Emodin Derivatives Research Articles

Emodin derivatives as novel potent DPP-4 inhibitors: Design, synthesis, and in vitro evaluation

Dipeptidyl peptidase-4 (DPP-4) inhibitors have gained recognition as effective agents for lowering blood sugar levels, significantly improving glycemic control for individuals with type 2 diabetes mellitus (T2DM). Emodin, an anthraquinone derived from the traditional herbs rhubarb (Rheum officinale) and Polygonum cuspidatum, has been identified as an important component in the development of new treatments for diabetes. In the present work, we explored the DPP-4 inhibitory activity of emodin derivatives. This study focused on the design, synthesis, and evaluation of emodin derivatives for their in vitro DPP-4 inhibitory activity. Molecular docking studies indicated that 3-o-toluoyl emodin (OTEM) had the lowest docking score (−134.073) against the DPP-4 protein among the tested compounds. OTEM also achieved the highest drug-likeness score of 0.56 and demonstrated DPP-4 inhibitory activity, with an IC50 value of 0.77 μM. Furthermore, structure-activity relationship (SAR) analysis suggested that the addition of an ortho-toluoyl group at the C-3 position could enhance DPP-4 inhibition. Additionally, quantitative structure-activity relationship (QSAR) model assessments revealed that log P was the only descriptor significantly influencing DPP-4 inhibitory activity. Therefore, the current study indicates that OTEM could serve as a promising lead compound to address the demand for antidiabetic agents.

Emodin Alcohols: Design, Synthesis, Biological Evaluation and Multitargeting Studies with DNA, RNA, and HSA.

A series of novel emodin alcohols were designed and prepared in an effort to overcome the increasing microorganism resistance. Novel emodin alcohols were prepared from commercial emodin and different nitrogen-containing heterocycles via different synthetic strategies, such as O-alkylation and N-alkylation. The antimicrobial activity of synthesized emodin compounds was evaluated in vitro by a two-fold serial dilution technique. The interaction of emodin compound 3d with biomolecule was researched using UV-vis spectroscopic method and fluorescence spectroscopy. Emodin compound 3d containing 2-methyl-5-nitro imidazole ring showed relatively good antimicrobial activity. Notably, it exhibited equivalent activity against S. aureus in comparison to the reference drug norfloxacin (MIC = 4 μg/mL). The combination of strong active compound 3d with reference drugs showed better antimicrobial activity with less dosage and a broader antimicrobial spectrum than their separate use. Further research displayed that emodin compound 3d could intercalate into S. aureus DNA to form the 3d-DNA complex, which might correlate with the inhibitory activity. The hydrogen bonds were found between S. aureus DNA gyrase and strong active compound 3d during the docking research, which were in accordance with the spectral experiment results. The interaction with yeast RNA of compound 3d could also form a complex via hydrogen bonds. The hydrogen bonds were found to play a major role in the transportation of emodin compound 3d by human serum albumin (HSA), as confirmed by molecular simulation. This work provides a promising starting point to optimize the structures of emodin derivatives as potent antimicrobial agents.

Investigating emodin derivatives against SARS-CoV-2 found in medicinal herbs

SARS-CoV-2 continues to mutate and circulate at alarming levels around the world and is exemplified by the emergence of the new variant JN.1. The emergence of novel SARS-CoV variants underscores the urgency for the development of new drugs. Phytochemicals, known for their safety and efficacy, have been widely used to address various ailments. This study aims at identifying the anti-SARS-CoV potential of emodin, a bioactive anthraquinone, and its derivatives. Key proteins, including hemagglutinin-esterase (HE), papain-like protease (PLpro), major protease (3CLpro), non-structural protein (nsp3) and spike protein(S) of SARS-CoV, were used as protein targets for the virtual screening of 110 emodin derivatives (ED) and remdesivir a proven antiviral drug. Among the 110 derivatives, ED21, ED25, ED5 inhibited HE, 3CLpro and S protein, respectively. ED29 inhibited both PLpro and nsp3 with high binding affinity. Similar receptor binding sites were occupied by remdesivir and emodin derivatives. These emodin derivatives are bound to similar amino acids in receptors as compared to remdesivir. Further dynamic simulations studies with ED21-HE, ED25-3CLpro, ED5-S, ED29-PLpro and ED29-nsp3 complexes showed all of them are stable with minimum root mean square deviation (RMSD), root mean square fluctuation (RMSF), solvent-accessible surface area (SASA) and radius of gyration (Rg) and are comparable to APO protein. All the ligands accepted Lipinski's rule of five. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis revealed only ED21 and ED5 as promising druglike candidates that can have high therapeutic value and no side effects. These in-silico findings contribute to the development of potent SARS-CoV-2 inhibitors, potentially advancing the quest for effective antiviral drugs.

