- Synthesis and biological evaluation of new nitrogen-containing diselenides
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The antioxidant properties of organoselenium compounds have been extensively investigated with the aim of developing new drugs, since oxidative stress is responsible for a variety of chronic human diseases. Herein, we reported the synthesis of new nitrogen-containing diselenides by a simple and efficient synthetic route. The products were obtained in good to excellent yields and their identification and characterization were achieved by NMR and HRMS techniques. The new derivatives may represent promising structures with different biological activities, which can act against oxidative stress through diverse mechanisms of action. The glutathione peroxidase-like assay (GPx-like activity) of the new synthesized compounds indicated that they reduced H2O2to water at the expense of PhSH. The best results were obtained with diselenide 2b, which was 9 times more active than the standard organoselenium drug ebselen and, in contrast, this compound was not reduced by hepatic TrxR. All of the new compounds inhibited Fe(II)-induced TBARS.
- Nascimento, Vanessa,Ferreira, Natasha L.,Canto, R?mulo F.S.,Schott, Karen L.,Waczuk, Emily P.,Sancineto, Luca,Santi, Claudio,Rocha, Jo?o B.T.,Braga, Antonio L.
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Read Online
- Structure-Guided Discovery of the Novel Covalent Allosteric Site and Covalent Inhibitors of Fructose-1,6-Bisphosphate Aldolase to Overcome the Azole Resistance of Candidiasis
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Fructose-1,6-bisphosphate aldolase (FBA) represents an attractive new antifungal target. Here, we employed a structure-based optimization strategy to discover a novel covalent binding site (C292 site) and the first-in-class covalent allosteric inhibitors
- Cao, Hongxuan,Chen, Han,Han, Xinya,Huang, Yunyuan,Liu, Jiaqi,Peng, Chao,Rao, Li,Ren, Yanliang,Sheng, Chunquan,Su, Chen,Tu, Jie,Wan, Chen,Wan, Jian,Wen, Wuqiang
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p. 2656 - 2674
(2022/02/09)
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- Benzoselenazolone compound and application thereof and bactericide
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The invention relates to the field of antifungal drugs, and discloses a benzoselenazolone compound and application thereof and a bactericide, and the benzoselenazolone compound has a structural general formula shown in a formula (I). The benzoselenazolone compound provided by the invention can take candida albicans fructose-1, 6-diphosphate aldolase (Ca-FBA-II) as a target spot to inhibit the activity of the candida albicans fructose 1, 6-diphosphate aldolase (Ca-FBA-II), and has a good resistance effect on drug-resistant bacteria generated by taking cytochrome P450 as an action target.
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- SELENIUM-CONTAINING ISOXAZOLAMINE COMPOUND, PREPARATION METHOD THEREFOR, AND USE THEREOF
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The present invention disclosed a series of novel selenium-containing isoxazolamine derivatives as shown in formula I, which could regulate the generation and/or activity of TNF-α and ferroptosis-like cell death. The present invention also disclosed the preparation method and the use thereof in preparing a drug for treating the diseases mediated by TNF-α and/or iron-dependent cell death.
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Paragraph 0067-0070
(2021/09/26)
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- Synthesis of new alkylated and methoxylated analogues of ebselen with antiviral and antimicrobial properties
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A series of new mono and disubstituted alkylated and methoxylated benzisoselanzol-3(2H)-ones and bis(2carbamoylaryl)diselenides were prepared in yields ranging from 55% to 95% starting from anthranilic acid and were evaluated for antiviral and antimicrobial activity. The compounds exhibited antiviral activity against Human herpes virus 1 and Encephalomyocarditis virus as well as antimicrobial activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Candida albicans. R1 O O R1 COOH N N R2 H Se R2 NH2 Se 2 R1, R2 = Me, OMe, Cl, t-Bu, H.
