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

The known oxygenated polyhalogenated diphenyl ether, 2-(2',4'-dibromophenoxy)-3,5-dibromophenol (1), with previously reported activity in multiple cytotoxicity assays was isolated from the sponge Lamellodysidea sp. and proved to be an amenable scaffold for semisynthetic library generation. The phenol group of 1 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. The chemical structures for 2, 8, and 9 were additionally determined via single-crystal X-ray diffraction analysis. All natural and semisynthetic compounds were evaluated for their ability to inhibit the growth of DU145, LNCaP, MCF-7, and MDA-MB-231 cancer cell lines. Compound 3 was shown to have near-equivalent activity compared to scaffold 1 in two in vitro assays, and the activity of the compounds with an additional benzyl ring appeared to be reliant on the presence and position of additional halogens.

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 (1) and echinosulfonic acids A-D (2-5). Our work includes the first synthesis of desulfato-echinosulfonic acid C, an α-hydroxy bis(3'-indolyl) alkaloid (17), and its full NMR characterisation. This synthesis provides corroborating evidence for the structure revision of echinosulfonic acids A-C. Additionally, we demonstrate a robust synthetic strategy toward a diverse range of α-methine bis(3'-indolyl) acids and acetates (11-16) without the need for silica-based purification in either one or two steps. By integrating our synthetic library of bis-indoles with bioactivity data for 2048 marine indole alkaloids (reported up to the end of 2021), we analyzed their overlap with marine natural product chemical diversity. Notably, the C-6 dibrominated α-hydroxy bis(3'-indolyl) and α-methine bis(3'-indolyl) analogues (11, 14, and 17) were found to contain significant overlap with antibacterial C-6 dibrominated marine bis-indoles, guiding our biological evaluation. Validating the results of our cheminformatics analyses, the dibrominated α-methine bis(3'-indolyl) alkaloids (11, 12, 14, and 15) were found to exhibit antibacterial activities against methicillin-sensitive and -resistant Staphylococcus aureus. Further, while investigating other synthetic approaches toward bis-indole alkaloids, 16 incorrectly assigned synthetic α-hydroxy bis(3'-indolyl) alkaloids were identified. After careful analysis of their reported NMR data, and comparison with those obtained for the synthetic bis-indoles reported herein, all of the structures have been revised to α-methine bis(3'-indolyl) alkaloids.

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

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 Polycarpa procera displayed activity. A subsequent bioassay-guided purification led to the isolation of one new α-syn aggregation inhibitory butenolide procerolide E (3) and one new α-syn aggregation inhibitory diphenylbutyrate methyl procerolate A (5). Herein we report the structure elucidation of procerolide E (3) and methylprocerolate A (5) and α-syn aggregation inhibitory activity of procerolides C-E (1-3), methyl procerolate A (5) and procerone A (4). We also report the α-syn binding activity of 3-bromo-4-methoxyphenylacetamide (6) and a synthetic butenolide library, which has allowed us to determine α-syn aggregation inhibitory structure-activity relationships for this class of compounds.

α-Synuclein Aggregation Inhibitory Prunolides and a Dibrominated ß-Carboline Sulfamate from the Ascidian Synoicum prunum.

Seven new polyaromatic bis-spiroketal-containing butenolides, the prunolides D-I (4-9) and cis-prunolide C (10), a new dibrominated ß-carboline sulfamate named pityriacitrin C (11), alongside the known prunolides A-C (1-3) were isolated from the Australian colonial ascidian Synoicum prunum. The prunolides D-G (4-7) represent the first asymmetrically brominated prunolides, while cis-prunolide C (10) is the first reported with a cis-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 (1-5 and 10) were found to significantly inhibit the aggregation (>89.0%) of α-synuclein in a ThT amyloid dye assay. The prunolides A-C (1-3) were also tested for inhibition of pSyn aggregate formation in a primary embryonic mouse midbrain dopamine neuron model with prunolide B (2) displaying statistically significant inhibitory activity at 0.5 µM. The antiplasmodial and antibacterial activities of the isolates were also examined with prunolide C (3) displaying only weak activity against the 3D7 parasite strain of Plasmodium falciparum. Our findings reported herein suggest that the prunolides could provide a novel scaffold for the exploration of future therapeutics aimed at inhibiting amyloid protein aggregation and the treatment of numerous neurodegenerative diseases.