Acryloyl esters of emodin for waterless dyeing and toxicological studies

AbstractTraditional textile dyeing processes usually require large quantities of water and energy and generate wastewater that can be harmful to the environment. Dyeing in supercritical carbon dioxide (sc‐CO2) media is promising in textile coloration due especially to it providing a waterless process and eliminating the need for an energy intensive drying step. The natural anthraquinone emodin showed promising results for dyeing different fibres through sc‐CO2 process. However, emodin is mutagenic. The aim of this study was to develop non‐mutagenic derivatives of emodin that can be applied to textiles using sc‐CO2. Emodin structure was modified incorporating acryloyl groups, which are considered suitable for decreasing potential for DNA intercalation, and thus mutagenicity. The presence of acryloyl groups would also enable atmospheric plasma induced bonding with fibres. Molecular modelling studies showed that emodin derivatives became less planar with increasing number of attached acryloyl groups, making intercalation unlikely. The derivatives produced were tested to assess mutagenicity in vitro (Salmonella/microsome assay, TA1537, 10% S9) and in vivo (micronucleus test in hemocytes of aquatic crustacean). We found that emodin can be derivatised using acryloyl chlorides to give mono‐ and di‐acrylate esters suitable for dyeing polyester fibres in sc‐CO2. However, the new dyes presented mutagenicity for both in vitro and in vivo. Although the derivatives provided greenish‐yellow alternatives to emodin for dyeing synthetic fibres, they do not appear to be viable alternatives from the point of view of preserving human and environmental health. Plasma bonding studies are underway.

Emodin derivatives as promising multi-aspect intervention agents for amyloid aggregation: molecular docking/dynamics simulation, bioactivities evaluation, and cytoprotection.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with complex pathogenesis. Despite the pathogenesis is unknown, the misfolding and accumulation of β-amyloid (Aβ) peptide play the important role in the occurrence and development of AD. Hence, multi-aspect intervention of the misfolded Aβ peptides aggregation is a promising therapy for AD. In previous work, we obtained the emodin derivatives (a-d) with multifunctional anti-AD activities, including metal ions chelation, cholinesterase inhibition, and hydroxyl/superoxide anion radical elimination. In this work, we predicted the interaction of emodin derivatives (a-d) with Aβ by combining molecular docking simulation and molecular dynamics simulation, and evaluated the ability to intervene with the self-, Cu2+- and AChE-induced Aβ aggregation via in vitro methods. The results indicated that a-d could act as the potent multi-aspect intervention agents for Aβ aggregation. In addition, a-d could effectively eliminate peroxyl radical, had virtually no neurotoxicity, and protect cells from oxidative and Aβ-induced damage. The prediction results of ADMET properties showed that a-d had suitable pharmacokinetic characteristics. It suggested that a-d could act as the promising multi-targeted directed ligands (MTDLs) for AD. These results may provide meaningful information for the development of the potential MTDLs for AD which are modified from natural-origin scaffolds.

Emodin derivative E35 and its combination with autophagy inhibitor against acute myeloid leukemia cells in vitro and in vivo

Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy with poor prognosis and high recurrence rate. The discovery of more effective therapeutic strategies for AML plays a crucial role. The present work showed that E35, a novel derivative of emodin, significantly inhibited cell proliferation and induced autophagy and apoptosis in AML cells. Treatment with E35 markedly induced Beclin-1, LC3-II, cleaved Caspase-9 and PARP, and suppressed mitogen-activated protein kinase (MAPK) pathway. E35 exposure evoked autophagic activity prior to apoptosis induction, and autophagy inhibition by 3-methyladenine (3-MA) dramatically increased E35-induced apoptosis in both AML cell lines and patient-derived AML cells. Nevertheless, study on AML xenograft model showed that the combination E35 with 3-MA exhibited much more inhibitory effects on leukemia cell growth in vivo. No obvious adverse reactions occurred in the xenograft animals administered E35 alone or its cotreatment with 3-MA. These findings suggest that E35 could exert anti-leukemia effects, and that the combination of E35 and autophagy inhibitor might prove a more highly efficient strategy for AML treatment.

