Anthraquinone Derivatives Research Articles

Lucidin 3-methyl ether from Rubia philippinensis suppresses the proliferation of multiple myeloma cells through the promotion of β-catenin degradation

Constitutive accumulation of β-catenin has been frequently observed in multiple myeloma. Extracts from genus Rubia plants exhibit cytotoxic activity against several types of cancer cells; however, little is known about their chemopreventive mechanisms and bioactive metabolites. Purpose: The study aimed to identify the underlying antiproliferative mechanisms of Rubia philippinensis extract in multiple myeloma cells and the major active metabolites responsible for cytotoxic activity of R. philippinensis. The effects of R. philippinensis extracts and lucidin 3-methyl ether on the Wnt/β-catenin pathway were determined by cell-based reporter assay, Western blot analysis, and RT-PCR. The antiproliferative activity was evaluated by cell viability assay and apoptosis analysis in RPMI8226 and MM.1S multiple myeloma cells. R. philippinensis extracts inhibited Wnt/β-catenin signaling and lucidin 3-methyl ether, an anthraquinone derivative, was identified as the major active metabolite responsible for the inhibition of Wnt/β-catenin signaling. Lucidin 3-methyl ether induced β-catenin phosphorylation at Ser33/Ser37/Thr41 residues and promoted proteasomal degradation of β-catenin via a GSK-3β-independent mechanism, thereby downregulating Wnt3a-induced β-catenin response transcription (CRT). Moreover, lucidin 3-methyl ether repressed the expression of β-catenin/T-cell factor (TCF)-dependent genes, such as cyclin D1, c-myc, and axin-2, thus inhibiting MM cell proliferation. Apoptosis was also elicited by lucidin 3-methyl ether, as indicated by the increase in the population of annexin V-FITC positive cells and caspase-3/7 activity in MM cells. These findings indicate that R. philippinensis and its active metabolite lucidin 3-methyl ether prevent cell proliferation through the suppression of the Wnt/β-catenin pathway and exhibit potential as chemopreventive agents for the treatment of MM.

Inhibition of human carbonyl reducing enzymes by plant anthrone and anthraquinone derivatives

Members of the aldo-keto reductase and short-chain dehydrogenase/reductase enzyme superfamilies catalyze the conversion of a wide range of substrates, including carbohydrates, lipids, and steroids. These enzymes also participate in the transformation of xenobiotics, inactivation of the cytostatics doxo- and daunorubicin, and play a role in the development of cancer. Therefore, inhibitors of such enzymes may improve therapeutic outcomes. Plant-derived compounds such as anthraquinones have been used for medicinal purposes for several centuries. In the current study, the inhibitory potential of selected anthrone and anthraquinone derivatives (from plants) was tested on six recombinant human carbonyl reducing enzymes (AKR1B1, AKR1B10, AKR1C3, AKR7A2, AKR7A3, CBR1) isolated from an Escherichia coli expression system. Overall, the least inhibition was observed with the anthrone derivative aloin, while IC50 values obtained with the anthraquinone derivatives (frangula emodin, aloe emodin, frangulin A, and frangulin B) and the aldo-keto reductase AKR1B10 were in the low micromolar range (3.5–16.6 μM). AKR1B1 inhibition was significantly weaker in comparison with AKR1B10 inhibition (IC50 values > 50 μM). The strongest inhibition was observed with the short-chain dehydrogenase/reductase CBR1. AKR7A2, AKR7A3, and AKR1C3 were not, or less inhibited by inhibitor concentrations of up to 50 μM. Analysis of the kinetic data suggests noncompetitive or uncompetitive inhibition mechanisms. The new inhibitors described here may serve as lead structures for the development of future drugs.

