In vitro and In vivo Activity of a New N-Oxide Derivative for Acne Vulgaris Treatment.

INTRODUCTION: Furoxan and benzofuroxan are compounds containing an N-oxide function, known for their diverse pharmacological properties, including antimicrobial and antiinflammatory effects. This study aimed to investigate these activities using an in-house library of N-oxide compounds. METHOD: Twenty compounds were tested against both Gram-positive and Gram-negative bacteria, including Cutibacterium acnes (C. acnes), a microorganism implicated in the development of acne vulgaris. One compound, (E)-4-(3-((2-(3-hydroxybenzoyl)hydrazone)methyl)phenoxy)-3- (phenylsulfonyl)-1,2,5-oxadiazol-2-N-oxide (compound 15), exhibited selective antimicrobial activity against C. acnes, with a Minimum Inhibitory Concentration (MIC) value of 2 µg/mL. Indirect measurement of Nitric Oxide (NO) release showed that compound 15 and isosorbide dinitrate, when treated with L-cysteine, produced nitrite levels of 20.1% and 9.95%, respectively. Using a NO scavenger (PTIO) in combination with compound 15 in a culture of C. acnes resulted in reduced antimicrobial activity, indicating that NO release is part of its mechanism of action. Cytotoxicity assessments using murine macrophages showed cellular viability above 70% at concentrations up to 0.78 µg/mL. RESULTS: Measurements of Interleukin-1 beta (IL1-ß) and Tumor Necrosis Factor-alpha (TNF-α) indicated that compound 15 did not reduce the levels of these pro-inflammatory cytokines. Sustained NO production by inducible Nitric Oxide Synthase (iNOS) in macrophages or neutrophils has been found to be involved in the inflammatory process in acne vulgaris and lead to toxicity in surrounding tissues. Nitrite levels in the supernatant of murine macrophages were found to be decreased at a concentration of 0.78 µg/mL of compound 15, indicating an anti-inflammatory effect. In vivo studies were conducted using Balb/c nude mice inoculated subcutaneously with C. acnes. Cream and gel formulations of compound 15 were applied to treat the animals, along with commercially available anti-acne drugs, for 14 days. Animals treated with a cream base containing 5% of compound 15 exhibited less acanthosis with mild inflammatory infiltration compared to other groups, highlighting its anti-inflammatory properties. CONCLUSION: Similar results were observed in the benzoyl peroxide group, demonstrating that compound 15 presented comparable anti-inflammatory activity to the FDA-approved drug. These promising results suggest that compound 15 has a dual mechanism of action, with selective antimicrobial activity against C. acnes and notable anti-inflammatory properties, making it a potential prototype for developing new treatments for acne vulgaris.

An Unusual Rearrangement of Pyrazole Nitrene and Coarctate Ring-Opening/Recyclization Cascade: Formal CH-Acetoxylation and Azide/Amine Conversion without External Oxidants and Reductants.

We report an unusual transformation where the transient formation of a nitrene moiety initiates a sequence of steps leading to remote oxidative C-H functionalization (R-CH3 to R-CH2OC(O)R') and the concomitant reduction of the nitrene into an amino group. No external oxidants or reductants are needed for this formal molecular comproportionation. Detected and isolated intermediates and computational analysis suggest that the process occurs with pyrazole ring opening and recyclization.

Regioselective Synthesis of NO-Donor (4-Nitro-1,2,3-triazolyl)furoxans via Eliminative Azide-Olefin Cycloaddition.

A facile and efficient method for the regioselective [3 + 2] cycloaddition of 4-azidofuroxans to 1-dimethylamino-2-nitroethylene under p-TSA catalysis affording (4-nitro-1,2,3-triazolyl)furoxans was developed. This transformation is believed to proceed via eliminative azide-olefin cycloaddition resulting in its complete regioselectivity. The developed protocol has a broad substrate scope and enables a straightforward assembly of the 4-nitro-1,2,3-triazole motif. Moreover, synthesized (4-nitro-1,2,3-triazolyl)furoxans were found to be capable of NO release in a broad range of concentrations, thus providing a novel platform for future drug design and related biomedical applications of heterocyclic NO donors.