Research Progress and New Perspectives of Anticancer Effects of Emodin.

Emodin is a natural compound found in several traditional Chinese medicines, including Rheum palmatum and Polygonum cuspidatum. Recent studies have shown that emodin exhibits potent anticancer effects against a variety of cancer types, including liver, breast, lung, and colon cancer. Emodin's anticancer effects are mediated through several mechanisms, including inhibition of cell proliferation, induction of apoptosis, and suppression of tumor angiogenesis and metastasis. In this review, we provide an overview of recent research progress and new perspectives on emodin's anticancer effect. We summarize the current understanding of the molecular mechanisms underlying emodin's anticancer activity, including its effects on signaling pathways such as the PI3K/Akt, MAPK, and NF-[Formula: see text]B pathways. We also discuss the potential of emodin as a therapeutic agent for cancer treatment, including its use in combination with conventional chemotherapeutic drugs and as a sensitizer for radiotherapy. Furthermore, we highlight recent advances in the development of emodin derivatives and their potential as novel anticancer agents. Finally, we discuss the challenges and opportunities for the translation of emodin's anticancer properties into clinical applications, including the need for further preclinical and clinical studies to evaluate its safety and efficacy. In conclusion, emodin represents a promising natural compound with potent anticancer properties, and its potential as a therapeutic agent for cancer treatment warrants further investigation. This review provides a comprehensive overview of the current research progress and new perspectives on emodin's anticancer effects, which may facilitate the development of novel therapeutic strategies for cancer treatment.

Antibacterial constituents of Rumex nepalensis spreng and its emodin derivatives

The CH2Cl2−MeOH (1:1) extract of roots of Rumex nepalensis (Polygonaceae) displayed significant antibacterial activity against five bacterial strains with MICs (62.5–31.2 μg.mL−1). The EtOAc soluble fraction displayed a significant activity against the same strains with MICs (31.2–3.9 μg.mL−1). The purification of the EtOAc fraction yielded one new phenylisobenzofuranone derivative, berquaertiide (1), along with 19 known compounds (2–20). Their structures were elucidated based on the analysis of their NMR and MS data. All the isolated compounds were assessed for their antibacterial activity. Compound 2 was the most active against all the tested strains (15.7 to 1.9 μg.mL−1), while compounds 3–7 displayed good activities on at least one of the tested strains. In addition, seven analogues (21–27) of compound 2 were prepared and further assessed for their antibacterial activity. Compounds 26 and 27 were most active than 2 against Salmonella enterica and Klebsiella pneumoniae with MIC (125 and 15.6 μg.mL−1, respectively).

Therapeutic Potential of Emodin for Gastrointestinal Cancers.

Gastrointestinal (GI) cancers cause one-third of all cancer-related deaths worldwide. Natural compounds are emerging as alternative or adjuvant cancer therapies given their distinct advantage of manipulating multiple pathways to both suppress tumor growth and alleviate cancer comorbidities; however, concerns regarding efficacy, bioavailability, and safety are barriers to their development for clinical use. Emodin (1,3,8-trihydroxy-6-methylanthraquinone), a Chinese herb-derived anthraquinone, has been shown to exert anti-tumor effects in colon, liver, and pancreatic cancers. While the mechanisms underlying emodin’s tumoricidal effects continue to be unearthed, recent evidence highlights a role for mitochondrial mediated apoptosis, modulated stress and inflammatory signaling pathways, and blunted angiogenesis. The goals of this review are to (1) highlight emodin’s anti-cancer properties within GI cancers, (2) discuss the known anti-cancer mechanisms of action of emodin, (3) address emodin’s potential as a treatment complementary to standard chemotherapeutics, (4) assess the efficacy and bioavailability of emodin derivatives as they relate to cancer, and (5) evaluate the safety of emodin.

