Anthraquinone Core Research Articles

NLOphoric Anthraquinone Dyes – A Review

AbstractThis review is about anthraquinone dyes. One of the advantages of organic NLOphores materials is the variety of chromophores explored for a wide range of potential applications in optoelectronics and biology. The second and third harmonic generations, as well as hyper‐Rayleigh scattering (HRS), the Z‐scan technique, degenerate four‐wave mixing (DFWM), and density functional theory (DFT), are all covered in this review. The most active sites for establishing enhanced NLO properties were found to be positions 2 and 6 of the anthraquinone core. The structural characteristics of dyes are used to divide them into subcategories. In each section, structures with a higher NLO response are highlighted. Researchers will benefit from this review when designing and synthesizing NLOphores.

Accelerated molecular dynamics study of the interaction mechanism between small molecule inhibitors and phosphoglycerate mutase 1.

In 2020, cancer-related deaths reached 9.96 million globally, of which China accounted for 3 million, ranking first in the world. Phosphoglycerate mutase 1 (PGAM1) is a key metabolic enzyme in glycolysis, catalysing the conversion of 3-phosphoglycerate to 2-phosphoglycerate. Based on the excellent anticancer activity of PGMI-004A and HKB99, new small molecules with an anthraquinone core were synthesised to inhibit tumour growth. Developing small molecules with an anthraquinone core targeting PGAM1 may be an effective strategy for treating cancer. In this study, accelerated molecular dynamics (aMD) simulation, dynamic cross-correlation map (DCCM) calculation, principal component analysis (PCA) and free energy landscape (FEL) analysis were used to analyse conformational changes of PGAM1 caused by binding of inhibitors 8KX, 9HU and HKB. DCCM calculations and PCA showed that inhibitor binding significantly affected the kinetic behaviour of PGAM1 and conformational rearrangement of PGAM1. The binding ability and mechanism of 8KX, 9HU and HKB to PGAM1 were studied using the molecular mechanics generalised Born surface area (MM-GBSA) method. The results showed that compared with 8KX, the binding ability of 9HU and HKB to PGAM1 was enhanced by sulphonamide reversal and aminocarboxyl trifluoromethyl substitution. There were several hydrophobic interactions between inhibitors and PGAM1, providing significant contributions for inhibitor binding. Calculation of residue-based free energy decomposition revealed that F22, R90, Y92, L95, V112, W115, R116, V121, P123, P124, R191 and M206 were key residues of the PGAM1-inhibitor interaction and could be used as effective targets for designing drugs that inhibit the activity of PGAM1.

New heteroarene-fused anthraquinones: Synthesis and PyBOP-mediated amination

In this study three independent synthetic approaches for fusing of oxo-bearing aza-heterocycles to the anthraquinone core were developed. In particular, quinoline-2-one, pyrimidine-4-one, pyrimidine-2,4-dione,[1,2,3]triazine-4-one, quinoxaline-2-one, quinoxaline-2,3-dione, and imidazole-2-one were successfully annelated expanding the scope of heteroarene-fused anthraquinone derivatives. Cyclic amines were introduced as potential pharmacophore fragments by the PyBOP-mediated substitution of the oxo group. The amination requires relatively mild conditions yielding the products with reasonable-to-good effectiveness, however some limitations were found. This work contributes to the synthesis and chemical modification of heteroarene-fused anthraquinone derivatives for application in anticancer research as potential protein-kinase inhibitors.

High-resolution mass spectrometry identification of dye compounds and their degradation products in American cochineal from a historic shipping cargo

Cochineal dyes constitute paradigmatic organic compounds that guide in the elucidation of historic cultural and economical exchanges. This study combines liquid chromatography and high-resolution tandem mass spectrometry to assess the degradation products of the organic dyes of American cochineal collected from the cargo of a 16th century sunken wreck. The identification of biological materials of historical and archeological origin is often challenging due to molecular degradation. In this scenario, the mapping of the chemical routes underlying the fate of the organic and biochemical compounds employed as taxonomic biomarkers becomes of crucial importance. This work shows that, under harsh environmental conditions, the original carminic and (flavo)kermesic acid structures of cochineal dyes are prone to chemical transformation, typically losing the carboxylic acid and glucoside groups. The anthraquinone core is preserved in the majority of degradation products identified in this study, with eventual side chains reminiscent of a partial degradation of the glucoside moiety. The comparison of these observations with the analysis of modern cochineal samples allows us to lay out an updated chart of dye compounds and degradation products which should constitute a seminal benchmark for future biomolecular analysis of historic and archeological dye materials.

