Design and synthesis of novel glycyrrhetin ureas as anti-inflammatory agents for the treatment of acute kidney injury.

To develop new anti-inflammatory drugs for the prevention and treatment of acute kidney injury, a series of novel glycyrrhetic ureas were designed, synthesized and evaluated for anti-inflammatory activity using RAW264.7 cells. Compounds 5r-5u (2.04, 2.50, 3.25 and 2.48 µM, respectively) with acidic or neutral amino acid showed potent anti-inflammatory activity (IC50 = 2-3 µM for NO inhibition), amongst them, compound 5r also inhibited tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in a dose-dependent manner. In cisplatin-induced AKI mice model, compound 5r significantly reduced the level of pro-inflammatory factors, ameliorated the pathological damage of kidney tissue, and maintained the normal metabolic capacity.

Synthesis and Evaluation of Glycyrrhetic Acid-aromatic Hybrids as Antiinflammatory Agents.

BACKGROUND: Inflammation is a biological response of body tissues to harmful stimuli, so it is desirable to search for novel anti-inflammatory agents with improved pharmaceutical profiles and reduced adverse effects. OBJECTIVE: This study was to explore natural anti-inflammatory agents and improve therapeutic application of glycyrrhetic acid (GA) through molecular hybridization with active aromatics. METHODS: Fourteen novel GA-aromatic hybrids were synthesized and evaluated for their antiinflammatory activities by inhibiting LPS-induced nitric oxide (NO) release in RAW264.7 cells. The synthesized compounds were characterized by single-crystal X-ray diffraction, 1H NMR, 13C NMR and HRMS. RESULTS: The structure-activity relationship (SAR) study indicated that compounds with styryl displayed better NO inhibitory activity. Among them, compounds 2a and 3c exhibited the most promising activity with IC50 values of 9.93 µM and 12.25 µM, respectively. In addition, X-ray singlecrystal diffraction data for compounds 2e and 3c showed that the absolute configuration of GA skeleton was consistent with that of natural 18 ß-glycyrrhetic acid. CONCLUSION: The results showed that GA-aromatic hybrids were a new class of anti-inflammatory agents and this study provided useful information on further optimization.

A Review: The Anti-inflammatory, Anticancer and Antibacterial Properties of Four Kinds of Licorice Flavonoids Isolated from Licorice.

Plants have always been an important source of medicines for humans, and licorice is a very significant herb in the development of humans. As a traditional herb, it is widely cultivated in China, Japan, Russia, Spain and India. With the development of organic chemistry and biochemistry, various chemical ingredients extracted from licorice have been studied and identified. Among them, many chemical components were considered to have strong pharmacological activities, such as anti-inflammatory, anti-ulcer, antibacterial, anticancer and so on. Based on those reports, licorice has attracted the attention of many researchers in recent years, and they are devoted to discovering the active ingredients and mechanism of action of active compounds. Licorice flavonoids are one of the main extracts of licorice root and stem and have many potential biological properties. This paper aims to summarize the four kinds of licorice flavonoids, including liquiritigenin, isoliquiritigenin, licochalcone (including licochalcone A and licochalcone B) and glabridin, about their biological activities of anti-inflammatory, anticancer, antibacterial.

Research Progress of Glycyrrhizic Acid on Antiviral Activity.

Glycyrrhizic acid (GA), a triterpene isolated from the roots and rhizomes of licorice, named Glycyrrhiza glabra, is the principal bioactive ingredient of anti-viral, anti-inflammatory and hepatoprotective effects. GA has been used in the clinical treatment of hepatitis, bronchitis, gastric ulcer, AIDS (acquired immunodeficiency syndrome), certain cancers and skin diseases. It has a direct effect on anti-HBV (hepatitis B virus) via affecting the HBsAg (hepatitis B surface antigen) to extracellular secretion, improving liver dysfunction in patients with chronic hepatitis B, and ultimately improving the immune status of HBV. GA can significantly inhibit the proliferation of HIV, showing an immune activation. The clinical application of GA on the prevention and treatments of various diseases may derive from its numerous pharmacological properties. This review provides the summary of the antiviral effects of GA on research progress and mechanism in recent years.

