Cheminformatics-Guided Exploration of Synthetic Marine Natural Product-Inspired Brominated Indole-3-Glyoxylamides and Their Potentials for Drug Discovery.

Marine natural products (MNPs) continue to be tested primarily in cellular toxicity assays, both mammalian and microbial, despite most being inactive at concentrations relevant to drug discovery. These MNPs become missed opportunities and represent a wasteful use of precious bioresources. The use of cheminformatics aligned with published bioactivity data can provide insights to direct the choice of bioassays for the evaluation of new MNPs.

Synthesis and Cheminformatics-Directed Antibacterial Evaluation of Echinosulfonic Acid-Inspired Bis-Indole Alkaloids.

Synthetic efforts toward complex natural product (NP) scaffolds are useful ones, particularly those aimed at expanding their bioactive chemical space. Here, we utilised an orthogonal cheminformatics-based approach to predict the potential biological activities for a series of synthetic bis-indole alkaloids inspired by elusive sponge-derived NPs, echinosulfone A () and echinosulfonic acids A-D (-). Our work includes the first synthesis of desulfato-echinosulfonic acid C, an α-hydroxy bis(3'-indolyl) alkaloid (), and its full NMR characterisation.

Semisynthesis and Cytotoxic Evaluation of an Ether Analogue Library Based on a Polyhalogenated Diphenyl Ether Scaffold Isolated from a Sponge.

The known oxygenated polyhalogenated diphenyl ether, 2-(2',4'-dibromophenoxy)-3,5-dibromophenol (), with previously reported activity in multiple cytotoxicity assays was isolated from the sponge sp. and proved to be an amenable scaffold for semisynthetic library generation. The phenol group of was targeted to generate 12 ether analogues in low-to-excellent yields, and the new library was fully characterized by NMR, UV, and MS analyses.

α-Synuclein Aggregation Inhibitory Procerolides and Diphenylalkanes from the Ascidian .

The aggregation of the neuronal protein α-synuclein (α-syn) is intrinsically linked to the development and progression of Parkinson's disease (PD). Recently we screened the MeOH extracts from 283 marine invertebrates for α-syn binding activity using an affinity mass spectrometry (MS) binding assay and found that the extract of the ascidian displayed activity. A subsequent bioassay-guided purification led to the isolation of one new α-syn aggregation inhibitory butenolide procerolide E () and one new α-syn aggregation inhibitory diphenylbutyrate methyl procerolate A ().

Facile dione protection to benzo[1,2-:6,5-']dithiophene-4,5-dione (BDTD) in triggering ultraviolet emission - A new member of the emissive 3,3'-bridged dithiophenes.

To date, 3,3'-bridged dithiophenes with bridges developed from the first period elements (either pristine or oxidised) are non emissive. Benzo[1,2-:6,5-']dithiophene-4,5-dione (BDTD) is a typical 3,3' fused-dithiophene with a dione bridge. It is a critical building block for semiconducting materials, and it is non emissive.

Cyclohexanedodecol-Assisted Interfacial Engineering for Robust and High-Performance Zinc Metal Anode.

Aqueous zinc-ion batteries (AZIBs) can be one of the most promising electrochemical energy storage devices for being non-flammable, low-cost, and sustainable. However, the challenges of AZIBs, including dendrite growth, hydrogen evolution, corrosion, and passivation of zinc anode during charging and discharging processes, must be overcome to achieve high cycling performance and stability in practical applications. In this work, we utilize a dual-functional organic additive cyclohexanedodecol (CHD) to firstly establish [Zn(HO)(CHD)] complex ion in an aqueous Zn electrolyte and secondly build a robust protection layer on the Zn surface to overcome these dilemmas.

α-Synuclein Aggregation Inhibitory Prunolides and a Dibrominated β-Carboline Sulfamate from the Ascidian .

Seven new polyaromatic bis-spiroketal-containing butenolides, the prunolides D-I (-) and -prunolide C (), a new dibrominated β-carboline sulfamate named pityriacitrin C (), alongside the known prunolides A-C (-) were isolated from the Australian colonial ascidian . The prunolides D-G (-) represent the first asymmetrically brominated prunolides, while -prunolide C () is the first reported with a -configuration about the prunolide's bis-spiroketal core. The prunolides displayed binding activities with the Parkinson's disease-implicated amyloid protein α-synuclein in a mass spectrometry binding assay, while the prunolides (- and ) were found to significantly inhibit the aggregation (>89.