Zinc-mediated efficient and selective reductive aza-Claisen rearrangement of N-allyl- and N-propargylaminoanthraquinones in ionic liquid.

An efficient method is described for the first time for reductive aza-Claisen rearrangement of 1-(N-allylamino)anthraquinones to 1-amino-2-(prop-2'-enyl)anthraquinones using zinc powder in 1-methylimidazolium tetrafluoroborate ([Hmim] BF4) as an ionic liquid in good to excellent yields. Extending of this method on 1-(N-propargylamino)anthraquinones causes the production of 1,2,3,4-tetrahydronaphtho[2,3-h]quinoline-7,12-diones containing a newly synthesized six membered heterocyclic ring on anthraquinone core via performing this reductive [3,3] sigmatropic reaction followed by cyclization in a tandem manner. These rearrangements can be executed even in the presence of some other functional groups with excellent chemoselectivity.

Upregulation of p53 through induction of MDM2 degradation: improved potency through the introduction of an alkylketone sidechain on the anthraquinone core

Overexpression of ubiquitin ligase MDM2 causes depletion of the p53 tumour-suppressor and thus leads to cancer progression. In recent years, anthraquinone analogs have received significant attention due to their ability to downregulate MDM2, thereby promoting p53-induced apoptosis. Previously, we have developed potent anthraquinone compounds having the ability to upregulate p53 via inhibition of MDM2 in both cell culture and animal models of acute lymphocytic leukaemia. Earlier work was focussed on mechanistic work, pharmacological validation of this class of compounds in animal models, and mapping out structural space that allows for further modification and optimisation. Herein, we describe our work in optimising the substituents on the two phenol hydroxyl groups. It was found that the introduction of an alkylketone moiety led to a potent series of analogs with BW-AQ-350 being the most potent compound yet (IC50 = 0.19 ± 0.01 µM) which exerts cytotoxicity by inducing MDM2 degradation and p53 upregulation.

Asymmetric Total Synthesis of Brasiliquinones B and C via Oxidative Cyclization of a Hydroquinone-Silyl Enol Ether Hybrid.

The asymmetric total synthesis of angucycline antibiotics (S)-brasiliquinones B and C was accomplished. The benz[a]anthraquinone core was constructed via oxidative cyclization of a hydroquinone-silyl enol ether hybrid. The resultant pentacyclic acetal was converted to the silyl enol ether, which was treated with Pd(II)/O2 to afford brasiliquinone C, after multistep conversion including dehydrogenation, desilylation and deacetalization, and hydroquinone oxidation. The (S)-configuration of natural brasiliquinones was confirmed based on the stereochemical correlation with the synthetic products.

Reductive elimination of alkoxy group in anthraquinone derivatives

Anthraquinone derivatives are constantly in a focus of synthetic chemists due to a diversity of valuable biological, photochemical and redox properties. However, quinone core limits applicability of chemical transformations making a search for new methods of modification of anthraquinones highly demanded. A convenient approach of regioselective reductive α-alkoxy group cleavage of anthraquinone derivatives was developed and evaluated. Most effectively transformation goes via a zinc reduction of quinone moiety and prototropic rearrangement in acidic media followed by the alkoxy group elimination. Strong donors in β-position of anthraquinone core are crucial for transformation and provide the elimination exclusively from α-position. The method simplifies an access to some bioactive 1,3-substituted anthraquinones and was applied for synthesis of natural products, e.g., rubiadin 1-methyl ether, anthragallol 1,2-dimethyl ether, and damnacanthol.