First Example of 1,2,5-Oxadiazole-Based Hypergolic Ionic Liquids: A New Class of Potential Energetic Fuels.

The development of liquid energetic fuels with improved properties is an important topic in space propulsion technologies. In this manuscript, a series of energetic ionic liquids incorporating a 1,2,5-oxadiazole ring and nitrate, dicyanamide or dinitramide anion was synthesized and their physicochemical properties were evaluated. The synthesized compounds were fully characterized and were found to have good thermal stabilities (up to 219 °C) and experimental densities (1.21-1.47 g cm-3 ). Advantageously, 1,2,5-oxadiazole-based ionic liquids have high combined nitrogen-oxygen contents (up to 64.4 %), while their detonation velocities are on the level of known explosive TNT, and combustion performance exceeds those of benchmark 2-hydroxyethylhydrazinium nitrate. Considering the established hypergolicity with H2 O2 in the presence of a catalyst, and insensitivity to impact, synthesized ionic liquids have strong application potential as energetic fuels for space technologies.

Synthesis and anti-inflammatory activity evaluation of NO-releasing furoxan/1,2,4-triazole hybrid derivatives.

An efficient synthesis method was developed for furoxan/1,2,4-triazole hybrids 5a-k from methyl 5-(halomethyl)-1-aryl-1H-1,2,4-triazole-3-carboxylates 1 through two-steps reaction including hydrolyzation and esterification. All of the furoxan/1,2,4-triazole hybrid derivatives were characterized by spectroscopy. On the other hand, the influence of newly synthesized multi-substituted 1,2,4-triazoles on the exogenous NO release ability, in vitro and in vivo anti-inflammatory activity, and in silico predictions were experimentally evaluated. Based on the exogenous NO release ability study and SAR studies of in vitro anti-inflammatory activity, all of compounds 5a-k exhibited slightly NO release ability and potential anti-inflammatory activity on LPS-induced RAW264.7 cells (IC50 = 5.74-15.3 µM) compared to Celecoxib (IC50 = 16.5 µM) and Indomethacin (IC50 = 56.8 µM). Furthermore, compounds 5a-k were also subjected to in vitro COX-1/COX-2 inhibition assays. Particularly, compound 5f exhibited extraordinary COX-2 inhibition (IC50 = 0.0455 µM) and selectivity (SI = 209). In addition, compound 5f was also examined in vivo pro-inflammatory cytokine productions and gastric safety and possessed the better inhibition of cytokine and safety compared with Indomethacin at the same concentration. Through the molecular modeling and in silico physicochemical and pharmacokinetic properties prediction, compound 5f was stabilized in COX-2 active binding site and possessed the fundamental strong H-bond interaction with Arg499 to form the significant physicochemical and pharmacological properties as a candidate drug. Following the in vitro, in vivo, and in silico study results, compound 5f demonstrated to be a potential anti-inflammatory agent and had comparable effects with Celecoxib.

Utilizing Estra-1,3,5,16-Tetraene Scaffold: Design and Synthesis of Nitric Oxide Donors as Chemotherapeutic Resistance Combating Agents in Liver Cancer.

A new series of nitric oxide-releasing estra-1,3,5,16-tetraene analogs (NO-∆-16-CIEAs) was designed and synthesized as dual inhibitors for EGFR and MRP2 based on our previous findings on estra-1,3,5-triene analog NO-CIEA 17 against both HepG2 and HepG2-R cell lines. Among the target compounds, 14a (R-isomer) and 14b (S-isomer) displayed potent anti-proliferative activity against both HepG2 and HepG2-R cell lines in comparison to the reference drug erlotinib. Remarkably, compound 14a resulted in a prominent reduction in EGFR phosphorylation at a concentration of 1.20 µM with slight activity on the phosphorylation of MEK1/2 and ERK1/2. It also inhibits MRP2 expression in a dose-dependent manner with 24% inhibition and arrested the cells in the S phase of the cell cycle. Interestingly, compound 14a (estratetraene core) exhibited a twofold increase in anti-proliferative activity against both HepG2 and HepG2-R in comparison with the lead estratriene analog, demonstrating the significance of the designed ∆-16 unsaturation. The results shed a light on compound 14a and support further investigations to combat multidrug resistance in chemotherapy of hepatocellular carcinoma patients.

