Acetylated galactopyranosyl N-heterocyclic monocarbene complexes of Silver(I) as novel anti-proliferative agents in a rhabdomyosarcoma cell line.

Herein, four silver(I) complexes bearing acetylated d-galactopyranoside-based N-heterocyclic carbene ligands were synthesized and fully characterized by elemental analysis, NMR, and X-ray photoelectron spectroscopy. All complexes were obtained with an anomeric ß-configuration and as monocarbene species. In this study, we investigated the biological effects of the silver(I) complexes 2a-d on the human rhabdomyosarcoma cell line, RD. Our results show concentration-dependent effects on cell density, growth inhibition, and activation of key signaling pathways such as Akt 1/2, ERK 1/2, and p38-MAPK, indicating their potential as anticancer agents. Notably, at 35.5 µM, the complexes induced mitochondrial network disruption, as observed with 2b and 2c, whereas with 2a, this disruption was accompanied by nuclear content release. These results provide insight into the utility of carbohydrate incorporated NHC complexes of silver(I) as new agents in cancer therapy.

Glycosyl Oxocarbenium Ions: Structure, Conformation, Reactivity, and Interactions.

Carbohydrates (glycans, saccharides, and sugars) are essential molecules in all domains of life. Research on glycoscience spans from chemistry to biomedicine, including material science and biotechnology. Access to pure and well-defined complex glycans using synthetic methods depends on the success of the employed glycosylation reaction. In most cases, the mechanism of the glycosylation reaction is believed to involve the oxocarbenium ion. Understanding the structure, conformation, reactivity, and interactions of this glycosyl cation is essential to predict the outcome of the reaction. In this Account, building on our contributions on this topic, we discuss the theoretical and experimental approaches that have been employed to decipher the key features of glycosyl cations, from their structures to their interactions and reactivity.We also highlight that, from a chemical perspective, the glycosylation reaction can be described as a continuum, from unimolecular SN1 with naked oxocarbenium cations as intermediates to bimolecular SN2-type mechanisms, which involve the key role of counterions and donors. All these factors should be considered and are discussed herein. The importance of dissociative mechanisms (involving contact ion pairs, solvent-separated ion pairs, solvent-equilibrated ion pairs) with bimolecular features in most reactions is also highlighted.The role of theoretical calculations to predict the conformation, dynamics, and reactivity of the oxocarbenium ion is also discussed, highlighting the advances in this field that now allow access to the conformational preferences of a variety of oxocarbenium ions and their reactivities under SN1-like conditions.Specifically, the ground-breaking use of superacids to generate these cations is emphasized, since it has permitted characterization of the structure and conformation of a variety of glycosyl oxocarbenium ions in superacid solution by NMR spectroscopy.We also pay special attention to the reactivity of these glycosyl ions, which depends on the conditions, including the counterions, the possible intra- or intermolecular participation of functional groups that may stabilize the cation and the chemical nature of the acceptor, either weak or strong nucleophile. We discuss recent investigations from different experimental perspectives, which identified the involved ionic intermediates, estimating their lifetimes and reactivities and studying their interactions with other molecules. In this context, we also emphasize the relationship between the chemical methods that can be employed to modulate the sensitivity of glycosyl cations and the way in which glycosyl modifying enzymes (glycosyl hydrolases and transferases) build and cleave glycosidic linkages in nature. This comparison provides inspiration on the use of molecules that regulate the stability and reactivity of glycosyl cations.

Cobalt carbide nanoprisms for direct production of lower olefins from syngas.