- Pi?tka-Ottlik, Magdalena,Burda-Grabowska, Ma?gorzata,Wo?na, Marta,Waleńska, Joanna,Kaleta, Rafa?,Zaczyńska, Ewa,Piasecki, Egbert,Giurg, Miros?aw
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p. 546 - 556
(2021/02/09)
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- High-throughput tandem-microwell assay for ammonia repositions FDA-Approved drugs to inhibit Helicobacter pylori urease
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To date, little attempt has been made to develop new treatments for Helicobacter pylori (H. pylori), although the community is aware of the shortage of treatments for H. pylori. In this study, we developed a 192-tandem-microwell-based high-throughput assay for ammonia that is a known virulence factor of H. pylori and a product of urease. We could identify few drugs, that is, panobinostat, dacinostat, ebselen, captan, and disulfiram, to potently inhibit the activity of ureases from bacterial or plant species. These inhibitors suppress the activity of urease via substrate-competitive or covalent-allosteric mechanism, but all except captan prevent the antibiotic-resistant H. pylori strain from killing human gastric cells, with a more pronounced effect than acetohydroxamic acid, a well-known urease inhibitor and clinically used drug for the treatment of bacterial infection. This study offers several bases for the development of new treatments for urease-containing pathogens and to study the mechanism responsible for the regulation of urease activity.
- Fang, Houqin,Huang, Shengshuo,Li, Fangzheng,Liao, Lujian,Liu, Fan,Liu, Qi,Wu, Fang,Wu, Xin-Yan,Xiao, Zhuping,Xu, Jinyi,Yu, Jing,Zhang, Yan-Xia,Zhou, Yueyang
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- Pyrimidine-selenium benzoic acid derivative as well as preparation method and application thereof as herbicide
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The invention belongs to the technical field of herbicides, and particularly relates to a pyrimidine-selenium benzoic acid derivative as well as a preparation method and application thereof as a herbicide. The compound is subjected to nucleophilic substit
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Paragraph 0045-0046
(2021/11/19)
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- Crystal form of 1, 4-[bis(1, 2-benzisoselenazole-3(2H)-ketone)] butane and preparation method and application thereof
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The crystal form I of 1, 4-[bis(1, 2-benzisoselenazole-3(2H)-ketone)] butane is radiated by Cu-Kalpha, and X-ray powder diffraction expressed by a 2theta angle has characteristic peaks at 6.17+/-0.20degree, 12.28+/-0.20 degree, 18.44+/-0.20 degree, 25.92+/-0.20 degree and 30.95+/-0.20 degree. The crystal form has good stability, is not suitable for crystal transformation, is beneficial to preparation, use, transportation and storage of pharmaceutical compositions and preparations, and fully guarantees the medication safety and the drug quality. In addition, the crystal form has high solubility, reasonable bioavailability, low toxicity and excellent tumor inhibition activity.
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Paragraph 0052-0059
(2021/01/04)
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- Ultrasound-assisted synthesis of alkali metals diselenides (M2Se2) and their application for the gram-scale preparation of 2,2’-diselenobis(benzoic acid)
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A simple and efficient method to convert elemental selenium into alkali metal diselenide was developed. The use of selenium and metal borohydride in a molar ratio of 1 to 0.125 in the presence of base, under “on water” conditions and ultrasound activation permitted the reduction of Se into Se22- to be completed within minutes. Thus obtained metal diselenide aqueous solution was then used in the multigram scale synthesis of 2,2’-diselenobis(benzoic acid) (DSBA) a valuable building block for the development of diverse and pivotal selenorganic compounds.
- Krasowska, Dorota,Begini, Francesca,Santi, Claudio,Mangiavacchi, Francesca,Drabowicz, Jozef,Sancineto, Luca
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- 1,2-BENZISOSELENAZOL-3(2H)-ONE AND 1,2-BENZISOTHIAZOL-3(2H)-ONE DERIVATIVES AS BETA-LACTAM ANTIBIOTIC ADJUVANTS
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Provided herein are compositions and methods useful in the treatment of beta-lactam antibiotic resistant bacteria.