Pharmacokinetics of Novel Furoxan/Coumarin Hybrids in Rats Using LC-MS/MS Method and Physiologically Based Pharmacokinetic Model.

Novel furoxan/coumarin hybrids were synthesized, and pharmacologic studies showed that the compounds displayed potent antiproliferation activities via downregulating both the phosphatidylinositide 3-kinase (PI3K) pathway and the mitogen-activated protein kinase (MAPK) pathway. To investigate the preclinical pharmacokinetic (PK) properties of three candidate compounds (CY-14S-4A83, CY-16S-4A43, and CY-16S-4A93), liquid chromatography, in tandem with the mass spectrometry LC-MS/MS method, was developed and validated for the simultaneous determination of these compounds. The absorption, distribution, metabolism, and excretion (ADME) properties were investigated in in vitro studies and in rats. Meanwhile, physiologically based pharmacokinetic (PBPK) models were constructed using only in vitro data to obtain detailed PK information. Good linearity was observed over the concentration range of 0.01−1.0 µg/mL. The free drug fraction (fu) values of the compounds were less than 3%, and the clearance (CL) values were 414.5 ± 145.7 mL/h/kg, 2624.6 ± 648.4 mL/h/kg, and 500.6 ± 195.2 mL/h/kg, respectively. The predicted peak plasma concentration (Cmax) and the area under the concentration-time curve (AUC) were overestimated for the CY-16S-4A43 PBPK model compared with the experimental ones (fold error > 2), suggesting that tissue accumulation and additional elimination pathways may exist. In conclusion, the LC-MS/MS method was successively applied in the preclinical PK studies, and the detailed information from PBPK modeling may improve decision-making in subsequent new drug development.

Trinitromethyl Energetic Groups Enhance High Heats of Detonation.

The introduction of groups with high enthalpies of formation can effectively improve the detonation performance of the compounds. A series of novel energetic compounds (10-13) with high enthalpies of formation, high density, and high nitrogen-oxygen content were designed and synthesized by combining gem-polynitromethyl, 1,2,4-oxadiazole, furoxan, and azo groups. All the new compounds were thoroughly characterized by IR, NMR, elemental analysis, and differential scanning calorimetry. Compounds 10 and 11 were also further characterized with single-crystal X-ray diffraction. Compound 11 has high density (1.93 g cm-3), high enthalpy of formation (993.5 kJ mol-1), high detonation velocity (9411 m s-1), and high heat of detonation (6889 kJ kg-1) and is a potentially excellent secondary explosive.

In silico evaluation of NO donor heterocyclic vasodilators as SARS-CoV-2 Mpro protein inhibitor.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes COVID-19 disease has been exponentially increasing throughout the world. The mortality rate is increasing gradually as effective treatment is unavailable to date. In silico based screening for novel testable hypotheses on SARS-CoV-2 Mpro protein to discover the potential lead drug candidate is an emerging area along with the discovery of a vaccine. Administration of NO-releasing agents, NO inducers or the NO gas itself may be useful as therapeutics in the treatment of SARS-CoV-2. In the present study, a 3D structure of SARS-CoV-2 Mpro protein was used for the rational setting of inhibitors to the binding pocket of enzyme which proposed that phenyl furoxan derivative gets efficiently dock in the target pocket. Molecular docking and molecular dynamics simulations helped to investigate possible effective inhibitor candidates bound to SARS-CoV-2 Mpro substrate binding pocket. Molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations revealed energetic contributions of active site residues of Mpro in binding with most stable proposed NO donor heterocyclic vasodilator inhibitor molecules. Furthermore, principal component analysis (PCA) showed that the NO donor heterocyclic inhibitor molecules 14, 16, 18 and 19 was strongly bound to catalytic core of SARS-CoV-2 Mpro protein, limiting its movement to form stable complex as like control. Thus, overall in silico investigations revealed that 5-oxopiperazine-2-carboxylic acid coupled furoxan derivatives was found to be key pharmacophore in drug design for the treatment of SARS-CoV-2, a global pandemic disease with a dual mechanism of action as NO donor and a worthwhile ligand to act as SARS-CoV-2 Mpro protein inhibitor.Communicated by Ramaswamy H. Sarma.

