyrrolo[1,2-a]indoles.

Functional cooperation of α-synuclein and VAMP2 in synaptic vesicle recycling.

The function of α-synuclein (α-syn) has been long debated, and two seemingly divergent views have emerged. In one, α-syn binds to VAMP2, acting as a SNARE chaperone-but with no effect on neurotransmission-while another posits that α-syn attenuates neurotransmitter release by restricting synaptic vesicle mobilization and recycling. Here, we show that α-syn-VAMP2 interactions are necessary for α-syn-induced synaptic attenuation. Our data connect divergent views and suggest a unified model of α-syn function.

α-Angelica lactone catalyzed oxidation of benzylic sp3 C-H bonds of isochromans and phthalans.

A metal-free organocatalytic system has been developed for highly efficient benzylic C-H oxygenations of cyclic ethers using oxygen as an oxidant. This oxidation reaction utilizes α-angelica lactone as a low cost/low molecular weight catalyst. The optimized reaction conditions allow the synthesis of valued isocoumarins and phthalides from readily available precursors in good yields. Mechanistic studies indicate that the reaction pathway likely involves a radical process via a peroxide intermediate.

Amyloid-ß Peptide Is Needed for cGMP-Induced Long-Term Potentiation and Memory.

High levels of amyloid-ß peptide (Aß) have been related to Alzheimer's disease pathogenesis. However, in the healthy brain, low physiologically relevant concentrations of Aß are necessary for long-term potentiation (LTP) and memory. Because cGMP plays a key role in these processes, here we investigated whether the cyclic nucleotide cGMP influences Aß levels and function during LTP and memory. We demonstrate that the increase of cGMP levels by the phosphodiesterase-5 inhibitors sildenafil and vardenafil induces a parallel release of Aß due to a change in the approximation of amyloid precursor protein (APP) and the ß-site APP cleaving enzyme 1. Moreover, electrophysiological and behavioral studies performed on animals of both sexes showed that blocking Aß function, by using anti-murine Aß antibodies or APP knock-out mice, prevents the cGMP-dependent enhancement of LTP and memory. Our data suggest that cGMP positively regulates Aß levels in the healthy brain which, in turn, boosts synaptic plasticity and memory.SIGNIFICANCE STATEMENT Amyloid-ß (Aß) is a key pathogenetic factor in Alzheimer's disease. However, low concentrations of endogenous Aß, mimicking levels of the peptide in the healthy brain, enhance hippocampal long-term potentiation (LTP) and memory. Because the second messenger cGMP exerts a central role in LTP mechanisms, here we studied whether cGMP affects Aß levels and function during LTP. We show that cGMP enhances Aß production by increasing the APP/BACE-1 convergence in endolysosomal compartments. Moreover, the cGMP-induced enhancement of LTP and memory was disrupted by blockade of Aß, suggesting that the physiological effect of the cyclic nucleotide on LTP and memory is dependent upon Aß.

The perceptions, health-seeking behaviours and access of Scheduled Caste women to maternal health services in Bihar, India.

The caste system is a complex social stratification system which has been abolished, but remains deeply ingrained in India. Scheduled Caste (SC) women are one of the historically deprived groups, as reflected in poor maternal health outcomes and low utilisation of maternal healthcare services. Key government schemes introduced in 2005 mean healthcare-associated costs should now be far less of a deterrent. This paper examines the factors contributing to this low use of maternal health services by investigating the perceptions, health-seeking behaviours and access of SC women to maternal healthcare services in Bihar, India. Eighteen in-depth, semi-structured interviews were conducted with SC women in Bihar. Data were analysed using Framework Analysis and presented using the AAAQ Toolbox. Main facilitating factors included the introduction of accredited social health activists (ASHAs), free maternal health services, the Janani Shishu Suraksha Karyakram (JSSK), and changes in the cultural acceptability of institutional delivery. Main barriers included inadequate ASHA coverage, poor information access, transport costs and unauthorised charges to SC women from healthcare staff. SC women in Bihar may be inequitably served by maternal health services, and in some cases may face specific discrimination. Recommendations to improve SC service utilisation include research into the improvement of postnatal care, reducing unauthorised payments to healthcare staff and improvements to the ASHA programme.