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Paragraph 0186; 0187
(2019/10/04)
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- The structure-activity profile of mercaptobenzamides’ anti-HIV activity suggests that thermodynamics of metabolism is more important than binding affinity to the target
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Mercaptobenzamide thioesters and thioethers are chemically simple HIV-1 maturation inhibitors with a unique mechanism of action, low toxicity, and a high barrier to viral resistance. A structure-activity relationship (SAR) profile based on 39 mercaptobenzamide prodrug analogs exposed divergent activity/toxicity roles for the internal and terminal amides. To probe the relationship between antiviral activity and toxicity, we generated an improved computational model for the binding of mercaptobenzamide thioesters (SAMTs) to the HIV-1 NCp7 C-terminal zinc finger, revealing the presence of a second low-energy binding orientation, hitherto undisclosed. Finally, using NMR-derived thiol–thioester exchange equilibrium constants, we propose that thermodynamics plays a role in determining the antiviral activity observed in the SAR profile.
- Nikolayevskiy, Herman,Robello, Marco,Scerba, Michael T.,Pasternak, Evan H.,Saha, Mrinmoy,Hartman, Tracy L.,Buchholz, Caitlin A.,Buckheit, Robert W.,Durell, Stewart R.,Appella, Daniel H.
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p. 818 - 837
(2019/06/27)
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- Probing the Formation of a Seleninic Acid in Living Cells by the Fluorescence Switching of a Glutathione Peroxidase Mimetic
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Glutathione peroxidase (GPx) is a selenoenzyme that protects cells against oxidative damage. Although the formation of a seleninic acid (-SeO2H) by this enzyme during oxidative stress has been proposed, a selenic acid has not been identified in cells. Herein, we report that the formation of a seleninic acid can be monitored in living cells by using a redox-active ebselen analogue with a naphthalimide fluorophore. The probe reacts with H2O2 to generate the highly fluorescent seleninic acid. The electron withdrawing nature of the -SeO2H moiety and strong Se???O interactions, which prevent the photoinduced electron transfer, are responsible for the fluorescence.
- Ungati, Harinarayana,Govindaraj, Vijayakumar,Narayanan, Megha,Mugesh, Govindasamy
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supporting information
p. 8156 - 8160
(2019/05/17)
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- Virtual screening guided design, synthesis and bioactivity study of benzisoselenazolones (BISAs) on inhibition of c-met and its downstream signalling pathways
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c-Met is a transmembrane receptor tyrosine kinase and an important therapeutic target for anticancer drugs. In this study, we designed a small library containing 300 BISAs molecules that consisted of carbohydrates, amino acids, isothiourea, tetramethylthiourea, guanidine and heterocyclic groups and screened c-Met targeting compounds using docking and MM/GBSA. Guided by virtual screening, we synthesised a series of novel compounds and their activity on inhibition of the autophosphorylation of c-Met and its downstream signalling pathway proteins were evaluated. We found a panel of benzisoselenazolones (BISAs) obtained by introducing isothiourea, tetramethylthiourea and heterocyclic groups into the C-ring of Ebselen, including 7a, 7b, 8a, 8b and 12c (with IC50 values of less than 20 μMin MET gene amplified lung cancer cell line EBC-1), exhibited more potent antitumour activity than Ebselen by cell growth assay combined with in vitro biochemical assays. In addition, we also tested the antitumour activity of three cancer cell lines without MET gene amplification/activation, including DLD1, MDA-MB-231 and A549. The neuroblastoma SK-N-SH cells with HGF overexpression which activates MET signalling are sensitive to MET inhibitors. The results reveal that our compounds may be nonspecific multitarget kinase inhibitors, just like type-II small molecule inhibitors. Western blot analysis showed that these inhibitors inhibited autophosphorylation of c-MET, and its downstream signalling pathways, such as PI3K/AKT and MARK/ERK. Results suggest that bensoisoselenones can be used as a scaffold for the design of c-Met inhibiting drug leads, and this study opens up new possibilities for future antitumour drug design.