The absence of genotoxicity of a mixture of aloin A and B and a commercial aloe gel beverage

Aloe products are increasingly valued as ingredients in food supplements and as flavoring agents. The global Aloe vera market is varied, large, growing, and increasingly important in food, cosmetics, and medicines. Aloin, an anthraquinone glycoside, is one of the major components by weight of the anthraquinone derivatives of Aloe vera gel. Principal metabolites, aloe emodin and emodin, are a source of debate concerning toxic vs salutary effects, hence the accurate toxicological characterization of these compounds has become increasingly important. The purpose of this study was to determine the genotoxic profile of a stabilized Aloe vera juice product derived from the inner filet and marketed as a beverage currently sold in the European Union containing 8 to 10 ppm aloin and a mixture of purified aloin A and B. The present data confirm that a commercial stabilized Aloe vera gel intended for consumption as a juice beverage is not genotoxic. Furthermore, both aloin A and B were negative in the same assays and therefore are also not genotoxic. These results are consistent with the work of other groups and contrast with data obtained using products containing the Aloe vera latex hydroxyanthracene derivatives (HADs).

Advances in Understanding the Role of Aloe Emodin and Targeted Drug Delivery Systems in Cancer.

Cancer is one of the important causes of death worldwide. Despite remarkable improvements in cancer research in the past few decades, several cancer patients still cannot be cured owing to the development of drug resistance. Natural sources might have prominence as potential drug candidates. Among the several chemical classes of natural products, anthraquinones are characterized by their large structural variety, noticeable biological activity, and low toxicity. Aloe emodin, an anthraquinone derivative, is a natural compound found in the roots and rhizomes of many plants. This compound has proven its antineoplastic, anti-inflammatory, antiangiogenic, and antiproliferative potential as well as ability to prevent cancer metastasis and potential in reversing multidrug resistance of cancer cells. The anticancer property of aloe emodin, a broad-spectrum inhibitory agent of cancer cells, has been detailed in many biological pathways. In cancer cells, these molecular mechanisms consist of inhibition of cell growth and proliferation, cell cycle arrest deterioration, initiation of apoptosis, antimetastasis, and antiangiogenic effect. In accordance with the strategy of developing potential drug candidates from natural products, aloe emodin's low bioavailability has been tried to be overcome by structural modifications and nanocarrier systems. Consequently, this review summarizes the antiproliferative and anticarcinogenic properties of aloe emodin, as well as the enhanced activity of its derivatives and the advantages of drug delivery systems on bioavailability.

In Silico-Based Discovery of Natural Anthraquinones with Potential against Multidrug-Resistant E. coli.

E. coli is a Gram-negative bacterium that causes different human infections. Additionally, it resists common antibiotics due to its outer protective membrane. Natural products have been proven to be efficient antibiotics. However, plant natural products are far less explored in this regard. Accordingly, over 16,000 structures covering almost all African medicinal plants in AfroDb in a structural-based virtual screening were used to find efficient anti-E. coli candidates. These drug-like structures were docked into the active sites of two important molecular targets (i.e., E. coli’s Ddl-B and Gyr-B). The top-scoring hits (i.e., got docking scores < −10 kcal/mol) produced in the initial virtual screening (0.15% of the database structures for Ddl-B and 0.17% of the database structures for Gyr-B in the database) were further refined using molecular dynamic simulation-based binding free energy (ΔG) calculation. Anthraquinones were found to prevail among the retrieved hits. Accordingly, readily available anthraquinone derivatives (10 hits) were selected, prepared, and tested in vitro against Ddl-B, Gyr-B, multidrug-resistant (MDR) E. coli, MRSA, and VRSA. A number of the tested derivatives demonstrated strong micromolar enzyme inhibition and antibacterial activity against E. coli, MRSA, and VRSA, with MIC values ranging from 2 to 64 µg/mL. Moreover, both E. coli’s Ddl-B and Gyr-B were inhibited by emodin and chrysophanol with IC50 values comparable to the reference inhibitors (IC50 = 216 ± 5.6, 236 ± 8.9 and 0.81 ± 0.3, 1.5 ± 0.5 µM for Ddl-B and Gyr-B, respectively). All of the active antibacterial anthraquinone hits showed low to moderate cellular cytotoxicity (CC50 > 50 µM) against human normal fibroblasts (WI-38). Furthermore, molecular dynamic simulation (MDS) experiments were carried out to reveal the binding modes of these inhibitors inside the active site of each enzyme. The findings presented in this study are regarded as a significant step toward developing novel antibacterial agents against MDR strains.

In Vitro Anticancer Screening and Preliminary Mechanistic Study of A-Ring Substituted Anthraquinone Derivatives.