Lower olefins-generally referring to ethylene, propylene and butylene-are basic carbon-based building blocks that are widely used in the chemical industry, and are traditionally produced through thermal or catalytic cracking of a range of hydrocarbon feedstocks, such as naphtha, gas oil, condensates and light alkanes. With the rapid depletion of the limited petroleum reserves that serve as the source of these hydrocarbons, there is an urgent need for processes that can produce lower olefins from alternative feedstocks. The 'Fischer-Tropsch to olefins' (FTO) process has long offered a way of producing lower olefins directly from syngas-a mixture of hydrogen and carbon monoxide that is readily derived from coal, biomass and natural gas. But the hydrocarbons obtained with the FTO process typically follow the so-called Anderson-Schulz-Flory distribution, which is characterized by a maximum C2-C4 hydrocarbon fraction of about 56.7 per cent and an undesired methane fraction of about 29.2 per cent (refs 1, 10, 11, 12). Here we show that, under mild reaction conditions, cobalt carbide quadrangular nanoprisms catalyse the FTO conversion of syngas with high selectivity for the production of lower olefins (constituting around 60.8 per cent of the carbon products), while generating little methane (about 5.0 per cent), with the ratio of desired unsaturated hydrocarbons to less valuable saturated hydrocarbons amongst the C2-C4 products being as high as 30. Detailed catalyst characterization during the initial reaction stage and theoretical calculations indicate that preferentially exposed {101} and {020} facets play a pivotal role during syngas conversion, in that they favour olefin production and inhibit methane formation, and thereby render cobalt carbide nanoprisms a promising new catalyst system for directly converting syngas into lower olefins.

In vitro and in silico studies of bis (indol-3-yl) methane derivatives as potential α-glucosidase and α-amylase inhibitors.

In this paper, bis (indol-3-yl) methanes (BIMs) were synthesised and evaluated for their inhibitory activity against α-glucosidase and α-amylase. All synthesised compounds showed potential α-glucosidase and α-amylase inhibitory activities. Compounds 5 g (IC50: 7.54 ± 1.10 µM), 5e (IC50: 9.00 ± 0.97 µM), and 5 h (IC50: 9.57 ± 0.62 µM) presented strongest inhibitory activities against α-glucosidase, that were ∼ 30 times stronger than acarbose. Compounds 5 g (IC50: 32.18 ± 1.66 µM), 5 h (IC50: 31.47 ± 1.42 µM), and 5 s (IC50: 30.91 ± 0.86 µM) showed strongest inhibitory activities towards α-amylase, ∼ 2.5 times stronger than acarbose. The mechanisms and docking simulation of the compounds were also studied. Compounds 5 g and 5 h exhibited bifunctional inhibitory activity against these two enzymes. Furthermore, compounds showed no toxicity against 3T3-L1 cells and HepG2 cells.HighlightsA series of bis (indol-3-yl) methanes (BIMs) were synthesised and evaluated inhibitory activities against α-glucosidase and α-amylase.Compound 5g exhibited promising activity (IC50 = 7.54 ± 1.10 µM) against α-glucosidase.Compound 5s exhibited promising activity (IC50 = 30.91 ± 0.86 µM) against α-amylase.In silico studies were performed to confirm the binding interactions of synthetic compounds with the enzyme active site.

Silver-N-heterocyclic carbene complexes-catalyzed multicomponent reactions: Synthesis, spectroscopic characterization, density functional theory calculations, and antibacterial study.

Nowadays, silver-N-heterocyclic carbene (silver-NHCs) complexes are widely used in medicinal chemistry due to their low toxic nature toward humans. Due to the success of silver-NHCs in medicinal applications, interest in these compounds is rapidly increasing. Therefore, the interaction of N,N-disubstituted benzimidazolium salts with Ag2 O in dichloromethane to prepare novel Ag(I)-NHCs complexes was carried out at room temperature for 120 h in the absence of light. The obtained complexes were identified and characterized by 1 H and 13 C nuclear magnetic resonance, Fourier-transform infrared, UV-Vis, and elemental analysis techniques. Then, the silver complexes were applied for three-component coupling reactions of aldehydes, amines, and alkynes. The effect of changing the alkyl substituent on the NHCs ligand on the catalytic performance was investigated. In addition, it has been found that the complexes are antimicrobially active and show higher activity than the free ligand. The silver-carbene complexes showed antimicrobial activity against specified microorganisms with MIC values between 0.24 and 62.5 µg/ml. These results showed that the silver-NHC complexes exhibit an effective antimicrobial activity against bacterial and fungal strains. A density functional theory calculation study was performed to identify the stability of the obtained complexes. All geometries were optimized employing an effective core potential basis, such as LANL2DZ for the Ag atom and 6-311+G(d,p) for all the other atoms in the gas phase. Electrostatic potential surfaces and LUMO-HOMO energy were computed. Transition energies and excited-state structures were obtained from the time-dependent density functional theory calculations.