Optimization techniques for novel c-Met kinase inhibitors.

INTRODUCTION: c-Met kinase plays an important part in the regulation of cell growth, invasion and anti-apoptosis. This enzyme is also an important target in cancer treatment. Through structural optimization and structure-activity studies of drugs currently on the market and those still in clinical trials, a great number of novel c-Met kinase inhibitors have been developed. This review focuses on recent developments in research regarding novel c-Met inhibitor synthesis, optimization, and structure-activity relationship (SAR) studies. Area covered: In this review, the authors discuss the representative research of c-Met inhibitors published in recent years. Furthermore, it provides background research of c-Met kinase inhibitors, the introduction of drugs on the market and in clinical research, and the research progress of novel small molecule inhibitors. In particular, this review emphasizes the important role of '5-atoms linker' in the design of some novel c-Met enzyme inhibitors. Expert opinion: Discovering novel c-Met kinase inhibitors via natural product chemistry may become a new research field. Though it is difficult, the key to developing better c-Met kinase inhibitors is structural optimization.

Novel unsaturated glycyrrhetic acids derivatives: Design, synthesis and anti-inflammatory activity.

To develop novel anti-inflammatory agents, a series of unsaturated glycyrrhetic acids were designed, synthesized and evaluated for anti-inflammatory activity using RAW264.7 cells. The structure-activity relationship (SAR) of NO inhibitory activity was analyzed. α,ß-Unsaturated glycyrrhetic acids showed better activity, among them, compounds 6k and 6l with piperazine unit exhibited the most potent nitric oxide (NO) and interleukin-6 (IL-6) inhibitory activity (IC50 = 13.3 and 15.5 µM respectively). Furthermore, compound 6k could also significantly suppress LPS-induced iNOS and COX-2 expression and IL-6 production through MAPKs and NF-kB signaling pathway.

Transvaginal Surgical Management of Cesarean Scar Pregnancy II (CSP-II): An Analysis of 25 Cases.

BACKGROUND: The aim of this study was to investigate the feasibility and clinical value of transvaginal surgical treatment for cesarean scar pregnancy (CSP-II). MATERIAL AND METHODS: This study was a retrospective analysis of 25 CSP-II patients who received transvaginal surgical treatments. These patients were admitted in our hospital between January 2010 and June 2012. RESULTS: All surgical treatments were successful without overt complications. The average operation time was 61.5 minutes, the average intraoperative blood loss was 60.5 ml, the average hospital stay was 9.4 days and the average time that blood ß-human chorionic gonadotropin (ß-HCG) returned to normal range was 15 days. In all 25 patients, the cesarean scar mass located at the anterior wall of the lower uterine segment disappeared by B-ultrasound examination within 1 or 2 weeks after surgery. Postoperatively, the normal menstrual period started again with an average time of 28.9 days. No menstruation-related abnormalities, such as menstrual dripping or an abnormal amount of blood, were reported after surgery. CONCLUSIONS: Transvaginal surgery for CSP-II is a novel surgical approach. It has several advantages, including a thorough one-time treatment lesion clearance, short operation time, minimized trauma, minimal intraoperative blood loss, quick reduction of blood ß-HCG, and rapid menstruation recovery. It is a simple and feasible surgical approach of great clinical value and few treatment-related complications.

Synthesis and discovery of 18α-GAMG as anticancer agent in vitro and in vivo via down expression of protein p65.