(2-Vinyltetrazolyl)furoxans as New Potential Energetic Monomers.

A regioselective approach toward the synthesis of a set of new (2-vinyltetrazolyl)furoxans as potential energetic monomers has been realized. All target energetic materials were thoroughly characterized by spectral and analytical methods. Moreover, crystal structures of two representative heterocyclic systems were studied by single-crystal X-ray diffraction. Prepared high-energy substances have high combined nitrogen-oxygen content (63-71 %), high enthalpies of formation and good detonation parameters (D: 6.7-7.8 km s-1 ; P: 18-28 GPa). Mechanical sensitivities of the synthesized vinyltetrazoles range these explosives from highly sensitive to completely insensitive. Using calculations of molecular electrostatic potentials (ESP), structural factors influencing the impact sensitivity were revealed. Overall, newly synthesized (2-vinyltetrazolyl)furoxans are of interest as promising energetic monomers due to the presence of the vinyl moiety and explosophoric heterocyclic combination, while their performance exceeds that of benchmark explosive TNT.

Development of novel nitric oxide-releasing quinolinedione/furoxan hybrids as NQO1 inhibitors for intervention of drug-resistanthepatocellular cancer.

A series of novel nitric oxide (NO)-releasing 5,8-quinolinedione/furoxan hybrids (8a-h and 9a-h) were designed and synthesized through coupling different alkanolamine substituted phenylsulfonyl furoxan with 5,8-quinolinedione. Most compounds displayed high cytotoxic activity against drug-sensitive/-resistant cancer cells. In particular, the IC50 of 9a (0.42 µM) was about 9-fold lower than that of ß-lap (3.69 µM) and 12-fold lower than that of SAHA (5.24 µM) in drug-resistant cancer cells. Also, 9a was demonstrated to selectively inhibit the growth of Bel7402/5-FU cancer cells. Mechanistic studies demonstrated that 9a could serve as an NO donor and nicotinamide quinone oxidoreductase 1 (NQO1) inhibitor (IC50 = 0.8 µM), which could induce the highest level of NO and reactive oxygen species (ROS) in Bel-7402/5-FU cancer cells. Furthermore, 9a could promote tumor cell apoptosis and autophagy via regulation of apoptosis-related protein (Bax, Bcl-2, and Caspase 3) and autophagy-associated proteins (LC3 and p62) in Bel-7402/5-FU cells. Taken together, 9a may be considered as a promising candidate for a further comprehensive study involving drug-resistant hepatocellular carcinoma.

Novel family of nitrogen-rich energetic (1,2,4-triazolyl) furoxan salts with balanced performance.

Nitrogen-rich energetic materials comprised of a combination of several heterocyclic subunits retain their leading position in the field of materials science. In this regard, a preparation of novel high-energy materials with balanced set of physicochemical properties is highly desired. Herein, we report the synthesis of a new series of energetic salts incorporating a (1,2,4-triazolyl) furoxan core and complete evaluation of their energetic properties. All target energetic materials were well characterized with IR and multinuclear NMR spectroscopy and elemental analysis, while compound 6 was further characterized by single-crystal X-ray diffraction study. Prepared nitrogen-rich salts have high thermal stability (up to 232°C), good experimental densities (up to 1.80 g cm-3) and high positive enthalpies of formation (344-1,095 kJ mol-1). As a result, synthesized energetic salts have good detonation performance (D = 7.0-8.4 km s-1; p = 22-32 GPa), while their sensitivities to impact and friction are quite low.