Heterocyclic ring expansion yields anthraquinone derivatives potent against multidrug resistant tumor cells

Chemical modifications of anthraquiones are aimed at novel derivatives with improved antitumor properties. Emergence of multidrug resistance (MDR) due to overexpression of transmembrane ATP binding cassette transporters, in particular, MDR1/P-glycoprotein (Pgp), can limit the use of anthraquinone based drugs. Previously we have demonstrated that annelation of modified five-membered heterocyclic rings with the anthraquinone core yielded a series of compounds with optimized antitumor properties. In the present study we synthesized a series of anthraquinone derivatives with six-membered heterocycles. Selected new compounds showed the ability to kill parental and MDR tumor cell lines at low micromolar concentrations. Molecular docking into the human Pgp model revealed a stronger interaction of 2-methylnaphtho[2,3-g]quinoline-3-carboxamide 17 compared to naphtho[2,3-f]indole-3-carboxamide 3. The time course of intracellular accumulation of compound 17 in parental K562 leukemia cells and in Pgp-positive K562/4 subline was similar. In contrast, compound 3 was readily effluxed from K562/4 cells and was significantly less potent for this subline than for K562 cells. Together with reported strategies of drug optimization of the anthracycline core, these results add ring expansion to the list of perspective modifications of heteroarene-fused anthraquinones.

Near-Infrared Emitting Poly(amidoamine) Dendrimers with an Anthraquinone Core toward Versatile Non-Invasive Biological Imaging.

Today, there is a very strong demand for versatile near-infrared (NIR) imaging agents suitable for non-invasive optical imaging in living organisms (in vivo imaging). Here, we created a family of NIR-emitting macromolecules that take advantage of the unique structure of dendrimers. In contrast to existing fluorescent dendrimers bearing fluorophores at their periphery or in their cavities, a NIR fluorescent structure is incorporated into the core of the dendrimer. Using the poly(amidoamine) dendrimer structure, we want to promote the biocompatibility of the NIR-emissive system and to have functional groups available at the periphery to obtain specific biological functionalities such as the ability to deliver drugs or for targeting a biological location. We report here the divergent synthesis and characterization by NMR and mass spectrometries of poly(amidoamine) dendrimers derived from the fluorescent NIR-emitting anthraquinone core (AQ-PAMAF). AQ-PAMAFs ranging from the generation -0.5 up to 3 were synthesized with a good level of control resulting in homogeneous and complete dendrimers. Absorption, excitation, and emission spectra, as well as quantum yields, of AQ-PAMAFs have been determined in aqueous solutions and compared with the corresponding properties of the AQ-core. It has been demonstrated that the absorption bands of AQ-PAMAFs range from UV to 750 nm while emission is observed in the range of 650-950 nm. Fluorescence macroscopy experiments confirmed that the NIR signal of AQ-PAMAFs can be detected with a satisfactory signal-to-noise ratio in aqueous solution, in blood, and through 1 mm thick tissue-mimicking phantom. The results show that our approach is highly promising for the design of an unprecedented generation of versatile NIR-emitting agents.

Rausuquinone, a non-glycosylated pluramycin-class antibiotic from Rhodococcus.

A new pluramycin-class polyketide, rausuquinone (1), and its known congener hydramycin (2) were isolated from the culture extract of the deep-sea water-derived Rhodococcus sp. RD015140. Compound 1 possesses a γ-pyrone-fused anthraquinone core with a 3-butene-1,2-diol side chain. Structures of 1 was determined by extensive analysis of 1D and 2D NMR spectroscopic data. Compound 1 showed antimicrobial activity against Gram-positive bacteria. This is the first discovery of aromatic polyketides from the genus Rhodococcus.

Selective colorimetric sensor for cyanide anion based on 1-hydroxyanthraquinone

The article addresses the synthesis, structure and properties of 2-benzoylamino-1-hydroxyanthraquinone (1a), which can function as a selective colorimetric sensor for the cyanide anion in aqueous media. Compound 1a was prepared in two simple steps in good yield and its structure was confirmed by X-ray diffraction analysis. UV–Vis and NMR spectroscopy, mass spectrometry and quantum chemistry studies revealed that in MeCN–H2O mixtures (95:5, v/v), cyanide ionizes the hydroxyl group of the anthraquinone, which results in a strong bathochromic effect. The association constant of cyanide anion with 1a was measured to be 104.88 M–1; the detection limit is about 0.22 μM. The presence of a benzoylamino group at position 2 of the anthraquinone core has a stabilizing effect on the anionic form of 1a due to the hydrogen bonding between the amide hydrogen atom and the oxygen atom of the ionized hydroxyl group.