- Zhang, Siqi,Song, Qiaoling,Wang, Xueting,Wei, Zhiqiang,Yu, Rilei,Wang, Xin,Jiang, Tao
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- Ebselen bearing polar functionality: Identification of potent antibacterial agents against multidrug-resistant Gram-negative bacteria
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Antibiotic-resistant bacteria has become one of the greatest challenges to global human health today. Innovative strategies are needed to identify new therapeutic leads to tackle infections of drug-resistant Gram-negative bacteria. We herein synthesize a series of EB analogues to investigate their antibacterial activities. Select polar functionality at N-terminus of EB exhibited higher activities against multi-drug-resistant Gram-negative pathogens, including E. coli, P. aeruginosa and K. pneumoniae. EB analogue 4g and 4i exhibited potent antibacterial activities against E. coli-ESBL (MIC = 1–4 μg/mL) and E. coli producing NDM-1 (MIC = 4–32 μg/mL), which is superior to the traditional antibiotics (cefazolin, imipenem). Furthermore, the time-kill kinetics studies and the inhibition zone tests indicated that analogue 4i effectively and rapidly cause death of E. coli-ESBL and E. coli-NDM-1. Additionally, accumulation assays and SEM images showed that 4i could permeate bacterial membranes, leading to an irregular cell morphology. Importantly, bacterial resistance for analogue 4i was difficult to induce against E. coli-ESBL. EB analogues here reported low cytotoxicity against L-929 cells and mice model in vivo. We believe that EB analogues with polar functionality could play a pivotal role in the development of novel antibacterial agents in eradicating multi-drug-resistant Gram-negative pathogens infections.
- Chen, Cheng,Yang, Kewu
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- Synthesis and antiproliferative evaluation of novel steroid-benzisoselenazolone hybrids
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The two different types of steroidal benzisoselenazolone hybrids were synthesized by incorporating benzisoselenazolone scaffold into dehydroepiandrosterone and B-norcholesterol. The antiproliferative activity of the synthesized compounds against some carcinoma cell lines were investigated. The results showed that some of these compounds have better inhibitory activity than abiraterone on the proliferation of tumor cells associated with human growth hormone, and have less cytotoxicity on normal human cells. In particular, the IC50 values of the compound 8a and 8f are 5.4 and 6.5 μmol/L against human ovarian carcinoma (SKOV3) cell line, and possess SI values of 13.9 and 10.5, respectively. The information obtained from the studies may be useful for the design of novel chemotherapeutic drugs.
- Cui, Jianguo,Wei, Meizhen,Pang, Liping,Gan, Chunfang,Xiao, Junan,Shi, Haixin,Zhan, Junyan,Liu, Zhiping,Huang, Yanmin
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- Aglycone Ebselen and β- D -Xyloside Primed Glycosaminoglycans Co-contribute to Ebselen β- D -Xyloside-Induced Cytotoxicity
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Most β-d-xylosides with hydrophobic aglycones are nontoxic primers for glycosaminoglycan assembly in animal cells. However, when Ebselen was conjugated to d-xylose, d-glucose, d-galactose, and d-lactose (8A-D), only Ebselen β-d-xyloside (8A) showed significant cytotoxicity in human cancer cells. The following facts indicated that the aglycone Ebselen and β-d-xyloside primed glycosaminoglycans co-contributed to the observed cytotoxicity: 1. Ebselen induced S phase cell cycle arrest, whereas 8A induced G2/M cell cycle arrest; 2. 8A augmented early and late phase cancer cell apoptosis significantly compared to that of Ebselen and 8B-D; 3. Both 8A and phenyl-β-d-xyloside primed glycosaminoglycans with similar disaccharide compositions in CHO-pgsA745 cells; 4. Glycosaminoglycans could be detected inside of cells only when treated with 8A, indicating Ebselen contributed to the unique property of intracellular localization of the primed glycosaminoglycans. Thus, 8A represents a lead compound for the development of novel antitumor strategy by targeting glycosaminoglycans.