Anti-breast cancer sinomenine derivatives via mechanisms of apoptosis induction and metastasis reduction.

Sinomenine, a morphinane-type isoquinoline-derived alkaloid, was first isolated from stems and roots of Sinomenium diversifolius (Miq.) in 1920. Later discovery by researchers confirmed various essential biological efficacy sinomenine exerted in vitro and in vivo. In this study, a series of 15 sinomenine/furoxan hybrid compounds were designed and synthesised in search of a TNBC drug candidate. Some of the target compounds exhibited strong antiproliferative activities against cancer cell lines, especially for TNBC cells, compared to positive controls. Among them, hybrid 7Cc exerted superior cytotoxic effects on cancer cell lines with exceptionally low IC50 (0.82 µM) against MDA-MB-231 cells with the highest safety index score. Further studies in mechanism displayed that 7Cc could induce an S phase cell cycle arrest, stimulate apoptosis in MDA-MB-231 cells, disrupt mitochondrial membrane potential and exert a genotoxic effect on DNA in cancer cells. In addition, 7Cc also notably inhibited MDA-MB-231 cells in both migration, invasion and adhesion.

Synthetic Strategies Toward Nitrogen-Rich Energetic Compounds Via the Reaction Characteristics of Cyanofurazan/Furoxan.

The structural units of amino-/cyano-substituted furazans and furoxans played significant roles in the synthesis of nitrogen-rich energetic compounds. This account focused on the synthetic strategies toward nitrogen-rich energetic compounds through the transformations based on cyanofurazan/furoxan structures, including 3-amino-4-cyanofurazan, 4-amino-3-cyano furoxan, 3,4-dicyanofurazan, and 3,4-dicyanofuroxan. The synthetic strategies toward seven kinds of nitrogen-rich energetic compounds, such as azo (azoxy)-bridged, ether-bridged, methylene-bridged, hybrid furazan/furoxan-tetrazole-based, tandem furoxan-based, hybrid furazan-isofurazan-based, hybrid furoxan-isoxazole-based and fused framework-based energetic compounds were fully reviewed, with the corresponding reaction mechanisms toward the nitrogen-rich aromatic frameworks and examples of using the frameworks to create high energetic substances highlighted and discussed. The energetic properties of typical nitrogen-rich energetic compounds had also been compared and summarized.

Design, Synthesis, and Biological Evaluation of a Novel VEGFR-2 Inhibitor Based on a 1,2,5-Oxadiazole-2-Oxide Scaffold with MAPK Signaling Pathway Inhibition.

Over the past few decades, the development of broad-spectrum anticancer agents with anti-angiogenic activity has witnessed considerable progress. In this study, a new series of pyrazolo[3,4-d]pyrimidines based on a phenylfuroxan scaffold were designed, synthesized, and evaluated, in terms of their anticancer activities. NCI-60 cell one-dose screening revealed that compounds 12a-c and 14a had the best MGI%, among the tested compounds. The target fluorinated compound 12b, as the most active one, showed better anticancer activity compared to the reference drug sorafenib, with IC50 values of 11.5, 11.6, and 13 µM against the HepG-2, A2780CP, and MDA-MB-231 cell lines, respectively. Furthermore, compound 12b (IC50 = 0.092 µM) had VEGFR-2-inhibitory activity comparable to that of the standard inhibitor sorafenib (IC50 = 0.049 µM). Furthermore, the ability of compound 12b in modulating MAPK signaling pathways was investigated. It was found to decrease the level of total ERK and its phosphorylated form, as well as leading to the down-regulation of metalloproteinase MMP-9 and the over-expression of p21 and p27, thus leading to subG1 cell-cycle arrest and, thus, the induction of apoptosis. Additionally, compound 12b decreased the rate of wound healing in the absence of serum, in comparison to DMSO-treated cells, providing a significant impact on metastasis inhibition. The quantitative RT-PCR results for E-cadherin and N-cadherin showed lower expression of the neuronal N-cadherin and increased expression of epithelial E-cadherin, indicating the ability of 12b to suppress metastasis. Furthermore, 12b-treated HepG2 cells expressed a low level of anti-apoptotic BCL-2 and over-expressed proapoptotic Bax genes, respectively. Using the DAF-FM DA fluorescence probe, compound 12b produced NO intracellularly as efficiently as the reference drug JS-K. In silico molecular docking studies showed a structural similarity through an overlay of 12b with sorafenib. Interestingly, the drug-likeness properties of compound 12b met the expectations of Pfizer's rule for the design of new drug candidates. Therefore, this study presents a novel anticancer lead compound that is worthy of further investigation and activity improvement.