Recent progress on donor and donor-donor carbenes.

Donor and donor-donor carbenes are two important kinds of carbenes, which have experienced tremendous growth in the past two decades. This review provides a comprehensive overview of the recent development of donor and donor-donor carbene chemistry. The development of this chemistry offers efficient protocols to construct a wide variety of C-C and C-X bonds in organic synthesis. This review is organized based on the different types of carbene precursors, including diazo compounds, hydrazones, enynones, cycloheptatrienes and cyclopropenes. The typical transformations, the reaction mechanisms, as well as their subsequent applications in the synthesis of complex natural products and bioactive molecules are discussed. Due to the rapidly increasing interest in this area, we believe that this review will provide a timely and comprehensive discussion of recent progress in donor and donor-donor carbene chemistry.

Synthesis and Evaluation of New Trivalent Ligands for Hepatocyte Targeting via the Asialoglycoprotein Receptor.

Since the asialoglycoprotein receptor (also known as the "Ashwell-Morell receptor" or ASGPR) was discovered as the first cellular mammalian lectin, numerous drug delivery systems have been developed and several gene delivery systems associated with multivalent ligands for liver disease targeting are undergoing clinical trials. The success of these systems has facilitated the further study of new ligands with comparable or higher affinity and less synthetic complexity. Herein, we designed two novel trivalent ligands based on the esterification of tris(hydroxymethyl) aminomethane (TRIS) followed by the azide-alkyne Huisgen cycloaddition with azido N-acetyl-d-galactosamine. The presented triazolyl glycoconjugates exhibited good binding to ASGPR, which was predicted using in silico molecular docking and assessed by a surface plasmon resonance (SPR) technique. Moreover, we demonstrated the low level of in vitro cytotoxicity, as well as the optimal spatial geometry and the required amphiphilic balance, for new, easily accessible ligands. The conjugate of a new ligand with Cy5 dye exhibited selective penetration into HepG2 cells in contrast to the ASGPR-negative PC3 cell line.

Pegylated triarylmethanes: Synthesis, antimicrobial activity, anti-proliferative behavior and in silico studies.

We describe herein the synthesis, characterization and biological studies of novel PEGylated triarylmethanes. Non-symmetrical and symmetrical triarylmethanes series have been synthesized by Friedel-Crafts hydroxyalkylation or directly from bisacodyl respectively followed by a functionalization with PEG fragments in order to increase bioavailability and biological effectiveness. The antimicrobial activity was investigated against Gram-positive and Gram-negative foodborne pathogens and against Candida albicans, an opportunistic pathogenic yeast. The anti-biocidal activity was also studied using Staphylococcus aureus as a reference bacterium. Almost all PEGylated molecules displayed an antifungal activity comparable with fusidic acid with MIC values ranging from 6.25 to 50 µg/mL. Compounds also revealed a promising antibiofilm activity with biofilm eradication percentages values above 80% for the best molecules (compounds 4d and 7). Compounds 7 and 8b showed a modest antiproliferative activity against human colorectal cancer cell lines HT-29. Finally, in silico molecular docking studies revealed DHFR and DNA gyrase B as potential anti-bacterial targets and in silico predictions of ADME suggested adequate drug-likeness profiles for the synthetized triarylmethanes.

Towards the Preparation of Stable Cyclic Amino(ylide)Carbenes.