- Tang, Yang,Zhang, Siqi,Chang, Yajing,Fan, Dacheng,Agostini, Ariane De,Zhang, Lijuan,Jiang, Tao
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p. 2937 - 2948
(2018/04/23)
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- Hybrids of arenobufagin and benzoisoselenazol reducing the cardiotoxicity of arenobufagin
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Arenobufagin is a naturally occurring bufadienolide showing promising antitumor activity accompanied however with apparent cardiac toxicity. Following the recent discovery that oxidative damage possibly be an important cause of the cardiac toxicity of cardenolides, a strategy fusing the antitumor agent arenobufagin with a benzoisoselenazol fragment, a reactive oxygen species (ROS) scavenger, has been developed. Six novel hybrids were synthesized and their ROS scavenging activities as well as their in vitro cytotoxicity against the human hepatocellular carcinoma cell line HepG2, an adriamycin-resistant subline HepG2/ADM, and the human myocardial cell line AC16 were evaluated. The results indicate that the hybrids exhibit various degrees of in vitro ROS scavenging activities, and weaker cytotoxicity than that of arenobufagin against the myocardial cell line AC16. These findings suggest the feasibility of a strategy in which the cardiotoxicity of the potential antitumor agent arenobufagin is reduced.
- Hou, Wen,Huang, Zhi-Xing,Xu, Hong-Gui,Lin, Jing,Zhang, Dong-Mei,Peng, Qun-Long,Lin, Hui,Chang, Yi-Qun,Wang, Long-Hai,Yao, Zhe,Sun, Ping-Hua,Chen, Wei-Min
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supporting information
p. 3391 - 3394
(2018/09/11)
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- Design, synthesis, and biological evaluation of histone deacetylase inhibitors possessing glutathione peroxidase-like and antioxidant activities against Alzheimer's disease
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A series of hybrids containing the pharmacophores of the histone deacetylase (HDAC) inhibitor, SAHA, and the antioxidant ebselen were designed and synthesized as multi-target-directed ligands against Alzheimer's disease. An in vitro assay indicated that some of these molecules exhibit potent HDAC inhibitory activity and ebselen-related pharmacological effects. Specifically, the optimal compound 7f was found to be a potent HDAC inhibitor (IC50 = 0.037 μM), possessing rapid hydrogen peroxide scavenging activity and glutathione peroxidase-like activity (ν0 = 150.0 μM min?1) and good free oxygen radical absorbance capacity (value of ORAC: 2.2). Furthermore, compound 7f showed significant protective effects against damage induced by H2O2 and the ability to prevent ROS accumulation in PC12 cells.
- Hu, Jinhui,An, Baijiao,Pan, Tingting,Li, Zhengcunxiao,Huang, Ling,Li, Xingshu
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p. 5718 - 5729
(2018/10/31)
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- Investigation of synergistic antimicrobial effects of the drug combinations of meropenem and 1,2-benzisoselenazol-3(2H)-one derivatives on carbapenem-resistant Enterobacteriaceae producing NDM-1
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The worldwide prevalence of NDM-1-producing bacteria has drastically undermined the clinical efficacy of the last line antibiotic of carbapenems, prompting a need to devise effective strategy to preserve their clinical value. Our previous studies have shown that ebselen can restore the efficacy of meropenem against a laboratory strain that produces NDM-1. Here we report the construction of a focused compound library of 1,2-benzisoselenazol-3(2H)-one derivatives which comprise a total of forty-six candidate compounds. The structure-activity relationship of these compounds and their potential to serve as an adjuvant to enhance the antimicrobial efficacy of meropenem against a collection of clinical NDM-1-producing carbapenem-resistant Enterobacteriaceae isolates was examined. Drug combination assays indicated that these derivatives exhibited synergistic antimicrobial activity when used along with meropenem, effectively restoring the activity of carbapenems against the resistant strains tested in a Galleria mellonella larvae in vivo infection model. The mode of inhibition of one compound, namely 11_a38, which was depicted when tested on the purified NDM-1 enzyme, indicated that it could covalently bind to the enzyme and displaced one zinc ion from the active site. Overall, this study provides a novel 1,2-benzisoselenazol-3(2H)-one scaffold that exhibits strong synergistic antimicrobial activity with carbapenems, and low cytotoxicity. The prospect of application of such compounds as carbapenem adjuvants warrants further evaluation.