Anthraquinone derivatives exhibit various biological activities, e.g., antifungal, antibacterial and in vitro antiviral activities. They are naturally produced in many fungal and plant families such as Rhamnaceae or Fabaceae. Furthermore, they were found to have anticancer activity, exemplified by mitoxantrone and pixantrone, and many are well known redox-active compounds. In this study, various nature inspired synthetic anthraquinone derivatives were tested against colon, prostate, liver and cervical cancer cell lines. Most of the compounds exhibit anticancer effects against all cell lines, therefore the compounds were further studied to determine their IC50-values. Of these compounds, 1,4-bis(benzyloxy)-2,3-bis(hydroxymethyl)anthracene-9,10-dione (4) exhibited the highest cytotoxicity against PC3 cells and was chosen for a deeper look into its mechanism of action. Based on flow cytometry, the compound was proven to induce apoptosis through the activation of caspases and to demolish the ROS/RNS and NO equilibrium in the PC3 cell line. It trapped cells in the G2/M phase. Western blotting was performed for several proteins related to the effects observed. Compound 4 enhanced the production of PARP and caspase-3. Moreover, it activated the conversion of LC3A/B-I to LC3A/B-II showing that also autophagy plays a role in its mechanism of action, and it caused the phosphorylation of p70 s6 kinase.

Tuning the electron transfer rates in near-infrared PbS quantum dots-anthraquinones complex by different chlorine-substituted

The electron transfer (ET) from photoinduced quantum dot (QDs) to electron acceptors through a nanoscale interface plays a crucial part in the functionality and efficiency of QDs-photonic device. The driving force play a crucial part in the ET process of most QD-based system relying on the Marcus ET theory. However, there has rarely reports about tuning the driving force with substituents in acceptor molecules. Here, the ET process between near-infrared (NIR) PbS quantum dot (QDs) and different chlorine-substituted Anthraquinone (AQ) derivatives was studied via the femtosecond transient absorption spectroscopy. The ET process was gradually accelerated by adding chlorine atoms in these AQ molecules. Through the calculation of Marcus ET theory, the driving force of the complexes was gradually increased with the number of chlorine atoms substituted in AQ molecules, thus facilitating ET process. Our findings broaden the application of NIR PbS-organic compounds in photovoltaic devices.

Phenothiazine, anthraquinone and related tricyclic derivatives as inhibitors of d-amino acid oxidase

A recent study has found that phenothiazine, anthraquinone and related tricyclic derivatives are good potency inhibitors of the monoamine oxidase (MAO) enzymes. Based on these findings, the present study investigated the possibility that these compounds may also inhibit another oxidase enzyme, d-amino acid oxidase (DAAO). The results show that seven of the study compounds exhibit good potency inhibition of DAAO with IC50 values that range from 0.309 to 6.27 µM. These values are comparable to that of the reference DAAO inhibitor, 3-methylpyrazole-5-carboxylic acid (IC50 = 1.34 µM). The most potent inhibitors are 2-chloro-7-methoxy-10H-phenothiazine (IC50 = 0.309 µM), 2-chlorophenothiazine (IC50 = 0.332 µM) and quinizarin (IC50 = 0.367 µM). It may be concluded that active DAAO inhibitors may serve as novel lead compounds for the design of DAAO inhibitors, compounds that may find future application in the treatment of neuropsychiatric disorders such as schizophrenia.

Efficient interface modification via multi-site coordination for improved efficiency and stability in organic solar cells

An anthraquinone derivative is developed to modify the SnO2 interface in organic solar cells via the multi-site coordination effect, yielding outstanding photovoltaic performances and device stability.

Reductive Elimination of Alkoxy Group in Anthraquinone Derivatives

Reductive Elimination of Alkoxy Group in Anthraquinone Derivatives

The versatile emodin: A natural easily acquired anthraquinone possesses promising anticancer properties against a variety of cancers.