Glycyrrhizic acid (GA) is a natural product with favorable antitumor activity. But, glycyrrhetinic acid monoglucuronide (GAMG) showed stronger antitumor activity than GA. It is of our interest to generate and identify novel compounds with regulation telomerase for cancer therapy. So, in this study, 18α-GAMG was synthesized via biotransformation. In vitro studies showed that it displayed potent anticancer activity and high selectivity on tumor liver cell SMMC-7721 versus human normal liver cell L-02. The further results in vivo confirmed that it could significantly improve pathological changes of N,N-diethylnitrosamine (DEN)-induced rat hepatic tumor. Western blot and immunofluorescence results indicated that the expression of p65-telomerase reverse transcriptase (TERT) was clearly down-regulated treated with it. Taken together, this study for the first time identified an active compound with high selectivity on tumor liver cell in mice. Furthermore, the title compound could inhibit the expression of protein p65 and TERT. These data support further studies to assess the rational design of more efficient p65 modulators in the future.

[STC-1 is involved in anti-hypoxia proliferative balance of renal cancer cells by down-regulation of intracellular Ca2+ and HIF-1α levels].

OBJECTIVE: To investigate effects of stanniocalcin-1 (STC-1) on proliferation balance under hypoxic condition in renal cancer cells and its mechanism. METHODS: Hypoxic model was induced on renal cancer GRC-1 cells (Group H), the cells were treated with STC-1 protein at concentrations of 0.1 nmol/L (H1), 0.5 nmol/L (H2), 1.0 nmol/L (H3), or normal saline (H0) for 48 h， respectively. Cells proliferation was measured by MTT assay; mRNA and protein expressions of hypoxia inducible factor 1α (HIF-1α) and STC-1 in GRC-1 cells were detected by RT-PCR and ELISA, respectively; the intracellular levels of Ca2+ and adenosine triphosphate (ATP) were determined by fluorescence spectrophotometry and spectrophotometry, respectively. RESULTS: The expression of HIF-1α, STC-1 and Ca2+ levels were increased in GRC-1 cells under hypoxia condition; STC-1 reversed these changes in a dose-effect manner. Hypoxia significantly inhibited cell proliferation and the generation of ATP in GRC-1 cells and exogenous STC-1 reversed the effects of hypoxia; ATP generation increased gradually with increasing STC-1 concentration, but the cell proliferation was reduced. CONCLUSION: Exogenous STC-1 can promote the proliferation of renal cancer cells in hypoxia condition by reducing HIF-1α expression and Ca2+ content and increased ATP production, but the progressive inhibition of HIF-1 α hindered the renal carcinoma cell proliferation further, which indicates that STC-1 may be involved in anti-hypoxia proliferative balance of renal cancer cells.

Synthesis of caffeic acid amides bearing 2,3,4,5-tetra-hydrobenzo[b][1,4]dioxocine moieties and their biological evaluation as antitumor agents.

A series of caffeic acid amides D1-D17 bearing 2,3,4,5-tetrahydrobenzo-[b][1,4]dioxocine units has been synthesized and their biological activities evaluated for potential antiproliferative and EGFR inhibitory activity. Of all the compounds studied, compound D9 showed the most potent inhibitory activity (IC50=0.79 µM for HepG2 and IC50=0.36 µM for EGFR). The structures of compounds were confirmed by 1H-NMR, ESI-MS and elemental analysis. Among all, the structure of compound D9 ((E)-N-(4-ethoxyphenyl)-3-(2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)acrylamide) was also determined by single-crystal X-ray diffraction analysis. Compound D9 was found to be a potential antitumor agent according to biological activity, molecular docking, apoptosis assay and inhibition of HepG2.

Synthesis, molecular docking and biological evaluation of glycyrrhizin analogs as anticancer agents targeting EGFR.

Glycyrrhizin (GA) analogs in the form of 3-glucuronides and 18-epimers were synthesized and their anticancer activities were evaluated. Alkaline isomerization of monoglucuronides is reported. In vitro and in vivo studies showed that glycyrrhetinic acid monoglucuronides (GAMGs) displayed higher anticancer activities than those of bisglucuronide GA analogs, while anticancer activity of the 18α-epimer was superior to that of the 18ß-epimer. 18α-GAMG was firstly nicely bound to epidermal growth factor receptor (EGFR) via six hydrogen bonds and one charge interaction, and the docking calculation proved the correlation between anticancer activities and EGFR inhibitory activities. Highly active 18α-GAMG is thus of interest for the further studies as a potential anticancer agent.