Cyclic amino(ylide)carbenes (CAYCs) are the ylide-substituted analogues of N-heterocyclic Carbenes (NHCs). Due to the stronger π donation of the ylide compared to an amino moiety they are stronger donors and thus are desirable ligands for catalysis. However, no stable CAYC has been reported until today. Here, we describe experimental and computational studies on the synthesis and stability of CAYCs based on pyrroles with trialkyl onium groups. Attempts to isolate two CAYCs with trialkyl phosphonium and sulfonium ylides resulted in the deprotonation of the alkyl groups instead of the formation of the desired CAYCs. In case of the PCy3-substituted system, the corresponding ylide was isolated, while deprotonation of the SMe2-functionalized compound led to the formation of ethene and the thioether. Detailed computational studies on various trialkyl onium groups showed that both the α- and ß-deprotonated compounds were energetically favored over the free carbene. The most stable candidates were revealed to be α-hydrogen-free adamantyl-substituted onium groups, for which ß-deprotonation is less favorable at the bridgehead position. Overall, the calculations showed that the isolation of CAYCs should be possible, but careful design is required to exclude decomposition pathways such as deprotonations at the onium group.

Impacts of Chemical-Assisted Thermal Pretreatments on Methane Production from Fruit and Vegetable Harvesting Wastes: Process Optimization.

The increasing population creates excess pressure on the plantation and production of fruits and vegetables across the world. Consumption demand during the whole year has made production compulsory in the covered production system (greenhouse). Production, harvesting, processing, transporting, and distribution chains of fruit and vegetables have resulted in a huge amount of wastes as an alternative source to produce biofuels. In this study, optimization of two pretreatment processes (NaOH and HCl assisted thermal) was investigated to enhance methane production from fruit and vegetable harvesting wastes (FVHW) that originate from greenhouses. NaOH concentration (0-6.5%), HCl concentration (0-5%), reaction temperature (60-100 °C), solid content (1-5%), time of reaction (1-5 h), and mixing speed (0-500 rpm) were chosen in a wide range of levels to optimize the process in a broad design boundary and to evaluate the positive and negative impacts of independent variables along with their ranges. Increasing NaOH and HCl concentrations resulted in higher COD solubilization but decreased the concentration of soluble sugars that can be converted directly into methane. Thus, the increasing concentrations of NaOH and HCl in the pretreatments have resulted in low methane production. The most important independent variables impacting COD and sugar solubilization were found to be chemical concentration (as NaOH and HCl), solid content and reaction temperature for the optimization of pretreatment processes. The high amount of methane productions in the range of 222-365 mL CH4 gVS-1 was obtained by the simple thermal application without using chemical agents as NaOH or HCl. Maximum enhancement of methane production was 47-68% compared to raw FVHW when 5% solid content, 1-hour reaction time and 60-100 °C reaction temperature were applied in pretreatments.

A Dinuclear Mechanism Implicated in Controlled Carbene Polymerization.

Carbene polymerization provides polyolefins that cannot be readily prepared from olefin monomers; however, controlled and living carbene polymerization has been a long-standing challenge. Here we report a new class of initiators, (π-allyl)palladium carboxylate dimers, which polymerize ethyl diazoacetate, a carbene precursor in a controlled and quasi-living manner, with nearly quantitative yields, degrees of polymerization >100, molecular weight dispersities 1.2-1.4, and well-defined, diversifiable chain ends. This method also provides block copolycarbenes that undergo microphase segregation. Experimental and theoretical mechanistic analysis supports a new dinuclear mechanism for this process.

Solid-phase synthesis of biocompatible N-heterocyclic carbene-Pd catalysts using a sub-monomer approach.

Taking inspiration from the assembly of so-called peptoids (N-alkylglycine oligomers) we present a new synthetic methodology whereby N-heterocyclic carbene (NHC) based Pd ligands were assembled using a sub-monomer approach and loaded with Pd via solid-phase synthesis. This allowed the rapid generation a library of NHC-palladium catalysts that were readily functionalised to allow bioconjugation. These catalysts were able to rapidly activate a caged fluorophore and 'switch-on' an anticancer prodrug in 3D cell culture.