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 (2) and the echinosulfonic acids A to D (9-12), 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 (2). 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-1H-indol-3-yl)methanone (3), followed by N-sulfonation of one indole moiety to furnish 6-bromo-3-(6-bromo-1H-indole-3-carbonyl)-1H-indole-1-sulfonate (2). The five marine alkaloids corrected herein each contain an indole sulfamate and are all carbon-bridged dibrominated bis-indoles: echinosulfone A (2) is a di(1H-indol-3-yl)methanone, while the echinosulfonic acids A to D (9-12) are methyl 2,2-bis(1H-indol-3-yl) acetates.

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.

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 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). We thus hypothesized that these latter structures might also modulate an immune response in a similar manner. To test this, we synthesized a series of new mannose derivatives modified with fatty esters at the 6-position and assessed the release of inflammatory cytokines in human U937 macrophages under the induction of lipopolysaccharides (LPS) after glycolipid treatment. The results showed that the amount of two major cytokines-tumour necrosis factor (TNF)-α and interleukin (IL)-6-released from LPS-stimulated U937 cells decreased significantly when compared to a control upon treatment with the prepared glycolipids, thus indicating a reduction in cytokine production by the macrophages.

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.

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.g., carboxyl, hydroxyl, and ester groups), the resultant SA-PProDOT polymer not only maintains the outstanding binding capabilities of sodium alginate but also enhances the mechanical integrity and lithium ion diffusion coefficient in the LiFePO4 (LFP) electrode during the operation of the batteries. Because of the conjugated network of the PProDOT and the lithium doping under the battery environment, the SA-PProDOT becomes conductive and matches the conductivity needed for LiFePO4 LIBs. Without the need of conductive additives such as carbon black, the resultant batteries have achieved the theoretical specific capacity of LiFePO4 cathode (ca. 170 mAh/g) at C/10 and ca. 120 mAh/g at 1C for more than 400 cycles.

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.

Facile dione protection to benzo[1,2-b:6,5-b']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-b:6,5-b']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. We serendipitously discovered that by protecting the diketone of BDTD with ethylene glycol, two isomers (BDTD-5 and 6) were obtained and both compounds effectively emit UV light in solution. Their maximum emission (382 and 375 nm for BDTD-5 and 6, respectively) are independent of the type of solvent. Both compounds exhibited fluorescence intensity enhancement in DMF-H2O with the increase of water fraction from 0-90%. BDTD-6 can also effectively emit in its crystalline state with a quantum yield (QY) of 14% and an average fluorescence lifetime of 1.6 ns. X-ray crystallographic analysis indicates that BDTD-6 possesses a 3D C-H…O interaction structure which produced its effective emission in the crystalline state. These two isomers not only have enlarged the emissive members of the 3,3'-fused dithiophene family, but also expand the emission boundary of emitters in this category to the UV area.

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. Here we present the first crystal structure of a fungal sialidase. When the apo structure was compared with bacterial sialidase structures, the active site of the Aspergillus enzyme suggested that Neu5Ac would be a poor substrate because of a smaller pocket that normally accommodates the acetamido group of Neu5Ac in sialidases. A sialic acid with a hydroxyl in place of an acetamido group is 2-keto-3-deoxynononic acid (KDN). We show that KDN is the preferred substrate for the A. fumigatus sialidase and that A. fumigatus can utilize KDN as a sole carbon source. A 1.45-Å resolution crystal structure of the enzyme in complex with KDN reveals KDN in the active site in a boat conformation and nearby a second binding site occupied by KDN in a chair conformation, suggesting that polyKDN may be a natural substrate. The enzyme is not inhibited by the sialidase transition state analog 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (Neu5Ac2en) but is inhibited by the related 2,3-didehydro-2,3-dideoxy-D-glycero-D-galacto-nonulosonic acid that we show bound to the enzyme in a 1.84-Å resolution crystal structure. Using a fluorinated KDN substrate, we present a 1.5-Å resolution structure of a covalently bound catalytic intermediate. The A. fumigatus sialidase is therefore a KDNase with a similar catalytic mechanism to Neu5Ac exosialidases, and this study represents the first structure of a KDNase.