Synthesis and biological evaluation of compounds which contain pyrazole, thiazole and naphthalene ring as antitumor agents.

A series of compounds which contain pyrazole, thiazole and naphthalene ring (1a-7a, 1b-7b, 1c-7c, 1d-7d) were firstly synthesized and their anti-proliferative activity, EGFR inhibitory activity, cytotoxicity and inhibition to Hela cell migration were evaluated. Compound 2-(3-(3,4-dimethylphenyl)-5-(naphthalen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (7d) displayed the most potent inhibitory activity (IC50=0.86µM for Hela and IC50=0.12µM for EGFR). Structure-activity relationship (SAR) analysis showed that the anti-proliferative activity was affected by A-ring-substituent (-OCH3>-CH3>-H>-Br>-Cl>-F). Docking simulation of compound 7d into EGFR active site showed that naphthalene ring of 7d with LYS721 formed two p-π bonds, which enhanced antitumor activity. Therefore, compound 7d may be developed as a potential antitumor agent.

[Effects of stanniocalcin-1 and hypoxia-inducible factor-1α on mitochondrial membrane potential stability in renal carcinoma cells].

OBJECTIVE: To explore the effects of stanniocalcin-1 (STC-1) and hypoxia-inducible factor-1α (HIF-1α) on the calcium and thus on the mitochondrial membrane potential (Δψm) in renal carcinoma cells. METHODS: We successfully established the renal carcinoma cell models with high HIF-1α gene expression. After various concentrations of STC-1 solutions were added to the culture medium, the proliferation of cells, expressions of HIF-1α and STC-1, levels of Ca(2+), Δψm, and mPTP were detected by MTT, RT-PCR, ELISA, fluorescence spectrophotometry, and ultraviolet spectrophotometry, respectively. RESULTS: The proliferation of renal carcinoma cells and Δψm were improved after HIF-1α gene transfection, STC-1 protein intervention, and STC-1 protein intervention after gene transfection. While the intracellular Ca(2+) level and mPTP were decreased significantly (P<0.05), all the changes were intensified with the gradual increase of STC-1. However, the increasing trend of cell proliferation gradually declined. CONCLUSION: HIF-1α may participate in malignant proliferation of renal carcinoma cells by promoting STC-1 proliferation or down-regulating Ca(2+); however, such an effect may be gradually attenuated due to the inhibitory effect of STC-1 on HIF-1α.

Synthesis, and antibacterial activity of novel 4,5-dihydro-1H-pyrazole derivatives as DNA gyrase inhibitors.

A series of novel 4,5-dihydropyrazole derivatives (4a-4t), containing the dinitrobenzotrifluoride moiety, as DNA gyrase inhibitors were designed and synthesized. Based on the preliminary results, compounds 4d, 4f and 4t with potent inhibitory activity in bacterial growth may be wonderful antibacterial agents; among them, compound 4t displayed the most potent activity with minimum inhibitory concentration (MIC) values of 3.125, 0.39, 0.39 and 0.39 µg mL(-1) against Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli respectively, which was comparable with penicillin and kanamycin B with corresponding MIC values of 3.125, 3.125, 0.39, 0.39 µg mL(-1) and 1.562, 1.562, 1.562, 1.562 µg mL(-1), respectively. In particular, compound 4d showed the most potent anti-Gram-positive bacterial activity with a MIC value of 0.39 µg mL(-1) against the tested Gram-positive bacterial strains and exhibited the most potent B. subtilis DNA gyrase and S. aureus DNA gyrase inhibitory activity with an IC50 of 0.125 µg mL(-1). Docking simulation was performed to insert compound 4d into the S. aureus DNA gyrase active site to determine the probable binding conformation.

Sulfonamides containing coumarin moieties selectively and potently inhibit carbonic anhydrases II and IX: design, synthesis, inhibitory activity and 3D-QSAR analysis.