Catalytic Cyclooligomerization of Enones with Three Methylene Equivalents.

Cyclic structures are highly represented in organic molecules, motivating a wealth of catalytic methods targeting their synthesis. Among the various ring-forming processes, cyclooligomerization reactions possess several attractive features but require addressing a unique challenge associated with controlling ring-size selectivity. Here we describe the catalytic reductive cocyclooligomerization of an enone and three carbene equivalents to generate a cyclopentane, a process that constitutes a formal [2 + 1 + 1 + 1]-cycloaddition. The reaction is promoted by a (quinox)Ni catalyst and uses CH2Cl2/Zn as the C1 component. Mechanistic studies are consistent with a metallacycle-based pathway, featuring sequential migratory insertions of multiple carbene equivalents to yield cycloalkanes larger than cyclopropanes.

Comparative analysis of deep sequenced methanogenic communities: identification of microorganisms responsible for methane production.

BACKGROUND: Although interactions between microorganisms involved in biogas production are largely uncharted, it is commonly accepted that methanogenic Archaea are essential for the process. Methanogens thrive in various environments, but the most extensively studied communities come from biogas plants. In this study, we employed a metagenomic analysis of deeply sequenced methanogenic communities, which allowed for comparison of taxonomic and functional diversity as well as identification of microorganisms directly involved in various stages of methanogenesis pathways. RESULTS: A comprehensive metagenomic approach was used to compare seven environmental communities, originating from an agricultural biogas plant, cattle-associated samples, a lowland bog, sewage sludge from a wastewater treatment plant and sediments from an ancient gold mine. In addition to the native consortia, two laboratory communities cultivated on maize silage as the sole substrate were also analyzed. Results showed that all anaerobic communities harbored genes of all known methanogenesis pathways, but their abundance varied greatly between environments and that genes were encoded by different methanogens. Identification of microorganisms directly involved in different stages of methane production revealed that hydrogenotrophic methanogens, such as Methanoculleus, Methanobacterium, Methanobrevibacter, Methanocorpusculum or Methanoregula, predominated in most native communities, whereas acetoclastic Methanosaeta seemed to be the key methanogen in the wastewater treatment plant. Furthermore, in many environments, the methylotrophic pathway carried out by representatives of Methanomassiliicoccales, such as Candidatus Methanomethylophilus and Candidatus Methanoplasma, seemed to play an important role in methane production. In contrast, in stable laboratory reactors substrate versatile Methanosarcina predominated. CONCLUSIONS: The metagenomic approach presented in this study allowed for deep exploration and comparison of nine environments in which methane production occurs. Different abundance of methanogenesis-related functions was observed and the functions were analyzed in the phylogenetic context in order to identify microbes directly involved in methane production. In addition, a comparison of two metagenomic analytical tools, MG-RAST and MetAnnotate, revealed that combination of both allows for a precise characterization of methanogenic communities.

Recent advances in ß-lactam synthesis.

During the past century, ß-lactams have been identified as the core of penicillin and since then several strategies have been developed for their synthesis. Traditional methods for ß-lactam synthesis usually involved amide bond formation and the Staudinger reaction. In recent years, by the advancement of photo- and transition metal-catalysis, several new methods have been reported for ß-lactam synthesis. For instance: ligand assisted metal catalyzed C-H activation/intermolecular oxidative amidation draws attention for ß-lactam synthesis. In this review we introduce methods for ß-lactam synthesis and present newly developed reactions. We approach the synthesis of ß-lactams according to different retro synthesis strategies.

Systematic Structure-Activity Relationship (SAR) Exploration of Diarylmethane Backbone and Discovery of A Highly Potent Novel Uric Acid Transporter 1 (URAT1) Inhibitor.