Antiviral Activities of Halogenated Emodin Derivatives against Human Coronavirus NL63.

The current COVID-19 outbreak has highlighted the need for the development of new vaccines and drugs to combat Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2). Recently, various drugs have been proposed as potentially effective against COVID-19, such as remdesivir, infliximab and imatinib. Natural plants have been used as an alternative source of drugs for thousands of years, and some of them are effective for the treatment of various viral diseases. Emodin (1,3,8-trihydroxy-6-methylanthracene-9,10-dione) is a biologically active anthraquinone with antiviral activity that is found in various plants. We studied the selectivity of electrophilic aromatic substitution reactions on an emodin core (halogenation, nitration and sulfonation), which resulted in a library of emodin derivatives. The main aim of this work was to carry out an initial evaluation of the potential to improve the activity of emodin against human coronavirus NL63 (HCoV-NL63) and also to generate a set of initial SAR guidelines. We have prepared emodin derivatives which displayed significant anti-HCoV-NL63 activity. We observed that halogenation of emodin can improve its antiviral activity. The most active compound in this study was the iodinated emodin analogue E_3I, whose anti-HCoV-NL63 activity was comparable to that of remdesivir. Evaluation of the emodin analogues also revealed some unwanted toxicity to Vero cells. Since new synthetic routes are now available that allow modification of the emodin structure, it is reasonable to expect that analogues with significantly improved anti-HCoV-NL63 activity and lowered toxicity may thus be generated.

An Update of Anthraquinone Derivatives Emodin, Diacerein, and Catenarin in Diabetes.

Diabetes is part of metabolic diseases and is characterized by high blood sugar levels over a prolonged period as result of an insulin-deficient production or an inappropriate response to insulin by our cells. This chronic disease was the direct cause of 1.6 million deaths in 2016 as reported by the World Health Organization. Emodin is a natural product and active ingredient of various Chinese herbs with the chemical formula 1,3,8-trihydroxy-6-methylanthraquinone. Diacerein is another naturally occurring anthraquinone (1,8-diacetoxy-3-carboxyanthraquinone) commonly used as commercial drug to treat osteoarthritis. These two anthraquinone derivatives have been shown to exert antidiabetic activities. Emodin seems to enhance the glucose tolerance and insulin sensibility via activation of PPARγ and modulation of metabolic-related genes. Diacerein seems to decrease inflammatory cytokines and increase insulin secretion enhancing insulin sensibility and therefore improving glucose control. Other naturally occurring anthraquinone derivatives, such as catenarin (1,4,6,8-tetrahydroxy-3-methylanthraquinone), have been shown to have antidiabetic activities although few studies have been performed. The synthesis of new emodin derivatives is increasing, but these new molecules have not been tested for diabetes treatment. In the current work, available literature on anthraquinone derivatives' effects in diabetes disease is reviewed. Moreover, we discuss the chemistry, food sources, bioavailability, and toxicity of the naturally occurring anthraquinone with antidiabetic effects.

Emodin derivatives with multi-factor anti-AD activities: AChE inhibitor, anti-oxidant and metal chelator

Four new emodin derivatives which inhibit Alzheimer's disease were designed and the related activities such as cholinesterase inhibitor, anti-oxidant and metal chelator were evaluated. Among them, compounds a and b had comparable inhibitory activities of acetylcholinesterase to control drug tacrine. In particular, compound a had the strongest inhibitory effect on acetylcholinesterase with IC50 value of 0.067 μM. Kinetic analysis of a and b indicated the mixed-type inhibition. Molecular simulation studies showed that they could bind both the catalytically active site and the peripheral anion site of acetylcholinesterase. The antioxidant activities were determined using the superoxide radical (.O2–) and hydroxyl radical (.OH) assays. All derivatives showed high anti-oxidative activities. The mechanisms of electrochemical oxidation of emodin and its derivations were studied by cyclic voltammetry. In addition, compounds a-d exhibited obvious chelating abilities with Cu2+, Fe3+, Zn2+ and Al3+ ions. Interestingly, complexes chelated with Cu2+ and Zn2+ showed better acetylcholinesterase inhibitory activities and antioxidative activities. Taken together, emodin derivatives have multi-factor anti-Alzheimer's disease activities, and they are worthy of further study as potential candidate drugs for Alzheimer's disease.

