Anthraquinone Core Research Articles

Trimerization of Vitamin K3: Molecular structure and density functional theoretic investigations

We demonstrate the unusual reactivity of Vitamin K3 with sodium ethoxide accompanying its trimerization which gave 6-(3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl) pentaphene-5,8,13,14-tetraone (1) as the product made up of substituted naphthoquinone and anthraquinone core. X-ray structure of the product revealed CH⋯O interaction; π-π stacking and C⋯O close contacts in its crystal. Electronic structure of 1 obtained from the M06-2X/6-311++G (d, p) theory is in consonance with the experiment. Besides the π-π stacking in its dimer are probed through the noncovalent interactions reduced density gradient analysis within the quantum theory of atoms in molecules.

Studies toward the Total Synthesis of Nogalamycin: Construction of the Complete ABCDEF-Ring System via a Convergent Hauser Annulation.

The convergent synthesis of the complete ABCDEF-ring system within nogalamycin, an anthracycline natural product, was studied. The pivotal Hauser annulation for the anthraquinone core construction was achieved by the fusion of two highly functionalized segments: a cyanophthalide (the AB-ring segment) and a tricyclic quinone monoketal (the DEF-ring segment). Key transformations toward the AB-ring segment include an enantioselective enolate α-hydroxylation, a diastereoselective hydroboration-oxidation, and a directed aromatic lithiation-formylation. To prepare the DEF-ring segment for annulation, a mild dearomatization of the F-ring phenol group by (diacetoxyiodo)benzene (PIDA) was employed.

Breakdown of Curly Arrow Rules in Anthraquinone

AbstractUnderstanding and controlling quantum interference (QI) in single molecules is fundamental to the development of QI‐based single‐molecule electronics. Simple rules such as counting rules, curly arrow rules (CARs), circuit rules, and more recently magic ratio rules have been developed to predict QI patterns in polycyclic aromatic hydrocarbons. CARs are widely used to predict destructive QI. Here we examine the validity of CARs in fully conjugated anthracene and dihydroxyanthracene, cross‐conjugated anthraquinone, and broken conjugated dihydroanthracene attached to either graphene or gold electrodes through π‐π stacking or thiol and Au−C anchors. For the first time, we demonstrate that CARs break down in molecular junctions formed by cross‐conjugated anthraquinone. In contrast with the destructive QI predicted by CARs for a meta‐connected anthraquinone core, we demonstrate that QI is constructive. This behavior is independent of the choice of electrode material or anchor groups. This is significant, because by changing the redox state of meta‐connected dihydroxyanthracene to form meta‐connected anthraquinone, the conductance of the junction increases by a couple of orders of magnitude due to the crossover from constructive to destructive QI. This opens new avenues for realization of QI‐based single‐molecule switches.

Breakdown of Curly Arrow Rules in Anthraquinone.

Understanding and controlling quantum interference (QI) in single molecules is fundamental to the development of QI-based single-molecule electronics. Simple rules such as counting rules, curly arrow rules (CARs), circuit rules, and more recently magic ratio rules have been developed to predict QI patterns in polycyclic aromatic hydrocarbons. CARs are widely used to predict destructive QI. Here we examine the validity of CARs in fully conjugated anthracene and dihydroxyanthracene, cross-conjugated anthraquinone, and broken conjugated dihydroanthracene attached to either graphene or gold electrodes through π-π stacking or thiol and Au-C anchors. For the first time, we demonstrate that CARs break down in molecular junctions formed by cross-conjugated anthraquinone. In contrast with the destructive QI predicted by CARs for a meta-connected anthraquinone core, we demonstrate that QI is constructive. This behavior is independent of the choice of electrode material or anchor groups. This is significant, because by changing the redox state of meta-connected dihydroxyanthracene to form meta-connected anthraquinone, the conductance of the junction increases by a couple of orders of magnitude due to the crossover from constructive to destructive QI. This opens new avenues for realization of QI-based single-molecule switches.

Advances in the Discovery of Anthraquinone-Based Anticancer Agents.