In order to systematically explore and better understand the structure-activity relationship (SAR) of a diarylmethane backbone in the design of potent uric acid transporter 1 (URAT1) inhibitors, 33 compounds (1a-1x and 1ha-1hi) were designed and synthesized, and their in vitro URAT1 inhibitory activities (IC50) were determined. The three-round systematic SAR exploration led to the discovery of a highly potent novel URAT1 inhibitor, 1h, which was 200- and 8-fold more potent than parent lesinurad and benzbromarone, respectively (IC50 = 0.035 µM against human URAT1 for 1h vs. 7.18 µM and 0.28 µM for lesinurad and benzbromarone, respectively). Compound 1h is the most potent URAT1 inhibitor discovered in our laboratories so far and also comparable to the most potent ones currently under development in clinical trials. The present study demonstrates that the diarylmethane backbone represents a very promising molecular scaffold for the design of potent URAT1 inhibitors.

Enantioselective Synthesis of Indolines, Benzodihydrothiophenes, and Indanes by C-H Insertion of Donor/Donor Carbenes.

We employ a single catalyst/oxidant system to enable the asymmetric syntheses of indolines, benzodihydrothiophenes, and indanes by C-H insertion of donor/donor carbenes. This methodology enables the rapid construction of densely substituted five-membered rings that form the core of many drug targets and natural products. Furthermore, oxidation of hydrazones to the corresponding diazo compounds proceeds in situ, enabling a relatively facile one- or two-pot protocol in which isolation of potentially explosive diazo alkanes is avoided. Regioselectivity studies were performed to determine the impact of sterics and electronics in donor/donor metal carbene C-H insertions to form indolines. This methodology was applied to a variety of substrates in high yield, diastereomeric, and enantiomeric ratios and to the synthesis of a patented indane estrogen receptor agonist with anti-cancer activity.

Stereoselective Tandem Bis-Electrophile Couplings of Diborylmethane.

A copper-catalyzed three-component linchpin coupling method for the stereoselective union of readily available epoxides and allyl electrophiles is disclosed. Transformations employ [B(pin)]2-methane as a conjunctive reagent, resulting in the formation of two C-C bonds at a single carbon center bearing a C(sp3) organoboron functional group. Products are obtained in 42-99% yield, and up to >20:1 dr. The utility of the approach is highlighted by stereospecific transformations entailing allylation, tandem cross coupling, and application to the synthesis 1,3-polyol motifs.

Functionalized ionic liquid-assisted chromatography-free synthesis of bis(indolyl)methanes.

A chromatography-free synthesis of bis(indolyl)methanes has been developed using sulfonic acid and sulfonyl hydrazine-functionalized ionic liquids as catalyst and scavenger, respectively. The employed excess aldehyde for completion of the reaction was scavenged by sulfonyl hydrazine-functionalized ionic liquid. Purification of products without column chromatography, ease of monitoring and shorter reaction time are the salient features of the developed protocol. The reuse and regeneration of the catalyst and scavenger have been achieved up to 5 and 2 times, respectively, without significant loss of activity.

Novel NHC Precursors: Synthesis, Characterization, and Carbonic Anhydrase and Acetylcholinesterase Inhibitory Properties.

Three series of imidazolidinium ligands (NHC precursors) substituted with 4-vinylbenzyl, 2-methyl-1,4-benzodioxane, and N-propylphthalimide were synthesized. N-Heterocyclic carbene (NHC) precursors were prepared from N-alkylimidazoline and alkyl halides. The novel NHC precursors were characterized by 1 H NMR, 13 C NMR, FTIR spectroscopy, and elemental analysis techniques. The enzymes inhibition activities of the NHC precursors were investigated against the cytosolic human carbonic anhydrase I and II isoenzymes (hCA I and II) and the acetylcholinesterase (AChE) enzyme. The inhibition parameters (IC50 and Ki values) were calculated by spectrophotometric method. The inhibition constants (Ki ) were found to be in the range of 166.65-635.38 nM for hCA I, 78.79-246.17 nM for hCA II, and 23.42-62.04 nM for AChE. Also, the inhibitory effects of the novel synthesized NHCs were compared to acetazolamide as a clinical CA isoenzymes inhibitor and tacrine as a clinical cholinergic enzymes inhibitor.