9,10-Anthraquinones Disubstituted with Linear Alkoxy Groups: Spectroscopy, Electrochemistry, and Peculiarities of Their 2D and 3D Supramolecular Organizations.

Spectroscopic, electrochemical, and structural properties of 2,6-dialkoxy-9,10-anthraquinones (Anth-OCn, n = 4, 6, 8, 10, and 12) of increasing alkoxy substituents length were investigated. UV–vis spectroscopy showed a substitution-induced bathochromic shift of the least energetic band from 325 nm in the case of unsubstituted anthraquinone to ca. 350 nm for the studied derivatives. Similarly as unsubstituted anthraquinone, the studied compound showed two reversible one electron reductions to a radical anion and spinless anions, respectively. The first reduction was affected by electron-donating properties of the substituents, its potential being shifted to ca. −1.5 V (vs Fc/Fc+), i.e., by 80 to 95 mV as compared to the case of unsubstituted anthraquinone. This corresponded to a decrease of |EA| from 3.27 to 3.19–3.17 eV. The experimental spectroscopic and electrochemical data were in full agreement with the DFT calculations. The introduction of the alkoxy substituent improved solution processibility of the studied compounds and facilitated the formation of their ordered supramolecular 2D aggregation on HOPG as well as single crystal growth from solutions. Comparative structural investigations carried out on single crystals and monolayers deposited on HOPG revealed two, mutually related, effects of the substituent length on the resulting supramolecular organization. The first one concerns both the 2D organization in the monolayers and 3D molecular arrangement in crystals: increasing substituent length evolution of the structure occurs from herringbone-type to lamellar. The second effect, observed in monolayers of the derivatives with longer substituents, concerns gradual evolution of their lamellar structures with increasing substituent length. This evolution is induced by the structure of the graphite substrate and involves increasing correlation of the molecules orientation (anthraquinone cores as well as alkoxy substituents) with the symmetry of the graphite substrate. As a result, their 2D and 3D structures become dissimilar.

Anthraquinone-containing compound in rhubarb prevents indole production via functional changes in gut microbiota.

Indole is produced from dietary tryptophan by tryptophanase in intestinal bacteria, such as Escherichia coli. In the liver, indole is converted into indoxyl sulfate, a uremic toxin and risk factor for chronic kidney disease (CKD). Probiotics and prebiotics are currently used for suppressing CKD, but there are no drugs that directly suppress indole production. In this study, we developed an optimized HPLC method for analyzing indole production and evaluated the effect of diets and rhubarb on indole production via the changes of gut microbiota. In high-carbohydrate and high-fat diet-fed mice, the indole production was significantly higher than in high-fiber diet-fed mice. We further used the high-carbohydrate diet-fed mice as a model for examining the effect of rhubarb on indole production. The 20% methanol-eluted fraction of aqueous rhubarb extract significantly suppressed indole production, and the eluate constituent rhein 8-O-β-D-glucopyranoside (RG) contributed to this effect in a concentration-dependent manner. The effect of RG depended on the anthraquinone core substructure, i.e., the aglycone moiety (rhein) of RG, which appeared to inhibit the tryptophanase function in gut microbiota. Thus, in addition to earlier reports that rhubarb is an effective CKD treatment, our study demonstrated that the anthraquinone moiety in rhubarb prevents uremic toxin production via functional changes in gut microbiota, which suppresses CKD progression.

A pH-Neutral, Aqueous Redox Flow Battery with a 3600-Cycle Lifetime: Micellization-Enabled High Stability and Crossover Suppression.

Redox-flow batteries (RFBs) are a highly promising large-scale energy storage technology for mitigating the intermittent nature of renewable energy sources. Here, the design and implementation of a micellization strategy in an anthraquinone-based, pH-neutral, nontoxic, and metal-free aqueous RFB is reported. The micellization strategy (1) improves stability by protecting the redox-active anthraquinone core with a hydrophilic poly(ethylene glycol) shell and (2) increases the overall size to mitigate the crossover issue through a physical blocking mechanism. Paired with a well-established potassium ferrocyanide catholyte, the micelle-based RFB displayed an excellent capacity retention of 90.7 % after 3600 charge/discharge cycles (28.3 days), corresponding to a capacity retention of 99.67 % per day and 99.998 % per cycle. The mechanistic studies of redox-active materials were also conducted and indicated the absence of side reactions commonly observed in other anthraquinone-based RFBs. The outstanding performance of the RFB demonstrates the effectiveness of the micellization strategy for enhancing the performance of organic material-based aqueous RFBs.