The anthracene-9,10-dione (anthraquinone) derivatives represent an exceptionally valuable class in anticancer drug development. An outstanding antitumor potency of the anthracycline antibiotics attracted the attention of medicinal chemists since the discovery of these chemotypes. The prominent anthraquinone-based drugs doxorubicin, mitoxantrone as well as more recent epirubicin, idarubicin, and valrubicin are successfully used in chemotherapy of hematological malignancies and solid tumors. The anthraquinone core remains a promising scaffold for the search of new optimized drug candidates. In this study, we analyze the progress in discovery and development of antitumor anthracene- 9,10-diones based on patent and journal publications in 2008-2017. The main goal is to dissect novel chemotypes of anthraquinone derivatives; other important issues such as the success in bioconjugate chemistry of anthraquinone containing agents as well as the patents on new applications of anthracyclines are beyond the scope of this review. A number of newly discovered natural products, the perspective directions for chemical modifications to optimize the anticancer properties, and novel intracellular targets demonstrate that anthracene- 9,10-diones deserve further in-depth investigation as an important source of drug candidates.

Synthesis of 1,4‐diaminoanthraquinones for the purification of lactate dehydrogenase

Cibacron blue 3G‐A is a dye commonly used for the purification of enzymes using affinity chromatography, often utilized in undergraduate biochemistry laboratory studies. Unfortunately, companies only have this product available intermittently, and when available it is sold at a fairly high price. Due to these issues, an alternative molecule that could be easily synthesized and would be similarly efficient at enzyme purification is desired. A distinct feature of Cibacron blue is its anthraquinone core. Anthraquinones are naturally‐occurring aromatic compounds commonly used in the manufacture of dyes. This synthesis utilizes a method of converting 1,4‐diaminoanthraquinones into diazonium salts to then allow the addition of various other functional groups, including anilines and phenols. After synthesis has been conducted, this small library of aminoanthraquinone derivatives will be tested for biological activity by examining spectrophotometric activity in the presence of lactate dehydrogenase (LDH). This will determine whether the products synthesized are efficient at binding to LDH and whether they can be successfully utilized for purification methods. This experiment details a simple, two‐step synthesis of various 1,4‐disubstituted aminoanthraquinone derivatives, which may be found to be useful alternatives to Cibacron blue. In addition, these products could potentially have other biological activity, due to the highly‐activated anthraquinone core.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Synthesis of Mono‐substituted Anthraquinone Derivatives to be Used in the Purification of Lactate Dehydrogenase

Cibacron Blue 3G‐A has been previously used in biochemical laboratories for purification of enzymes containing the dinucleotide fold. Lactate dehydrogenase is one such enzyme that can be purified using Cibacron Blue 3G‐A in affinity chromatography. Rising costs and inaccessibility to Cibacron Blue 3G‐A have created a demand to find a more cost effective replacement. Electron withdrawing and donating properties of the anthraquinone core substituent groups are believed to affect the affinity of the core for various enzymes. A range of anthraquinone dyes were synthesized to determine the importance of the substituents' electronic properties with the coupling of ortho substituted aniline nucleophiles to the anthraquinone core via a diazonium salt link. The aniline substituents include: methyl, methoxy, chloro, and sulfonyl groups. For each anthraquinone dye synthesized, the λmax value was determined to effectively monitor the kinetics of the dyes. Spectrometric assays measured the oxidation of NADH to NAD+ determining the dye's affinity for enzymes containing the dinucleotide fold.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Phase Behavior of a New Class of Anthraquinone-Based Discotic Liquid Crystals.

Five novel columnar liquid crystalline compounds (4.1-4.5) consisting of a central anthraquinone core carrying four alkoxy chains (R = n-C6H13, n-C8H17, n-C10H21, n-C12H25, and 3,7-dimethyl octyl) with two diagonally opposite 1-ethynyl-4-pentylbenzene units were synthesized, and their phase transitions were investigated between changes in the molecular structure and their self-assembly into the columnar mesophases. Small and wide-angle X-ray scattering (SAXS/WAXS) studies were performed to deduce the exact nature of the mesophases, and their corresponding electron density maps were derived from the intensities of the peaks observed in the diffraction patterns. A comparison of compounds with different alkoxy chains indicated that the soft crystal columnar rectangular (Crcolrec) phase was stable at lower temperature for the shortest peripheral alkoxy chain (4.1; R = n-C6H13) and was found to exhibit the columnar hexagonal (Colh) phase and then the discotic nematic (ND) phase with increasing temperature. In contrast, increasing the peripheral chain length to n-C8H17 or the branched one (4.2 and 4.5) stabilized the Colh phase at lower temperature and showed the ND phase at higher temperature. Further increase in chain length (4.3 and 4.4; n-C10H21, n-C12H25) demonstrated the formation of the ND phase. Conductivity measurement in the Colh mesophase was found to be almost 10 times higher in magnitude than the corresponding Crcolrec phase. The HOMO-LUMO band gap of all the compounds was found to be in the range from 2.79 to 2.82 eV, which is quite less and comparable with the optical energy band gap.