Expanding the Scope of Primary Amine Catalysis: Stereoselective Synthesis of Indanedione-Fused 2,6-Disubstituted trans-Spirocyclohexanones.

A cinchona-alkaloid-derived chiral primary-amine-catalyzed enantioselective method for the synthesis of the thermodynamically less stable indanedione-fused 2,6-trans-disubstituted spirocyclohexanones is demonstrated. Both the enantiomeric forms of the trans isomer are obtained in excellent yields and enantioselectivities. Furthermore, one of the enantiopure trans-spiranes bearing an additional α-substitution on the cyclohexanone ring was then epimerized into its thermodynamically stable cis counterpart, with little loss of enantioselectivity to demonstrate the feasibility of such a transformation. Mechanistic investigations revealed two competing pathways, a concerted Diels-Alder reaction and a stepwise Michael addition, for the formation of corresponding products.

Organocatalytic enantioselective direct vinylogous Michael addition of α,ß-unsaturated γ-butyrolactam to ß-acyl acrylates and 1,2-diacylethylenes.

A highly efficient Michael addition of α,ß-unsaturated γ-butyrolactam to various ß-acyl acrylates and ene-diones to provide synthetically useful compounds was developed. The products were obtained with high diastereo- and enantioselectivities (up to >25:1 dr and 99% ee) containing adjacent tertiary stereocenters.

Early and selective impairments in axonal transport kinetics of synaptic cargoes induced by soluble amyloid ß-protein oligomers.

The downstream targets of amyloid ß (Aß)-oligomers remain elusive. One hypothesis is that Aß-oligomers interrupt axonal transport. Although previous studies have demonstrated Aß-induced transport blockade, early effects of low-n soluble Aß-oligomers on axonal transport remain unclear. Furthermore, the cargo selectivity for such deficits (if any) or the specific effects of Aß on the motility kinetics of transported cargoes are also unknown. Toward this, we visualized axonal transport of vesicles in cultured hippocampal neurons treated with picomolar (pm) levels of cell-derived soluble Aß-oligomers. We examined select cargoes thought to move as distinct organelles and established imaging parameters that allow organelle tracking with consistency and high fidelity - analyzing all data in a blinded fashion. Aß-oligomers induced early and selective diminutions in velocities of synaptic cargoes but had no effect on mitochondrial motility, contrary to previous reports. These changes were N-methyl D-aspartate receptor/glycogen synthase kinase-3ß dependent and reversible upon washout of the oligomers. Cluster-mode analyses reveal selective attenuations in faster-moving synaptic vesicles, suggesting possible decreases in cargo/motor associations, and biochemical experiments implicate tau phosphorylation in the process. Collectively, the data provide a biological basis for Aß-induced axonal transport deficits.

Fast vesicle transport is required for the slow axonal transport of synapsin.

Although it is known that cytosolic/soluble proteins synthesized in cell bodies are transported at much lower overall velocities than vesicles in fast axonal transport, the fundamental basis for this slow movement is unknown. Recently, we found that cytosolic proteins in axons of mouse cultured neurons are conveyed in a manner that superficially resembles diffusion, but with a slow anterograde bias that is energy- and motor-dependent (Scott et al., 2011). Here we show that slow axonal transport of synapsin, a prototypical member of this rate class, is dependent upon fast vesicle transport. Despite the distinct overall dynamics of slow and fast transport, experimentally induced and intrinsic variations in vesicle transport have analogous effects on slow transport of synapsin as well. Dynamic cotransport of vesicles and synapsin particles is also seen in axons, consistent with a model where higher-order assemblies of synapsin are conveyed by transient and probabilistic associations with vesicles moving in fast axonal transport. We posit that such dynamic associations generate the slow overall anterogradely biased flow of the population ("dynamic-recruitment model"). Our studies uncover the underlying kinetic basis for a classic cytosolic/soluble protein moving in slow axonal transport and reveal previously unknown links between slow and fast transport, offering a clearer conceptual picture of this curious phenomenon.

Chemoselective intramolecular Wittig reactions for the synthesis of oxazoles and benzofurans.