A series of sulfonamides containing coumarin moieties had been prepared that showed a very interesting profile for the inhibition of two human carbonic anhydrase inhibitors. These compounds were evaluated for their ability to inhibit the enzymatic activity of the physiologically dominant isozymes hCA II and the tumor-associated isozyme hCA IX. The most potent inhibitor against hCA II and IX were compounds 5d (IC50 = 23 nM) and 5l (IC50 = 24 nM), respectively. These sulfonamides containing coumarin moieties may prove interesting lead candidates to target tumor-associated CA isozymes, wherein the CA domain is located extracellularly. Eighteen compounds were scrutinized by CoMFA and CoMSIA techniques of 3D quantitative structure-activity relationship. Nine of the compounds were evaluated for cytotoxicity against human macrophage.

Potentiating 1-(2-hydroxypropyl)-2-styryl-5-nitroimidazole derivatives against antibacterial agents: design, synthesis and biology analysis.

A series of novel 1-(2-hydroxypropyl)-2-styryl-5-nitroimidazole derivatives had been designed, synthesized, isolated and evaluated as potentiators of antibacterial agents. All these synthesized compounds were determined by elemental analysis, (1)H NMR, and MS. Their biological activities were also evaluated against two Gram-negative bacterial strains: Escherichia coli and Pseudomonas aeruginosa and two Gram-positive bacterial strains: Bacillus thuringiensis and Bacillus subtilis by MTT method as potential FabH inhibitory. The results showed that compound 30 exhibited the most potent E. coli FabH inhibitory activity with IC50 of 4.6 µM. Molecular modeling simulation studies were performed in order to predict the biological activities of the proposed compounds. All compounds have been tested for toxicity by MTT assay on human macrophage.

1-{2-[(4-Chloro-benzyl-idene)amino]phen-yl}-3-phenyl-thio-urea.

The asymmetric unit of the title compound, C(20)H(16)ClN(3)S, contains two independent mol-ecules, A and B. In mol-ecule A, the dihedral angles between the central benzene ring and the pendant chloro-benzene and phenyl rings are 6.37 (15) and 64.79 (15)°, respectively. The corresponding values in mol-ecule B are 28.21 (14) and 82.11 (16)°, respectively. Each mol-ecule features an intra-molecular N-H⋯N hydrogen bond, which generates an S(5) ring. In the crystal, mol-ecules A and B form dimers, being linked by two N-H⋯S hydrogen bonds with graph-set notation R(2) (2)(8).

2-[(4-Bromo-phenyl-imino)-meth-yl]-4,6-di-iodo-phenol.

The title compound, C(13)H(8)BrI(2)NO, was prepared by the reaction of 3,5-diiodo-salicyl-aldehyde with 4-bromo-phenyl-amine in ethanol. There is an intra-molecular O-H⋯N hydrogen bond in the mol-ecule, which generates an S(6) ring. The dihedral angle between the benzene rings is 2.6 (3)°.

2,4-Diiodo-6-[(propyl-imino)-meth-yl]phenol.

The title compound, C(10)H(11)I(2)NO, was prepared by the reaction of 3,5-diiodo-salicyl-aldehyde with propyl-amine in ethanol. The mol-ecule adopts an E conformation with respect to the C=N bond and the aromatic ring. The aromatic ring and the imino unit are close to being coplanar, with a dihedral angle of 2.6 (3)° between their planes. This planarity is assisted by the formation of an intra-molecular O-H⋯O hydrogen bond.

2-[(2-Chloro-phen-yl)imino-meth-yl]-4,6-di-iodo-phenol.

The asymmetric unit of the title compound, C(13)H(8)ClI(2)NO, contains half of the mol-ecule situated on a mirror plane. The hy-droxy group is involved in the formation of an intra-molecular O-H⋯N hydrogen bond. π-π inter-actions between the benzene rings of neighbouring mol-ecules [centroid-centroid distance = 3.629 (3) Å] form stacks along the b axis. In the crystal, weak C-H⋯O and C-H⋯Cl inter-actions are observed.