Highly Conductive Two-Dimensional Metal-Organic Frameworks for Resilient Lithium Storage with Superb Rate Capability.

Redox-active organic cathode materials have drawn growing attention because of the broad availability of raw materials, eco-friendliness, scalable production, and diverse structural flexibility. However, organic materials commonly suffer from fragile stability in organic solvents, poor electrochemical stability in charge/discharge processes, and insufficient electrical conductivity. To address these issues, using Cu(II) salt and benzenehexathiolate (BHT) as the precursors, we synthesized a robust and redox-active 2D metal-organic framework (MOF), [Cu(CS)], namely, Cu-BHT.

Structure Revisions of the Sponge-Derived Dibrominated Bis-indole Alkaloids, Echinosulfone A and the Echinosulfonic Acids A to D.

The structures of the sponge-derived dibrominated bis-indole alkaloids, namely, echinosulfone A () and the echinosulfonic acids A to D (-), have been revised based upon reanalysis of their NMR spectroscopic and MS spectrometric data, comparison of this data with those reported for structurally related compounds, and based on their common biogenesis. The reinterpreted spectroscopic evidence has been corroborated by the total synthesis of the revised structure of echinosulfone A (). This was achieved by bis-carbonylation at C-3 of the magnesium salt of 6-bromoindole with triphosgene to afford the new dibrominated bis-indole ketone, bis(6-bromo-1-indol-3-yl)methanone (), followed by N-sulfonation of one indole moiety to furnish 6-bromo-3-(6-bromo-1-indole-3-carbonyl)-1-indole-1-sulfonate ().

Synthesis of Butenolides via a Horner-Wadsworth-Emmons Cascading Dimerization Reaction.

The efficient synthesis of a range of structurally related butenolides has been observed while we were exploring the substrate-scope of a Horner-Wadsworth-Emmons (HWE) reaction. While aliphatic aldehydes gave the expected HWE product, aromatic aldehydes furnished butenolides, resulting from the dimerization of the HWE product during desilylation of the initially formed HWE adduct. In addition to isolating butenolides in a high yield, we have also determined precisely when dimerization occurs.

Carbohydrate-based nanocarriers and their application to target macrophages and deliver antimicrobial agents.

Many deadly infections are produced by microorganisms capable of sustained survival in macrophages. This reduces exposure to chemadrotherapy, prevents immune detection, and is akin to criminals hiding in police stations. Therefore, the use of glyco-nanoparticles (GNPs) as carriers of therapeutic agents is a burgeoning field.

Facile amidinations of 2-aminophenylboronic acid promoted by boronate ester formation.

Amidine synthesis by amine addition to nitriles normally requires high temperatures or harsh catalysts. Here, we report that boronate esters can facilitate amidination of proximal amines with moderate heating. With amidines present in a number of drugs and the synthetic handle provided by the boron, this chemistry should find useful applications.

A new approach to the synthesis of legionaminic acid analogues.

Legionaminic acid is a member of the nonulosonic acids, which are a class of sugars considered to be a virulence factor within a wide variety of pathogenic bacteria. We have developed a synthetic pathway towards C-7 analogues of legionaminic acid starting from Neu5Ac, resulting in the complete synthesis of both legionaminic acid, and its C-7 epimer, from a common precurser. Our approach involves the late-stage introduction of the requisite C-7 nitrogen functionality, thus making our strategy amenable to the introduction of a range of different amide groups at C-7 of legionaminic acid.

Peptides, Peptidomimetics, and Carbohydrate-Peptide Conjugates as Amyloidogenic Aggregation Inhibitors for Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder accounting for 60-80% of dementia cases. For many years, AD causality was attributed to amyloid-β (Aβ) aggregated species. Recently, multiple therapies that target Aβ aggregation have failed in clinical trials, since Aβ aggregation is found in AD and healthy patients.

A Simple Glycolipid Mimic of the Phosphatidylinositol Mannoside Core from Mycobacterium tuberculosis Inhibits Macrophage Cytokine Production.

Glycolipids from Mycobacterium tuberculosis have a profound impact on the innate immune response of the host. Macrophage-inducible C-type lectin (Mincle) is a pattern-recognition receptor that has been shown to bind trehalose dimycolate (TDM) from the mycobacterium and instigate intracellular signalling in the immune cell. There are structural similarities between the structures of TDM and phosphatidyl inositol mannoside (PIM).

Back to (non-)Basics: An Update on Neutral and Charge-Balanced Glycosidase Inhibitors.