A chemoselective approach was developed for the synthesis of highly functionalized oxazoles and benzofurans using an intramolecular Wittig reaction as the key step. By choosing proper trapping reagent or method of addition of reagents, chemoselectivity can be controlled toward either oxazole or benzofuran derivatives.

Preparation of functionalized heteroaromatics using an intramolecular Wittig reaction.

The development of efficient methods for the synthesis of heteroaromatic compounds is always of great importance for chemists. In this 'Perspective', we describe a general approach for the synthesis of functionalized heteroaromatics via intramolecular Wittig reactions. In all cases, the reaction proceeds via in situ generated phosphorus ylides. We especially emphasize the importance of chemoselective intramolecular Wittig reactions using designed Michael acceptors and suitable acyl chloride as trapping reagents, which allows formation of two different classes of heteroaromatics from the same substrates. This metal-free approach is quite general and works in a number of examples, furnishing the corresponding products in moderate to good yields under relatively mild reaction conditions.

Exploring the phototoxicity of GSH-resistant 2-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)quinoline-based Ir(III)-PTA complexes in MDA-MB-231 cancer cells.

Metal complexes play a crucial role in photo-activated chemotherapy (PACT), which has recently been used to treat specific disorders. Triple-negative breast cancer has an enormously high rate of relapse due to the existence and survival of cancer stem cells (CSCs) characterized by increased amounts of glutathione (GSH). Hence, designing a phototoxic molecule is an enticing area of research to combat triple-negative breast cancer (TNBC) via GSH depletion and DNA photocleavage. Herein, we focus on the application of PTA and non-PTA Ir(III) complexes for phototoxicity in the absence and presence of GSH against MDA-MB-231 TNBC cells. Between these two complexes, [Cp*IrIII(DD)PTA]·2Cl (DDIRP) exhibited better phototoxicity (IC50 ∼ 2.80 ± 0.52 µM) compared to the non-PTA complex [Cp*IrIII(DD)Cl]·Cl (DDIR) against TNBC cells because of the high GSH resistance power of the complex DDIRP. The significant potency of the complex DDIRP under photo irradiation in both normoxia and hypoxia conditions can be attributed to selective transportation, high cellular permeability and uptake towards the nucleus, GSH depletion by GSH-GSSG conversion, the ability of strong DNA binding including intercalation, and oxidative stress. The strong affinity to serum albumin, which serves as a carrier protein, aids in the transport of the complex to its target site while preventing glutathione (GSH) deactivation. Consequently, the complex DDIRP was developed as a suitable phototoxic complex in selective cancer therapy, ruling over the usual chemotherapeutic drug cisplatin and the PDT drug Photofrin. The ability of ROS generation under hypoxic conditions delivers this complex as a hypoxia-efficient selective metallodrug for the treatment of TNBC.

Re(I)[2-aryl-1H-imidazo[4,5-f][1,10]phenanthroline] tricarbonyl chloride complexes for selective cancer therapy via a potential DNA damage mechanism.

Recently, achieving selective cancer therapy with trifling side effects has been a great challenge in the eradication of cancer. Thus, to amplify the cytoselective approach of complexes, herein, we developed a series of Re(I)[2-aryl-1H-imidazo[4,5-f][1,10]phenanthroline] tricarbonyl chloride complexes and screened their potency against HeLa and MCF-7 cell lines together with the evaluation of their toxicity towards a normal kidney cell line (HEK-293). On meticulous investigation, complex [ReI(CO)3Cl(K2-N,N-(2c))] (3c) was found to be the most potent anticancer entity among other complexes. Complex 3c also showed competency to induce apoptosis in MCF-7 cells through G2/M phase cell-cycle arrest in association with the generation of ample reactive oxygen species (ROS), eventually leading to DNA intercalation and internucleosomal cleavage. The order of the cytotoxicity of these complexes depended on their lipophilic character and the electron-withdrawing halogen substitution at the para-position of the phenyl ring in the imidazophenanthroline ligand.

Organocatalytic enantioselective direct vinylogous Michael addition of γ-substituted butenolides to 3-aroyl acrylates and 1,2-diaroylethylenes.

Adding value: The direct vinylogous Michael addition of γ-substituted butenolides with a series of 3-aroyl acrylates and 1,2-diaroylethylenes has been demonstrated. This organocatalytic method delivers highly enantio- and diastereomerically pure γ,γ-disubstituted butenolides with adjacent quaternary and tertiary stereocenters (see scheme).