Recent results from non-basic glycosidase inhibitors: How structural diversity can inform general strategies for improving inhibition potency.

This review covers the literature in the past 15 years on glycosidase inhibitors lacking a basic nitrogen (for example iminosugars/azasugars) with a focus on natural terpenoids, and mono- and polycyclic aromatic hydrocarbons. From quite diverse structures, insight into inhibitor structural features that may be applicable to optimisation of all glycosidase inhibitors including iminosugars are identified.

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(H2O)5(CHD)]2+ complex ion in an aqueous Zn electrolyte and secondly build a robust protection layer on the Zn surface to overcome these dilemmas. Systematic experiments and theoretical calculations are carried out to interpret the working mechanism of CHD. At a very low concentration of 0.1 mg mL-1 CHD, long-term reversible Zn plating/stripping could be achieved up to 2200 h at 2 mA cm-2, 1000 h at 5 mA cm-2, and 650 h at 10 mA cm-2 at the fixed capacity of 1 mAh cm-2. When matched with V2O5 cathode, the resultant AZIBs full cell with the CHD-modified electrolyte presents a high capacity of 175 mAh g-1 with the capacity retention of 92% after 2000 cycles under 2 A g-1. Such a performance could enable the commercialization of AZIBs for applications in grid energy storage and industrial energy storage.

Three Streptococcus pneumoniae sialidases: three different products.

Streptococcus penumoniae is a major human pathogen responsible for respiratory tract infections, septicemia, and meningitis and continues to produce numerous cases of disease with relatively high mortalities. S. pneumoniae encodes up to three sialidases, NanA, NanB, and NanC, that have been implicated in pathogenesis and are potential drug targets. NanA has been shown to be a promiscuous sialidase, hydrolyzing the removal of Neu5Ac from a variety of glycoconjugates with retention of configuration at the anomeric center, as we confirm by NMR. NanB is an intramolecular trans-sialidase producing 2,7-anhydro-Neu5Ac selectively from α2,3-sialosides. Here, we show that the first product of NanC is 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (Neu5Ac2en) that can be slowly hydrated by the enzyme to Neu5Ac. We propose that the three pneumococcal sialidases share a common catalytic mechanism up to the final product formation step, and speculate on the roles of the enzymes in the lifecycle of the bacterium.

Sialic acid dependence in rotavirus host cell invasion.

We used NMR spectroscopy, molecular modeling and infectivity competition assays to investigate the key interactions between the spike protein (VP8(*)) from 'sialidase-insensitive' human Wa and 'sialidase-sensitive' porcine CRW-8 rotaviruses and the glycans of gangliosides G(M1) and G(D1a). Our data provide strong evidence that N-acetylneuraminic acid is a key determinant for binding of these rotaviruses. This is in contrast to the widely accepted paradigm that sialic acids are irrelevant in host cell recognition by sialidase-insensitive rotaviruses.

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. In studies directed towards the development of a more direct heparanase assay, a series of glucuronides and glycosyl glucuronides were synthesised as putative heparanase substrates. These compounds were designed with various aryl aglycones that could be measured spectrophotometrically upon hydrolysis of the glycosidic linkage by heparanase. It was found that the N-sulfated 4-nitrophenyl glycosyl glucuronide 24 and the N-sulfated methylumbelliferyl glycosyl glucuronide 26 were hydrolysed by recombinant human heparanase. These compounds represent the simplest substrates of heparanase reported to date.

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), [Cu3(C6S6)]n, namely, Cu-BHT. The Cu-BHT MOFs have a highly conjugated structure, affording a high electronic conductivity of 231 S cm-1, which could further be increased upon lithiation in lithium-ion battery (LIB) applications. A reversible four-electron reaction reveals the Li storage mechanism of the Cu-BHT for a theoretical capacity of 236 mAh g-1. The as-prepared Cu-BHT cathode delivers an excellent reversible capacity of 175 mAh g-1 with ultralow capacity deterioration (0.048% per cycle) upon 500 cycles at a high current density of 300 mA g-1. Therefore, we believe this work would provide a practical strategy for the development of high-power energy storage materials.

Boronolectin with divergent fluorescent response specific for free sialic acid.

A fluorescent boronate receptor with a unique response to free sialic acid has been developed; this divergent response system may find use in design of other fluorophores to discriminate between structurally similar analytes.