Synthesis of lathyrane diterpenoid nitrogen-containing heterocyclic derivatives and evaluation of their anti-inflammatory activities.

As our ongoing work on lathyrane diterpenoid derivatization, three series of lathyrane diterpenoid derivatives were designed and synthesized based combination principles, including pyrazole, thiazole and furoxan moieties. Biological evaluation indicated that compound 23d exhibited excellently inhibitory activity on LPS-induced NO production in RAW264.7 cells (IC50 = 0.38 ± 0.18 µM). The preliminary structure-activity relationships (SARs) suggested that phenylsulfonyl substituted furoxan moiety had the strongest ability to improve anti-inflammatory activity of lathyrane diterpenoids. Furthermore, compound 23d significantly reduced the level of ROS. Its molecular mechanism was related to inhibiting the transcriptional activation of Nrf2/HO-1 pathway. Based on these considerations, 23d might be a promising anti-inflammatory agent, which is noteworthy for further exploration.

Design, synthesis and biological activity evaluation of novel scopoletin-NO donor derivatives against MCF-7 human breast cancer in vitro and in vivo.

In this study, eleven new 3- and 7-positions modified scopoletin derivatives (18a-k) were designed, synthesized, and biologically evaluated against human breast cancer cell lines. Most compounds showed improved antiproliferative activity against MCF-7 and MDA-MB-231 cells and weaker cytotoxicity on human breast epithelial cell line MCF-10A than lead compound 5. Among them, compound 18e exhibited the most potent antiproliferative activity against MCF-7 cells (IC50 = 0.37 ± 0.05 µM). Particularly, 18e produced the highest levels of nitric oxide (NO) intracellularly, and its antiproliferation effect was attenuated by hemoglobin (an NO scavenger). Further pharmacological research showed that 18e blocked the cell cycle at the G2/M phase, downregulated the phosphorylation of PI3K and Akt in MCF-7 cells and regulated the expressions of the apoptosis proteins to induce apoptosis. Moreover, 18e inhibited the growth of MCF-7 in vivo. Overall, 18e is a novel anticancer agent with the abilities of high concentration of NO releasing and the inhibition of PI3K/Akt signaling pathway, and may be a promising agent against MCF-7 human breast cancer.

Design and Synthesis of Nitrogen-Rich Azo-Bridged Furoxanylazoles as High-Performance Energetic Materials.