An efficient organocatalytic enantioselective synthesis of spironitrocyclopropanes.

An organocatalytic asymmetric synthesis of spironitrocyclopropanes has been demonstrated starting from 2-arylidene-1,3-indandiones and bromonitroalkanes catalyzed by a cinchona-derived bifunctional organocatalyst. The products were obtained with excellent enantioselectivities, diastereoselectivities and with good yields.

Domain organization and function in GluK2 subtype kainate receptors.

Glutamate receptor ion channels (iGluRs) are excitatory neurotransmitter receptors with a unique molecular architecture in which the extracellular domains assemble as a dimer of dimers. The structure of individual dimer assemblies has been established previously for both the isolated ligand-binding domain (LBD) and more recently for the larger amino terminal domain (ATD). How these dimers pack to form tetrameric assemblies in intact iGluRs has remained controversial. Using recently solved crystal structures for the GluK2 kainate receptor ATD as a guide, we performed cysteine mutant cross-linking experiments in full-length tetrameric GluK2 to establish how the ATD packs in a dimer of dimers assembly. A similar approach, using a full-length AMPA receptor GluA2 crystal structure as a guide, was used to design cysteine mutant cross-links for the GluK2 LBD dimer of dimers assembly. The formation of cross-linked tetramers in full-length GluK2 by combinations of ATD and LBD mutants which individually produce only cross-linked dimers suggests that subunits in the ATD and LBD layers swap dimer partners. Functional studies reveal that cross-linking either the ATD or the LBD inhibits activation of GluK2 and that, in the LBD, cross-links within and between dimers have different effects. These results establish that kainate and AMPA receptors have a conserved extracellular architecture and provide insight into the role of individual dimer assemblies in activation of ion channel gating.

Synthesis, characterization, photophysical and electrochemical properties, and biomolecular interaction of 2,2'-biquinoline based phototoxic Ru(II)/Ir(II) complexes.

The phototoxic nature of drugs has been seen to convey immense importance in photo activated chemotherapy (PACT) for the selective treatment of disease. Rationally, in order to eradicate the vehemence of cancer in a living body, the design of phototoxic molecules has been of growing interest in research to establish a selective strategy for cancer therapy. Therefore, the present work portrays the synthesis of a phototoxic anticancer agent by incorporating ruthenium(II) and iridium(III) metals into a biologically active 2,2'-biquinoline moiety, BQ. The complexes, RuBQ and IrBQ, have been revealed as effective anticancer agents with remarkable toxicity in the presence of light compared to the dark towards HeLa and MCF-7 cancer cell lines due to the production of a profuse amount of singlet oxygen (1O2) upon irradiation by visible light (400-700 nm). Complex IrBQ exhibited the best toxicity (IC50 = 8.75 µM in MCF-7 and 7.23 µM in HeLa) in comparison to the RuBQ complex under visible light. RuBQ and IrBQ displayed considerable quantum yields (Φf) along with a good lipophilic property, indicating the cellular imaging capability of both complexes upon significant accumulation in cancer cells. Also, the complexes have shown significant binding propensity with biomolecules, viz. deoxyribonucleic acid (DNA) as well as serum albumin (BSA, HSA).

Indian jujube a potential fruit tree to improve the livelihood.

Indian Jujube, also known as Ber or Ziziphus Mauritiana Lam., is a fruit-bearing tree endemic to South Asia, including India, Pakistan, Bangladesh, and Sri Lanka. The tree belongs to the buckthorn family and is known for its fruit, a tiny, round, or oblong-shaped drupe roughly the size of a cherry or a small plum. Indian Jujube has been growing for thousands of years. It is a popular fruit throughout the tropical and subtropical regions of Asia, Africa, and South America. Despite the fruit's delicious flavour and health benefits, it is also known for its therapeutic value. Many studies have suggested that various components of ber trees, such as fruit, seed leaves, roots, and flowers, include bioactive substances that demonstrate the potential for antioxidant activity and have anticancer, antibacterial, and antidiabetic effects. Due to the crop's minimal management requirements, it may slow down climate change and the threat of extreme soil and weather conditions, such as drought resistance, strong winds, erosion, high salt, and floods. The main objectives of the current systematic review are to understand Ber's chemical compositions, health benefits, culinary uses, major nutraceutical features, and its function in fostering livelihoods and climatic tolerance.