Effects of Emodin Derivative on Cell Cycle, Apoptosis and NF-κB Pathway in Burkitt Lymphoma Cells

To investigate the effect and mechanism of a novel emodin derivative YX-18 on Burkitt lymphoma (BL) cells. MTT assay was used to detect the effect of YX-18 on the proliferation of BL cell lines CA46 and Raji. Annexin V-PE/7-AAD double staining assay was used for detecting the effect of YX-18 on the apoptosis of CA46 and Raji cells. PI/RNase staining was used to test the effect of YX-18 on CA46 and Raji cell cycle. JC-1 method was used to measure the changes of mitochondrial membrane potential after YX-18 treatment, and DAPI staining was used to detect the morphology of apoptotic cells. Western blot was used to analyze the distribution changes of NF-κB pathway protein (P65, P-P65, IκB, P-IκB) in the cytoplasm and cell nucleus, and also the expression changes of cyclin-related protein P21, CDK2, P-CDK2, Cycling D1, Cycling E1, and the apoptosis-related protein Caspase-3, Caspase-8, Caspase-9 and the proliferation-related protein C-MYC, BCL-2 by YX-18. Real-time fluorescence-quantitative PCR was used to evaluate the effects of YX-18 on mRNA levels of C-MYC and Ki-67 genes in CA46 and Raji cells, and EBNA-1 and EBER genes of EBV in Raji (EBV+) cells. Novel Emodin derivative YX-18 could effectively inhibit the proliferation of BL cell lines CA46 and Raji, showing a time-dependent effect (24, 48 and 72 h: rCA46=0.89, 0.75, 0.75, rRaji=0.87, 0.73, 0.64). IC50 of CA46 cells and Raji cells treated with YX-18 for 24 h was 1.77±0.04 µmol/L and 1.97±0.22µmol/L, respectively. CA46 cells and Raji cells were treated with YX-18 at concentration of 2.0 and 4.0 µmol/L for 24 h. Compared with the control group, both strains of cells showed a very significant apoptosis at the concentration of 2.0 and 4.0 µmol/L (P<0.01), showing a concentration-dependent effect (rCA46=0.99, rRaji=0.92). Moreover, the cleavaged Caspase-3, 8 and 9 proteins were activated by YX-18 into verious degrees in both two cell lines. Both the two cell lines displayed by YX-18 cell cycle arrest at G0/G1 phase (P<0.01) after exposed to YX-18 for 24 hours at the concentration of 1.0, 2.0 µmol/L in CA46 cells and at 0.5 and 1 µmol/L in Raji cells, respectively. YX-18 decreased expression level of cyclin D1, cyclin E1, CDK2, p-cdk2 proteins and increased p21Waf1/Cip1 level in CA46 and Raji cells. YX-18 significantly declined mitochondrial membrane potential in both cells at the concentration of 2.0 and 4.0 µmol/l (P<0.01) with concentration-dependent manner (rCA46=-0.96, rRaji=-0.99). Western blot tests indicated that YX-18 down-regulated nucleus P65 and intracellular cytoplasm P65, P-IκB, P-P65 protein, and upregulated intracellular IκB level with dose-dependent manner. Meanwhile, the expression level of the cell proliferation-related molecules C-MYC and BCL-2 was decreased significantly. YX-18 suppressed mRNA levels of C-MYC and Ki-67 in both cell lines, and EBNA-1 in EBV-positive Raji cells in a concentration-dependent way. The novel emodin derivative YX-18 can significantly inhibit the proliferation of Burkitt lymphoma cells, and induce the cell apoptosis and cycle arrest. The inhibitory effect of YX-18 on the proliferation of Burkitt lymphoma cells may be related with the effect of Caspase apoptosis pathway, the proliferation and apoptosis-related molecules, such as C-MYC and Ki-67, and also to the inhibition of NF-κB pathway.