A series of novel energetic materials comprising of azo-bridged furoxanylazoles enriched with energetic functionalities was designed and synthesized. These high-energy materials were thoroughly characterized by IR and multinuclear NMR (1 H, 13 C, 14 N) spectroscopy, high-resolution mass spectrometry, elemental analysis, and differential scanning calorimetry (DSC). The molecular structures of representative amino and azo oxadiazole assemblies were additionally confirmed by single-crystal X-ray diffraction and X-ray powder diffraction. A comparison of contributions of explosophoric moieties into the density of energetic materials revealed that furoxan and 1,2,4-oxadiazole rings are the densest motifs while the substitution of the azide and amino fragments on the nitro and azo ones leads to an increase of the density. Azo bridged energetic materials have high nitrogen-oxygen contents (68.8-76.9 %) and high thermal stability. The synthesized compounds exhibit good experimental densities (1.62-1.88 g cm-3 ), very high enthalpies of formation (846-1720 kJ mol-1 ), and, as a result, excellent detonation performance (detonation velocities 7.66-9.09 km s-1 and detonation pressures 25.0-37.7 GPa). From the application perspective, the detonation parameters of azo oxadiazole assemblies exceed those of the benchmark explosive RDX, while a combination of high detonation performance and acceptable friction sensitivity of azo(1,2,4-triazolylfuroxan) make it a promising potential alternative to PETN.

Synthesis of oxadiazole-2-oxide derivatives as potential drug candidates for schistosomiasis targeting SjTGR.

BACKGROUND: Schistosomiasis is a chronic parasitic disease that affects millions of people's health worldwide. Because of the increasing drug resistance to praziquantel (PZQ), which is the primary drug for schistosomiasis, developing new drugs to treat schistosomiasis is crucial. Oxadiazole-2-oxides have been identified as potential anti-schistosomiasis reagents targeting thioredoxin glutathione reductase (TGR). METHODS: In this work, one of the oxadiazole-2-oxides derivatives furoxan was used as the lead compound to exploit a series of novel furoxan derivatives for studying inhibitory activity against both recombinant Schistosoma japonicum TGR containing selenium (rSjTGR-Sec) and soluble worm antigen protein (SWAP) containing wild-type Schistosoma japonicum TGR (wtSjTGR), in order to develop a new leading compound for schistosomiasis. Thirty-nine novel derivatives were prepared to test their activity toward both enzymes. The docking method was used to detect the binding site between the active molecule and SjTGR. The structure-activity relationship (SAR) of these novel furoxan derivatives was preliminarily analyzed. RESULTS: It was found that several new derivatives, including compounds 6a-6d, 9ab, 9bd and 9be, demonstrated greater activity toward rSjTGR-Sec or SWAP containing wtSjTGR than did furoxan. Interestingly, all intermediates bearing hydroxy (6a-6d) showed excellent inhibitory activity against both enzymes. In particular, compound 6d with trifluoromethyl on a pyridine ring was found to have much higher inhibition toward both rSjTGR-Sec (half-maximal inhibitory concentration, IC50,7.5nM) and SWAP containing wtSjTGR (IC50 55.8nM) than furoxan. Additionally, the docking method identified the possible matching sites between 6d and Schistosoma japonicum TGR (SjTGR), which theoretically lends support to the inhibitory activity of 6d. CONCLUSION: The data obtained herein showed that 6d with trifluoromethyl on a pyridine ring could be a valuable leading compound for further study.

Synthesis and antitumor activities of NO-donating rhein derivatives / 中国药科大学学报

@#Seven target compounds coupled by rhein and furoxan were synthesized and their chemical structures were confirmed by 1H NMR, IR, and MS. All target compounds were evaluated for anti-proliferative activity against human hepatoma cells HepG2 and Bel-7402, human colon cancer cells HCT116, human osteosarcoma cells U2OS, drug-resistant cells Bel-7402/5-FU and normal hepatocytes cells LO2 in vitro by thiazolyl blue(MTT) colorimetry. The results indicated that all target compounds had more potent anti-proliferative activity than their parent compound rhein. Additionally, compound 4g had stronger proliferation inhibitory activity on HepG2, Bel-7402, U2OS and Bel-7402/5-FU,with little effect on the proliferation of normal cells, exhibiting selective inhibitory activity. Griess assay was used to measure the release of nitric oxide in vitro. Results showed that compound 4g could increase the releases NO in HepG2 cells, which may be associated with its antitumor effects. Furthermore, the antitumor activity of compound 4g was attenuated by NO scavenger (hemoglobin), which indicates that the antitumor activity of compound 4g may be partly related to the release of NO.