Optimisation of Mix Proportion of 3D Printable Mortar Based on Rheological Properties and Material Strength Using Factorial Design of Experiment.

In the production of 3D printable mortar (3DPM), numerous efforts have been made globally to effectively utilise various cementitious materials, admixtures, and fibres. The determination of rheological and material strength properties is crucial for successful 3D concrete printing because the materials used in 3DPM must possess the unique characteristic of making mortar flowable while being strong enough to support the weight of subsequent layers in both fresh and hardened states. The complexity of the required characteristics makes it challenging to develop an optimised mix composition that satisfies both the rheological and material strength requirements, given the wide range of available admixtures, supplementary cementitious materials, and fibres. Fly ash, basalt fibre and superplasticiser when blended with cement can help to improve the overall performance of 3DPM. The objective of this research is to optimise the rheological properties and material strength of 3D printable mortars (3DPM) containing cement, fly ash, basalt fibre, and superplasticiser. This study aims to produce 3DPM with an optimised mix composition to meet the requirements of both rheological and material strength characteristics using the factorial design approach and desirability function. Different dosages of cement, fly ash, basalt fibre, and superplasticiser are chosen as the primary design parameters to develop statistical models for the responses of rheological and material strength properties at 7 and 28 days. The results expressed in terms of the measured properties are valid for mortars made with cement ranging from 550 to 650 kg/m3, fly ash from 5% to 20% (of cement), superplasticiser from 2 to 4 kg/m3, and basalt fibre from 1 to 3 kg/m3. The rheological properties are evaluated using slump flow, cone penetrometer, and cylindrical slump tests, while the mechanical strength is evaluated using a three-point bending test and compressive test. A full factorial design experiment (FoE) is used to determine the significant parameters effecting the measured properties. Prediction models are developed to express the measured properties in terms of the primary parameters. The influence of cement, fly ash, basalt fibre, and superplasticiser is analysed using polynomial regression to determine the main effects and interactions of these primary parameters on the measured properties. The results show that the regression models established by the factorial design approach are effective and can accurately predict the performance of 3DPM. Cement, fly ash, and superplasticiser dosages have significant effects on the rheological and mechanical properties of mortar, while basalt fibre is able to influence the static yield stress and flexural strength of 3DPM. The utilisation of regression models and isoresponse curves allows for the identification of significant trends and provides valuable insight into the behaviour of the material, while desirability function is useful to optimise overall performance of mix proportions to meet the desired performance objective at fresh and hardened states.

Luminescent 11-{Naphthalen-1-yl}dipyrido[3,2-a:2',3'-c]phenazine-Based Ru(II)/Ir(III)/Re(I) Complexes for HCT-116 Colorectal Cancer Stem Cell Therapy.

Due to a number of unpleasant considerations, marketed drugs have steadily lost their importance in the treatment of cancer. In order to find a viable cancer cell diagnostic agent, we therefore focused on metal complexes that displayed target adequacy, permeability to cancer cells, high standard water solubility, cytoselectivity, and luminescent behavior. In this aspect, luminescent 11-{naphthalen-1-yl} dipyrido [3,2-a:2',3'-c] phenazine based Ru(II)/Ir(III)/Re(I) complexes have been prepared for HCT-116 colorectal cancer stem cell therapy. Our study successfully established the possible cytotoxicity of IrL complex at different doses on HCT-116 colorectal cancer stem cells (CRCSCs). Additionally, an immunochemistry analysis of the complex IrL showed that the molecule was subcellularly localized in the nucleus and other regions of the cytoplasm, where it caused nuclear DNA damage and mitochondrial dysfunction. The level of BAX and Bcl-2 was further quantified by qRT-PCR. The expression of proapoptotic BAX showed increased expression in the complex IrL-treated cell compared to the control, indicating the potential of complex IrL for apoptotic induction. Upon further validation, complex IrL was developed as an inhibitor of autophagy for the eradication of cancer stem cells.