Glycosidases have important anti-cancer, anti-viral and anti-diabetic properties. This review covers the literature in the past 15 years since our initial review in this journal on "neutral" glycosidase inhibitors lacking a basic nitrogen found in iminosugars and azasugars or inhibitors that are neutral by virtue of being "charge-balanced" (zwitterionic). These structurally diverse inhibitors include lactones, lactams, epoxides such as cyclophellitol, and sulfonium ion derivatives of the natural product salacinol.

Cellular Effects of Pyocyanin, a Secreted Virulence Factor of Pseudomonas aeruginosa.

Pyocyanin has recently emerged as an important virulence factor produced by Pseudomonas aeruginosa. The redox-active tricyclic zwitterion has been shown to have a number of potential effects on various organ systems in vitro, including the respiratory, cardiovascular, urological, and central nervous systems. It has been shown that a large number of the effects to these systems are via the formation of reactive oxygen species.

Total Synthesis of Native 5,7-Diacetylpseudaminic Acid from N-Acetylneuraminic Acid.

The pseudaminic acids are a family of 5,7-diamino-3,5,7,9-tetradeoxynonulosonic acids that are functional components of flagellin and pili proteins within clinically relevant Gram-negative bacteria. Herein, we describe the total synthesis of the most common pseudaminic acid, 5,7-diacetylpseudaminic acid, from N-acetylneuraminic acid. The divergent nature of the route reported here provides a robust and versatile means to access other members of the family, together with analogues, for probing the functional role of the pseudaminic acids and pseudaminic acid derived proteins in the future.

A review of the bioactivity of coffee, caffeine and key coffee constituents on inflammatory responses linked to depression.

Coffee is a widely consumed beverage containing numerous biologically active constituents predominantly belonging to the polyphenol and alkaloid classes. It has been established that coffee has a beneficial effect on numerous disease states including depression. A number of prospective and retrospective cohort studies have assessed the effects of coffee consumption on the relative risk of developing major depressive disorder in humans.

Multifunctional SA-PProDOT Binder for Lithium Ion Batteries.

An environmentally benign, highly conductive, and mechanically strong binder system can overcome the dilemma of low conductivity and insufficient mechanical stability of the electrodes to achieve high performance lithium ion batteries (LIBs) at a low cost and in a sustainable way. In this work, the naturally occurring binder sodium alginate (SA) is functionalized with 3,4-propylenedioxythiophene-2,5-dicarboxylic acid (ProDOT) via a one-step esterification reaction in a cyclohexane/dodecyl benzenesulfonic acid (DBSA)/water microemulsion system, resulting in a multifunctional polymer binder, that is, SA-PProDOT. With the synergetic effects of the functional groups (e.

A new approach towards the synthesis of pseudaminic acid analogues.

The pseudaminic acids are a family of 5,7-diamino-3,5,7,9-tetradeoxynonulosonic acids that are essential components of bacterial polysaccharides and glycoproteins. This paper describes our approach towards the synthesis of analogues of pseudaminic acid, and involves the efficient introduction of the requisite nitrogen functionalities from a readily available precursor.

Pyocyanin-induced toxicity in A549 respiratory cells is causally linked to oxidative stress.

Pyocyanin, a virulence factor produced by Pseudomonas aeruginosa, has many damaging effects on mammalian cells. Several lines of evidence suggest that this damage is primarily mediated by its ability to generate ROS and deplete host antioxidant defence mechanisms. However, a causal role for oxidative stress has not yet been demonstrated conclusively.

Synthesis of simple heparanase substrates.

Heparanase degrades heparan sulfate (HS) chains on proteoglycans; elevated levels of heparanase expression correlate with tumour cell metastatic potential and vascularity, and reduced post-operative survival of cancer patients. Consequently, heparanase expression is considered a biomarker for cancer detection. Although several heparanase assays have been developed, most require the preparation of heterogeneous, (radio)labelled HS substrates and rely on the separation of enzymatically-degraded products on the basis of molecular size.

The Aspergillus fumigatus sialidase is a 3-deoxy-D-glycero-D-galacto-2-nonulosonic acid hydrolase (KDNase): structural and mechanistic insights.

Aspergillus fumigatus is a filamentous fungus that can cause severe respiratory disease in immunocompromised individuals. A putative sialidase from A. fumigatus was recently cloned and shown to be relatively poor in cleaving N-acetylneuraminic acid (Neu5Ac) in comparison with bacterial sialidases.