Inducing Apoptosis through Upregulation of p53: Structure-Activity Exploration of Anthraquinone Analogs.

We previously reported a series of p53-elevating anthraquinone compounds with considerable cytotoxicity for acute lymphatic leukemia (ALL) cells. To further develop this class of compounds, we examined the effect of a few key structural features on the anticancer structure-activity relationship in ALL cells. The active analogs showed comparable cytotoxicity and upregulation of p53 but did not induce significant downregulation of MDM2 as seen with the lead compound AQ-101, indicating the importance of the anthraquinone core scaffold for MDM2 regulation. The result from the current study not only contributes to the SAR framework of these anthraquinone derivatives but also opens up new chemical space for further optimization work.

Mitigating Chemical Paths to Capacity Fade in Organic Flow Batteries

In this issue of Chem, Michael Aziz, Roy Gordon, and collaborators report soluble, functionalized anthraquinones that serve to deactivate and recover from chemical reactions that lead to capacity fade in organic redox flow battery electrolytes. The result is an unprecedented low rate of capacity fade of

β-Hydroxylation of anthraquinone derivatives with benzaldehyde oxime as a source of hydroxyl group

Hydroxyanthraquinones are of significant interest due to their broad spectrum of biological activity, coloring properties and synthetic applications. Here, we describe a mild and convenient method for β-hydroxylation of anthraquinone derivatives that can be used during late stages of modifications. The scheme is based on the Miller-Loudon-Snyder reaction, which uses benzaldoxime as a source of a hydroxyl group. The influence of different leaving groups and neighboring substituents at the anthraquinone core on reaction rate and yield has been evaluated. A series of β-hydroxyanthraquinone derivatives was synthesized using the developed approach.

Synthesis of Barleriaquinones-I & II

Synthesis of two naturally occurring anthraquinones, Barleriaquinone-I (BQ-I) and Barleriaquinone-II (BQ-II) is achieved from commercially available naphthalene-1,5-diol. The anthraquinone core is constructed by utilizing simultaneous Heck and cross coupling reaction as the key step.

Synthesis of 1,4‐disubstituted aminoanthraquinone derivatives for purification of lactate dehydrogenase

Cibacron Blue 3G‐A is a dye commonly used for the purification of various enzymes, in particular, isolating lactate dehydrogenase. Companies have Cibacron Blue available periodically but it is rather expensive. Because of these problems, an alternative dye that can be easily synthesized and has similar properties to Cibacron Blue is desired. Cibacron Blue is a dye designed to mimic natural biological ligands, such as NAD+/NADH. A suitable replacement should exhibit comparable affinity and purifying ability for targeted proteins. Cibacron Blue contains an anthraquinone core, which is a distinct feature due to its versatility. Many different functional groups can be substituted on to the anthraquinone core giving it a multitude of different properties and functions. The goal of this research is to synthesize an anthraquinone derivative that exhibits similar properties and functions as Cibacron Blue. The alternatives include aromatic anilines at the 1,4 positions of the anthraquinone to emulate Cibacron Blue's structure at the anthraquinone core and allow for attachment to a solid support. These were synthesized by treatment of 1,4‐bistosyloxyanthraquinone with two substituted anilino nucleophiles to build a library. These alternatives should mimic the adenine moiety of NAD+, which are accommodated in a hydrophobic crevice formed by five chain regions of lactate dehydrogenase. The left side of the anthraquinone is left unsubstituted since it is believed this is where it binds to the hydrophobic nucleic fold of enzymes. After the synthesis of the small library of aminoanthraquinone derivatives was completed, they are characterized. Binding affinity was tested using Fluorescence quenching. This method allows for comparisons between the binding of lactate dehydrogenase to the synthesized products and binding of lactate dehydrogenase to NADH using Kd values. The Kd value is an equilibrium dissociation constant that is used to evaluate binding affinity.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.