Cancers are generally recognized as the leading cause of death and a predominant barrier to prolonging life expectancy in both developed and developing countries. Emodin is a typical anthraquinone derivative from various plants that exhibits a wide spectrum of biological activities, such as anticancer, antibacterial, hepatoprotective and anti-inflammatory activities. Much previous preclinical evidence has demonstrated that emodin exhibits reliable effects on several cancer types, including lung cancer, liver cancer, colon cancer, breast cancer, pancreatic cancer, leukemia, cervical cancer, and ovarian cancer, etc. The related molecular mechanisms corresponding to the anticancer activities of emodin are involved in the induction of apoptosis, inhibition of cell proliferation, enhanced reactive oxygen species (ROS) accumulation, and induction of autophagy, etc. In the present review, we summarized the sources, anticancer properties in vitro and in vivo, molecular mechanisms, metabolic transformation and toxicities of emodin. In addition, we also discussed the limitations of the present investigations of emodin against cancers and gave some perspectives for them, which would be beneficial for the further exploration and development of this natural compound as a clinical cancer drug.

Emodin ameliorates antioxidant capacity and exerts neuroprotective effect via PKM2-mediated Nrf2 transactivation

Pyruvate kinase M2 (PKM2) is overexpressed in neuronal cells. However, there are few studies on the involvement of PKM2 modulators in neurodegenerative diseases. Emodin, a dominating anthraquinone derivative extracting from the rhizome of rhubarb, has received expanding consideration due to its pharmacological properties. Our data reveal that emodin could resist hydrogen peroxide- or 6-hydroxydopamine-mediated mitochondrial fission and apoptosis in PC12 cells (a neuron-like rat pheochromocytoma cell line). Notably, emodin at nontoxic concentrations significantly inhibits PKM2 activity and promotes dissociation of tetrameric PKM2 into dimers in cells. The PKM2 dimerization enhances the interaction of PKM2 and NFE2-related factor 2 (Nrf2), which further triggers the activation of the Nrf2/ARE pathway to upregulate a panel of cytoprotective genes. Modulating the PKM2/Nrf2/ARE axis by emodin unveils a novel mechanism for understanding the pharmacological functions of emodin. Our findings indicate that emodin is a potential candidate for the treatment of oxidative stress-related neurodegenerative disorders.

Phenothiazine, anthraquinone and related tricyclic derivatives as inhibitors of monoamine oxidase

Inhibitors of the monoamine oxidase (MAO) enzymes are important agents for the treatment of central nervous system disorders and have established roles in the therapy of neuropsychiatric diseases such as depression and in the neurodegenerative disorder, Parkinson’s disease. A number of good potency MAO inhibitors consist of tricyclic ring systems as exemplified by the structures of harmine and the phenothiazine compound methylene blue. In an attempt to discover novel MAO inhibitors, 30 phenothiazine, anthraquinone and related tricyclic derivatives were selected and evaluated as potential inhibitors of human MAO-A and MAO-B. The results show that, in general, the tricyclic compounds are specific inhibitors of MAO-A over the MAO-B isoform. Quinizarin (IC50 = 0.065 µM), 2-chloro-7-methoxy-10H-phenothiazine (IC50 = 0.576 µM) and xanthone (IC50 = 0.623 µM) proved to be the most potent MAO-A inhibitors, while the most potent MAO-B inhibition was recorded with 2-chloro-7-methoxy-10H-phenothiazine (IC50 = 1.34 µM), 1,2-diaminoanthraquinone (IC50 = 2.41 µM) and emodin (IC50 = 3.24 µM). These compounds may undergo further preclinical evaluation and development, and may also serve as potential lead compounds for the future design of MAO inhibitors.

Liposome-encapsulated anthraquinone improves efficacy and safety in triple negative breast cancer

Breast cancer is the most common cancer among women and a leading cause of death worldwide. Triple negative breast cancer (TNBC) is a highly aggressive subtype which is the most challenging to treat. Due to heterogeneity and a lack of specific molecular targets, small molecule-based chemotherapy is the preferred course of treatment. However, these drugs have high toxicity due to off-target effects on healthy tissues, and tumors may develop resistance. Here, we present a polyethylene glycol-modified nanoscale liposomal formulation (LipoRV) of a new anthraquinone derivative which has potent effects on multiple TNBC cell lines. LipoRV readily inhibited the cell cycle, induced cell apoptosis, and reduced long-term proliferative potential of TNBC cells. In a xenograft animal model, LipoRV successfully cleared tumors and demonstrated a good safety profile, without detrimental effects on biochemical markers. Finally, RNA sequencing of LipoRV-treated TNBC cells was carried out, indicating that LipoRV may have immunomodulatory properties. These findings demonstrate that a liposomal anthraquinone-based molecule has excellent promise for TNBC therapy in the future.