Synthesis and crystal structures of two purpurin derivatives: 1,4-dihy-droxy-2-propoxyanthra-quinone and 2-but-oxy-1,4-di-hydroxy-anthra-quinone.

The title compounds were obtained by deprotonation of 1,2,4-tri-hydroxy-anthra-quinone (purpurin) using sodium hydride followed by reaction with either 1-bromo-propane or 1-bromo-butane. 1,4-Dihy-droxy-2-propoxyanthra-quinone crystallizes as a 1:1 solvate from aceto-nitrile, C17H14O5·CH3CN. The anthra-quinone core of the mol-ecule is essentially planar and both hy-droxy groups participate in intra-molecular O-H⋯O (carbon-yl) hydrogen bonds. The propyl chain is angled slightly above the plane of the anthra-quinone moiety with a maximum deviation of 0.247 (2) Å above the plane for the terminal carbon atom. In contrast, 2-but-oxy-1,4-di-hydroxy-anthra-quinone, C18H16O5, crystallizes from nitro-methane with two independent mol-ecules in the asymmetric unit. The anthra-quinone core of each independent mol-ecule is essentially planar and both hy-droxy groups on both mol-ecules participate in intra-molecular O-H⋯O(carbon-yl) hydrogen bonds. The butyl chain in one mol-ecule is also angled slightly above the plane of the anthra-quinone moiety, with a maximum deviation of 0.833 (5) Å above the plane for the terminal carbon atom. In contrast, the butyl group on the second mol-ecule is twisted out of the plane of the anthra-quinone core with a torsion angle of 65.1 (3)°, resulting in a maximum deviation of 1.631 (5) Å above the plane for the terminal carbon atom.

Rectifying enhancement induced by conjugation breaking in thiolated arylethynylene single-molecular diodes

Rectifying properties of three cyano side group substituted arylethynylene thiolate molecules are theoretically investigated based on abinitio calculations. The current-voltage curves show that rectifying performance of the junctions correlates negatively with conjugation of the molecules, which reveals a much more pronounced rectification behavior for that with broken-conjugated dihydroanthracene core (sAH) than the counterpart with linearly-conjugated anthracene core (sAC) or cross-conjugated anthraquinone core (sAQ). It is demonstrated that the conjugation breaking induced localization of molecular orbital and asymmetric evolution of its spatial distribution under positive and negative biases play the key role for the rectification enhancement in sAH.

Synthesis and characterisation of liquid crystalline anthraquinone dyes with excellent dichroism and solubility

ABSTRACTA novel series of dichroic anthraquinone dyes have been successfully synthesised with conventional Sonogashira reaction. These synthesised anthraquinone dyes were found to have high dichroic ratios, good solubilities, excellent hues and to be potential candidates for guest–host liquid crystal displays. The dichroic ratio is as high as 13.26, which is in the top level of the anthraquinone dyes reported so far. In addition, this paper provides an effective method to modulate the optic properties of anthraquinone dyes from the molecular level via the introduction of different radicals on the anthraquinone cores.

Impact of medium and ambient environment on the photodegradation of carmine in solution and paints

The fundamental chemistry underlying the photo-induced degradation of cochineal (carmine), a red dye extracted from South American scale insects and used as an artist colorant, and its stability in solution and as a lake pigment in different paint media exposed to light in various ambient environments is examined. The influence of oxygen on the photodegradation was examined for dye solutions and for solid paint samples containing the lake pigment, and the effect of ambient humidity was assessed for the paint samples. The degradation was followed using absorbance spectroscopy, and characterized using IR and LC-MS. Results indicate lower reaction rates of the carminic acid chromophore in solution and in oil paints during light exposure in anoxic conditions; whereas watercolor paints demonstrated a stronger dependence of the rates on the ambient humidity. A ring opening of the anthraquinone core is suggested in the breakdown of the dye and pigment. This study illustrates that solution phase systems may serve as simple models to assess the kinetics and mechanism of photochemical breakdown of organic-based pigments in solid samples.