In Vitro Investigation of the Cytotoxic Activity of Emodin 35 Derivative on Multiple Myeloma Cell Lines

Background Bortezomib is used for treating multiple myeloma (MM); however, it has considerable adverse effects. Emodin has been reported to exhibit inhibitory effects on MM cell lines. We investigated the efficacy of emodin 35 (E35), an emodin derivative, using U266 and MM1s cell lines in treating MM and the efficacy of combining bortezomib and E35. Methods MTT assays were used to observe the effects of E35 on MM cell growth. The effects on cellular apoptosis were then observed using Annexin V/propidium iodide (PI) staining assay. The expression of apoptosis-related genes, including the caspase family, was examined. The efficacy of combining bortezomib and E35 was investigated by examining the expression of the Akt/mTOR/4EBP1 signaling pathway-related proteins. Results We report that E35 inhibited the growth of U266 and MM1s cells by inducing cellular apoptosis. Moreover, E35 downregulated the expression of apoptosis-related genes and suppressed the phosphorylation of Akt/mTOR/4EBP1 signaling pathway-related genes, thus exhibiting synergistic effects with bortezomib. All observed effects were dose-dependent. Conclusion The results showed that E35 exhibited cytotoxic effects in MM cell lines in protein levels. Thus, E35, particularly in combination with bortezomib, may be considered as a promising treatment for MM; however, this requires further investigation in vivo.

Design, synthesis, and biological evaluation of pyrazole-linked aloe emodin derivatives as potential anticancer agents.

In connection with our continuous efforts to generate new derivatives from lead compounds isolated from traditional medicinal plants, a series of aloe-emodin derivatives (6a-6e) were synthesized and assessed for their potential anticancer activity against a panel of cancer cell lines. The results showed that most of the derivatives are more active than the aloe-emodin and particularly, 6b and 6e manifested potent activity with IC50 values of 1.32 & 1.6 μM and 0.99 & 2.68 μM against MDA-MB-231 and MCF-7 cells, respectively. Moreover, 6b and 6e induce early and late apoptosis as well as arrest the cell cycle at the G2/M phase in MDA-MB-231 cells. In conclusion, the results confirmed that the aloe-emodin derivatives could be a potential drug candidate for better treatment of breast cancer.

Emodin Derivatives as Multi-Target-Directed Ligands Inhibiting Monoamine Oxidase and Antagonizing Vasopressin V1A Receptors.

The brain neurotransmitter level is associated with the pathology of various neurodegenerative diseases, and age-dependent increase in the blood level of vasopressin, human brain monoamine oxidase (hMAO) level, oxidative stress, and imbalance in aminergic signaling are common disease-modifying factors leading to various neurodegenerative disorders. Based on the reports of emodin in hMAO inhibition and antagonist effect on the vasopressin V1A receptor, in this study we synthesized six emodin derivatives and evaluated their effects on MAO activity and G protein-coupled receptors. Among them, 4-hydroxyemodin and 5-hydroxyemodin were potent inhibitors of hMAO, and 2-hydroxyemodin and 5-hydroxyemodin were good V1AR antagonists. In silico molecular docking simulation revealed that the hydroxyl group at C2, C4, and C5 of the respective compounds interacted with prime residues, which corroborates the in vitro effect. Likewise, these three derivatives were predicted to have good drug-like properties. Overall, our study demonstrates that the hydroxyl derivatives of emodin are multi-target-directed ligands that may act as leads for the design and development of a therapy for central nervous system disorders.

Study on the antibacterial activities of emodin derivatives against clinical drug-resistant bacterial strains and their interaction with proteins.

Novel haloemodin (HEI2) synthesized by modifying emodin, a traditional Chinese medicine component, possesses remarkable antibacterial activity, being much more effective than its parent nucleus, emodin. Firstly, we discovered that HEI2 increases bacterial cell membrane permeability to potassium ions more drastically than emodin. We thus further investigated the interaction of haloemodin and protein using a fluorescence quenching and circular dichroism (CD) study based on bovine serum albumin (BSA). HEI2 spontaneously bound to BSA at Trp 212 residue (subdomain IIA) by hydrogen bonds and van der Waals interactions to forms HEI2-BSA complexes, and this binding decreased the α-helical content of BSA. We also confirmed that emodin bound to BSA by hydrophobic interaction alone. These results suggest that the main responses for the substantial antibacterial activities of HEI2 are a disruption of the bacterial plasma membrane function and the interaction with biological functional proteins. Furthermore, the study of the interaction of drugs with BSA, which has a fluorescent group tryptophan residue similar to many bio-functional proteins, will be a simple and inexpensive scope-reducing method in screening new drugs.