Naphthopyrone and anthraquinone derivatives from Comanthus delicata

• Fourteen pigments were isolated from the crinoid Comanthus delicata . • Five new napthopyrone derivatives, delicapyrons A − E ( 1 − 5 ), were elucidated. • 1 and 2 possess novel bisnaphthopyrone structures firstly described to date. • 7 significantly induced apoptosis in SK-Mel-2 cells and increased caspase 3 activity. Five new naphthopyrone derivatives, delicapyrons A − E ( 1 − 5 ), and nine known compounds were isolated from the MeOH extract of the Vietnamese crinoid Comanthus delicata . Their structures were elucidated by spectroscopic methods, including HRQTOFMS and 1D and 2D NMR experiments. The new compounds 1 and 2 possess novel bisnaphthopyrone structures containing linear and angular naphthopyrone units that were linked together via a methylene group and are first described herein. Among the isolated compounds, delicapyron B ( 2 ) exhibited significant and selective cytotoxicity against SK-Mel-2 and MCF7 human cancer cell lines, whereas delicapyron D ( 4 ), comaparvin ( 6 ), 6-methoxycomaparvin ( 7 ), and 5,8-dihydroxy-6,10-dimethoxy-2-methyl-4 H -naphtho[1,2- b ]pyran-4-one ( 8 ) showed this activity against the SK-Mel-2 cell line. In addition, compound 7 significantly induced cell death through apoptosis in SK-Mel-2 cells and increased caspase 3 activity at both 20 and 100 μM.

3D-QSAR, Molecular Docking, and MD Simulations of Anthraquinone Derivatives as PGAM1 Inhibitors.

PGAM1 is overexpressed in a wide range of cancers, thereby promoting cancer cell proliferation and tumor growth, so it is gradually becoming an attractive target. Recently, a series of inhibitors with various structures targeting PGAM1 have been reported, particularly anthraquinone derivatives. In present study, the structure–activity relationships and binding mode of a series of anthraquinone derivatives were probed using three-dimensional quantitative structure–activity relationships (3D-QSAR), molecular docking, and molecular dynamics (MD) simulations. Comparative molecular field analysis (CoMFA, r2 = 0.97, q2 = 0.81) and comparative molecular similarity indices analysis (CoMSIA, r2 = 0.96, q2 = 0.82) techniques were performed to produce 3D-QSAR models, which demonstrated satisfactory results, especially for the good predictive abilities. In addition, molecular dynamics (MD) simulations technology was employed to understand the key residues and the dominated interaction between PGAM1 and inhibitors. The decomposition of binding free energy indicated that the residues of F22, K100, V112, W115, and R116 play a vital role during the ligand binding process. The hydrogen bond analysis showed that R90, W115, and R116 form stable hydrogen bonds with PGAM1 inhibitors. Based on the above results, 7 anthraquinone compounds were designed and exhibited the expected predictive activity. The study explored the structure–activity relationships of anthraquinone compounds through 3D-QSAR and molecular dynamics simulations and provided theoretical guidance for the rational design of new anthraquinone derivatives as PGAM1 inhibitors.

Melanosis coli as a factor in the development of colorectal cancer

Melanosis coli is characteristic of patients with a long history of constipation and the use of laxatives – anthraquinone derivatives, which are quite prescribed by doctors and patients independently. As a rule, melanosis develops after 4–9 months of taking drugs from this group and is most common in women in the older age group. Pathogenetically, melanosis is characterized by the deposition of pigment in the lamina propria of the mucous membrane, manifested by a pronounced dark coloration of the mucosa, depending on the degree of pigmentation of the colon, melanosis is divided into three degrees. The most common localization is in the right colon, but cases with the spread of pigmentation to the left colon and other parts have been described. Diagnosis does not cause difficulties, melanosis coli is detected during routine endoscopic examination, and is confirmed by pathomorphological examination. Melanosis is an actual problem in terms of the risk of developing colorectal cancer (CRC). There are already convincing data proving that the frequency of detection of adenomas increases not only due to the absence of pigment accumulation by them, but also the pathogenetic aspects of the influence of melanosis on the occurrence and development of adenomas have been described. Proteomic analysis allows to determine the expression of various proteins, which confirms the role of melanosis in the development of colorectal cancer. It is also interesting to note that sometimes there are some difficulties in the differential diagnosis of melanosis, for example, with ischemic lesions of the colon. Patients with melanosis coli require close attention, timely diagnosis and treatment.