Syntheses of 2-substituted 1-amino-4-bromoanthraquinones (bromaminic acid analogues) - precursors for dyes and drugs.

Anthraquinone (AQ) derivatives play a prominent role in medicine and also in textile industry. Bromaminic acid (1-amino-4-bromoanthraquinone-2-sulfonic acid) is an important precursor for obtaining dyes as well as biologically active compounds through the replacement of the C4-bromo substituent with different (ar)alkylamino residues. Here we report methods for the synthesis of bromaminic acid analogues bearing different substituents at the 2-position of the anthraquinone core. 1-Aminoanthraquinone was converted to its 2-hydroxymethyl-substituted derivative which, under different reaction conditions, yielded the corresponding carbaldehyde, carboxylic acid, and nitrile derivatives. The latter was further reacted to obtain 1-amino-2-tetrazolylanthraquinone. Subsequent bromination using bromine in DMF led to the corresponding bromaminic acid derivatives in excellent isolated yields (>90%) and high purities. Alternatively, 1-amino-4-bromo-2-hydroxymethylanthraquinone could be directly converted to the desired 2-substituted bromaminic acid analogues in high yields (85–100%). We additionally report the preparation of bromaminic acid sodium salt and 1-amino-2,4-dibromoanthraquinone directly from 1-aminoanthraquinone in excellent yields (94–100%) and high purities. The synthesized brominated AQs are valuable precursors for the preparation of AQ drugs and dyes.

Total synthesis of isoquinocyclinone.

The total synthesis of the heptacyclic natural product isoquinocyclinone has been achieved. A Hauser annulation was used to assemble the anthraquinone core structure. The unique 2,4,5,6-tetrahydropyrrolo[2,3-b]pyrrole substructure was prepared by alkyne addition to a lactone intermediate and subsequent Ni(0) -mediated cyanide addition, the conversion of an O,O- into an N,O-acetal, and final intramolecular N-alkylation.

Phytochemistry and Pharmacognosy of Naturally Occurring Prenyloxyanthraquinones

Several natural compounds containing an anthraquinone core linked to a prenyloxy chain have been reported in the literature in recent years. The discovery in the plant kingdom of such secondary metabolites is a novel acquisition in the phytochemistry research field and in many cases led to a re-consideration of the secondary metabolite pool of well known anthraquinone-containing plants. In this review article we will focus on the phytochemistry and pharmacognosy of prenyloxyanthraquinones putting in evidence the natural sources and their biological properties as anti-microbial and anticancer agents.

A Study on Synthesis of New Blue and Red Color Dyes Based on Anthraquinone Moiety

Three new compounds are synthesized as color filter dyes by substituting a pyridine group into 1,4-position, 1,5-position, and 1,8-position of anthraquinone core moiety. Changes in physical properties of the synthesized compounds according to the substitution position are systematically investigated in terms of optical properties and thermal properties. The extinction coefficient value (ϵ) of the synthesized materials is extremely high and is above 4.22 in a log scale, and Td is above 300°C with high thermal stability.

Chameleonic Reactivity of Vicinal Diazonium Salt of Acetylenyl-9,10-anthraquinones: Synthetic Application toward Two Heterocyclic Targets

The nature of products in the diazotization of 1-amino-2-acetylenyl-9,10-anthraquinones strongly depends on the nature of substituents at both the alkyne and at the anthraquinone core. Donor substitution (NHAr, OH) at the fourth position stabilizes the diazonium salt at C1, decelerating electrophilic cyclization at the arylethynyl substituent at C2. This effect allows the replacement of the diazonium with azide group and subsequent closure into isoxazole ring with preservation of the alkyne. In contrast, electrophilic 5-exo-dig cyclizations to condensed pyrazoles is observed for the combination of donor substituents at the aryl alkyne moiety and an OAc substituent at C4. The latter process provides a new synthetic route to 3-ethynyl-[1,9-cd]isoxazol-6-ones that are difficult to access otherwise. DFT calculations suggest that donor substituents have only a minor effect on alkyne and diazonium polarization in the reactant but provide specific transition state stabilization by stabilizing the incipient vinyl cation. This analysis provides the first computational data on electrophilic 5-exo-dig cyclization in its parent form and the nucleophile-promoted version. This cyclization is a relatively fast but endothermic process that is rendered thermodynamically feasible by the enol-keto tautomerization with concomitant aromatization in the five-membered heteroaromatic ring. Computations suggest that the importance of nucleophilic assistance in the transition state for a relatively weak nucleophile such as water is minor because the energy gain due to the Lewis base coordination to the carbocationic center is more than compensated for by the unfavorable entropic term for the bimolecular proces.