E35 ablates acute leukemia stem and progenitor cells in vitro and in vivo.

Leukemia stem cells (LSCs) have critical functions in acute leukemia (AL) pathogenesis, participating in its initiation and relapse. Thus, identifying new molecules to eradicate LSCs represents a high priority for AL management. This work identified E35, a novel Emodin derivative, which strongly inhibited growth and enhanced apoptosis of AL stem cell lines, and primary stem and progenitor cells from AL cases, while sparing normal hematopoietic cells. Furthermore, functional assays in cultured cells and animals suggested that E35 preferentially ablated primitive leukemia cell populations without impairing their normal counterparts. Moreover, molecular studies showed that E35 remarkably downregulated drug‐resistant gene and dramatically inhibited the Akt/mammalian target of rapamycin signaling pathway. Notably, the in vivo anti‐LSC activity of E35 was further confirmed in murine xenotransplantation models. Collectively, these findings indicate E35 constitutes a novel therapeutic candidate for AL, potentially targeting leukemia stem and progenitor cells.

Synthesis and anti‐inflammatory effects of novel emodin derivatives bearing azole moieties

Twelve azole derivatives of emodin were designed to possess anti-inflammatory activity and synthesized via a two-step sequence composed of the Williamson ether reaction and N-alkylation. The anti-inflammatory properties of these compounds were evaluated in RAW264.7 cells by measuring lipopolysaccharide (LPS)-induced nitric oxide (NO) production. The introduction of imidazole and four carbons into the scaffold of emodin led to the discovery of the potent compound 7e, which showed the best inhibition of NO production among twelve analogs. In our experiential setting, the IC50 of compound 7ein NO production is 1.35 µM, which is lower than that of indomethacin. Mechanically, compound 7e effectively inhibited the protein and messenger RNA expressions of cyclooxygenase-2 and inducible NO synthase, as well as that of the proinflammatory cytokine interleukin-6, and the cytokines interleukin-1β and tumor necrosis factor-α in the LPS-stimulated RAW 264.7 macrophages. Compound 7e exerted inhibitory effects on the nuclear factor κB pathwayby reducing the LPS-induced phosphorylation of the inhibitor of NF-κB and the nuclear translation of p-p65. These results suggest the potential of compound 7e in improving inflammatory conditions and diseases.

Components synergy between stilbenes and emodin derivatives contributes to hepatotoxicity induced by Polygonum multiflorum

Polygonum multiflorum Thunb. (PM) is a famous traditional Chinese medicine with liver tonic effect, but arousing great concerns for hepatotoxicity issue. In this study, we elucidated the contribution of the two major compounds, emodin-8-O-β-D-glucoside (EG) and 2,3,5,4´-tetrahydroxyl diphenylethylene-2-O-glucoside (TSG), in PM-induced liver injury.Based on LC-MS, the two concerned compounds were detected simultaneously in the sera of patients with PM-induced liver injury. In the lipopolysaccharide (LPS)-mediated inflammatory stress rat model, by the analysis of plasma biochemistry and liver histopathology, we observed that the solo treatment of EG, not TSG, could induce significant liver injury; and the combined administration of EG and TSG caused more severe liver injury than that of EG.Metabolomics analysis revealed that the EG-triggered liver injury was associated with significant disturbances of sphingolipids and primary bile acids metabolism pathways. In the combined administration group, much more disturbances in EG-triggered metabolic pathways, as well as alterations of several additional pathways such as retinol metabolism and vitamin B6 metabolism, were observed.Taken together, we considered EG was involved in the idiosyncratic liver injury of PM, and TSG played a synergetic role with EG, which contributed to the understanding of the hepatotoxic basis of PM.