Virtual Screening to Identify the Protein Network Interaction of Hypericin with Red Complex Pathogens

Introduction: Hypericin is the anthraquinone derivative and has many properties like antiviral, antifungal and antibacterial. The red complex pathogens which include Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia in association with other microbes found in the periodontal pockets, cause severe inflammation resulting in periodontitis. Novel bioactive agents from several sources have been tested against the microbial pathogens to deduce antimicrobial activity. &#x0D; Aim: The aim of the study is to virtually screen and identify the protein network interaction of hypericin in red complex pathogens.&#x0D; Methodology: The STITCH v5.0 pipeline was primarily used to identify the drug-protein interactions. The VirulentPred and VICMPred software were used for elucidating the functional class of the proteins and virulence property. The sub cellular localization of virulent proteins was analysed with pSORTb v3.0 software. Further, the epitopes in virulent proteins were identified using BepiPred v1.0 linear epitope prediction tool.&#x0D; Results: Heat shock protein 90 of Porphyromonas gingivalis were found to involve in the cellular process and DNA topoisomerase IV subunit B, heat shock protein 90, DNA gyrase subunit A and DNA gyrase subunit B of Treponema denticola were found to be the virulent factors. The virulent proteins were located in the cytoplasm, which would further increase the potential effect of the drug to serve as antimicrobial agents. Finally, epitopes were predicted on the virulent proteins which can be specifically docked to further ascertain their interactions with the phytocompound.&#x0D; Conclusion: Hypericin with all its potential and biological benefits can be addressed, can be used as an antimicrobial agent to eradicate dental pathogens which are recalcitrant to treatment. The mode of action of hypericin is, it is targeting crucial proteins in red complex pathogens. Further in vitro studies should be performed on a wide range of pathogens to substantiate the true interactions between the drugs and the protein repertoire of pathogens.

A new anthraquinone from mangrove endophytic fungus Aspergillus sp. 16-5C

A new anthraquinone, asperquinone A (1), and four known anthraquinone derivatives 2–5 were isolated from the mangrove endophytic fungus Aspergillus sp. 16-5C. These structures were elucidated by spectroscopic analysis and the absolute configuration of 1 was unambiguously determined by ECD calculation. Compounds 1–5 showed no significant inhibitory effect against Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB).

Phytochemistry, Ethnopharmacological Uses, Biological Activities, and Therapeutic Applications of Cassia obtusifolia L.: A Comprehensive Review

Cassia obtusifolia L., of the Leguminosae family, is used as a diuretic, laxative, tonic, purgative, and natural remedy for treating headache, dizziness, constipation, tophobia, and lacrimation and for improving eyesight. It is commonly used in tea in Korea. Various anthraquinone derivatives make up its main chemical constituents: emodin, chrysophanol, physcion, obtusifolin, obtusin, au rantio-obtusin, chryso-obtusin, alaternin, questin, aloe-emodin, gluco-aurantio-obtusin, gluco-obtusifolin, naphthopyrone glycosides, toralactone-9-β-gentiobioside, toralactone gentiobioside, and cassiaside. C. obtusifolia L. possesses a wide range of pharmacological properties (e.g., antidiabetic, antimicrobial, anti-inflammatory, hepatoprotective, and neuroprotective properties) and may be used to treat Alzheimer’s disease, Parkinson’s disease, and cancer. In addition, C. obtusifolia L. contributes to histamine release and antiplatelet aggregation. This review summarizes the botanical, phytochemical, and pharmacological features of C. obtusifolia and its therapeutic uses.