Mono‐ and bis‐quinidine organocatalysts in the asymmetric methanolysis of cis‐1,2,3,6‐tetrahydrophthalic anhydride: A conformational and mechanistic NMR study

The enantioselective organocatalytic methanolysis of cis-1,2,3,6-tetrahydrophthalic anhydride mediated by quinidine derivatives with pyridazine or anthraquinone core was investigated, carrying out a detailed nuclear magnetic resonance study of the conformational preferences of the alkaloid catalysts in the pure solvent and in the presence of the reaction substrates and products. No significant interaction between the meso-anhydride and the alkaloid derivatives was detected. In contrast, evidence for a considerable influence of the alcohol reactant on the conformational state of some of the chiral organocatalysts could be obtained, which lends support to the hypothesis of general-base catalysis mechanism, as opposed to the nuclephilic one. The catalytic properties of the studied derivatives showed no obvious correlation with their conformational prevalence in the resting state, suggesting that the alkaloid 9-O substituent should have a more active role than merely enforcing the chiral fragments to adopt a preferential reactive conformation. A strong enantioselective interaction between the enantiomers of the hemiester product and the alkaloid derivatives was also observed, leading to the conclusion that in the actual reaction conditions a relatively large fraction of the latter is in the protonated form.

Targeting anthracycline-resistant tumor cells with synthetic aloe-emodin glycosides.

The cytotoxic activity of aloe-emodin (AE), a natural anthranoid that readily permeates anthracycline-resistant tumor cells, was improved by the attachment of an amino-sugar unit to its anthraquinone core. The new class of AE glycosides (AEGs) showed a significant improvement in cytotoxicity-up to more than 2 orders of magnitude greater than those of AE and the clinically used anthracycline doxorubicin (DOX)-against several cancer cell lines with different levels of DOX resistance. Incubation with the synthetic AEGs induced cell death in less than one cell cycle, indicating that these compounds do not directly target the cell division mechanism. Confocal microscopy provided evidence that unlike DOX, AEGs accumulated in anthracycline-resistant tumor cells in which resistance is conferred by P-glycoprotein efflux pumps. The results of this study demonstrate that AEGs may serve as a promising scaffold for the development of cytotoxic agents capable of overcoming anthracycline resistance in tumor cells.

Comparison of three GPCR structural templates for modeling of the P2Y12 nucleotide receptor

The P2Y(12) receptor (P2Y(12)R) is an ADP-activated G protein-coupled receptor (GPCR) that is an important target for antithrombotic drugs. Three homology models of P2Y(12)R were compared, based on different GPCR structural templates: bovine rhodopsin (bRHO), human A(2A) adenosine receptor (A(2A)AR), and human C-X-C chemokine receptor type 4 (CXCR4). By criteria of sequence analysis (25.6% identity in transmembrane region), deviation from helicity in the second transmembrane helix (TM2), docked poses of ligands highlighting the role of key residues, accessibility of a conserved disulfide bridge that is reactive toward irreversibly-binding antagonists, and the presence of a shared disulfide bridge between the third extracellular loop (EL3) and the N-terminus, the CXCR4-based model appeared to be the most consistent with known characteristics of P2Y(12)R. The docked poses of agonist 2MeSADP and charged anthraquinone antagonist PSB-0739 in the binding pocket of P2Y(12)R-CXC agree with previously published site-directed mutagenesis studies of Arg256 and Lys280. A sulfonate at position 2 of the anthraquinone core created a strong interaction with the Lys174(EL2) side chain. The docking poses of the irreversibly-binding, active metabolite (existing as two diastereoisomers in vivo) of the clinically utilized antagonist Clopidogrel were compared. The free thiol group of the 4S diastereoisomer, but not the 4R isomer, was found in close proximity (~4.7Å) to the sulfur atom of a disulfide bridge involving Cys175, suggesting greater activity in covalent binding. Therefore, ligand docking to the CXCR4-based model of the P2Y(12)R predicted poses of both reversibly and irreversibly-binding small molecules, consistent with observed pharmacology and mutagenesis studies.