- Jin, Wen Bin,Xu, Chen,Cheng, Qipeng,Qi, Xiao Lin,Gao, Wei,Zheng, Zhiwei,Chan, Edward W.C.,Leung, Yun-Chung,Chan, Tak Hang,Wong, Kwok-Yin,Chen, Sheng,Chan, Kin-Fai
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p. 285 - 302
(2018/07/13)
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- Novel selenadiazole derivatives as selective antitumor and radical scavenging agents
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Twenty-seven novel benzo[c][1,2,5]selenadiazole-5-carboxylic acid (BSCA) derivatives were designed and synthesized. Anti-proliferative activity of these structures was tested in vitro against a panel of five human cancer cell lines, including prostate (PC-3), colon (HT-29), leukemia (CCRF-CEM), lung (HTB-54) and breast (MCF-7). Four compounds (5, 6, 7 and 19) showed potent inhibitory activity with GI50 values below 10 μM in at least one of the cancer cell lines. The selectivity of these compounds was further examined in two non-malignant cell lines derived from breast (184B5) and lung (BEAS-2B). Compound 7 exhibited promising anti-proliferative activity (GI50 = 3.7 μM) in MCF-7 cells, together with high selectivity index (SI > 27.1). The induction of cell death by compound 7 was independent of the apoptotic process and it did not affect cell cycle progression either. Likewise, radical scavenging properties of the new selenadiazole derivatives were confirmed by testing their ability to scavenge DPPH radicals. Four compounds (1, 2, 8 and 9) showed potent radical scavenging activity, compound 9 being the most effective. Overall, while compound 7 was identified as the most cell growth inhibitory agent and selectively toxic to cancer cells, compound 9 proved to be the most potent antioxidant among the selenadiazole derivatives synthesized. This series of compounds can serve as an excellent scaffold to achieve new and potent antioxidant compounds useful for several diseases, i.e. cancer, neurodegenerative, heart diseases and leishmaniasis, considering the high radical scavenging activity and low toxicity showed by most of the compounds.
- Ruberte, Ana Carolina,Plano, Daniel,Encío, Ignacio,Aydillo, Carlos,Sharma, Arun K.,Sanmartín, Carmen
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supporting information
p. 14 - 27
(2018/08/03)
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- Water-dependent synthesis of biologically active diaryl diselenides
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A new one-step method for the synthesis of diaryl diselenides has been developed. The reaction of o-iodobenzamides with dilithium diselenide can be controlled by the presence of water providing a simple and efficient protocol to obtain benzisoselenazolones or diaryl diselenides. A series of N-Aryl ebselen derivatives and the corresponding diselenides was obtained. All synthesized compounds were tested in vitro as antioxidants and cytotoxic agents. N-(2,3,4-Trimethoxyphenyl)benzisoselenazol-3(2H)-one was the best in vitro antioxidant and the corresponding diselenide the most potent cytotoxic agent against prostate cancer cell line DU145, being inactive towards healthy prostate cell line PNT1A. Formula parented.
- Pacu?a, Agata J.,Obieziurska, Magdalena,?cianowski, Jacek,Kaczor, Katarzyna B.,Antosiewicz, J?drzej
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p. 153 - 164
(2018/07/05)
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- Evaluation of substituted ebselen derivatives as potential trypanocidal agents
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Human African trypanosomiasis is a disease of sub-Saharan Africa, where millions are at risk for the illness. The disease, commonly referred to as African sleeping sickness, is caused by an infection by the eukaryotic pathogen, Trypanosoma brucei. Previously, a target-based high throughput screen revealed ebselen (EbSe), and its sulfur analog, EbS, to be potent in vitro inhibitors of the T. brucei hexokinase 1 (TbHK1). These molecules also exhibited potent trypanocidal activity in vivo. In this manuscript, we synthesized a series of sixteen EbSe and EbS derivatives bearing electron-withdrawing carboxylic acid and methyl ester functional groups, and evaluated the influence of these substituents on the biological efficacy of the parent scaffold. With the exception of one methyl ester derivative, these modifications ablated or blunted the potent TbHK1 inhibition of the parent scaffold. Nonetheless, a few of the methyl ester derivatives still exhibited trypanocidal effects with single-digit micromolar or high nanomolar EC50values.
- Gordhan, Heeren M.,Patrick, Stephen L.,Swasy, Maria I.,Hackler, Amber L.,Anayee, Mark,Golden, Jennifer E.,Morris, James C.,Whitehead, Daniel C.
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p. 537 - 541
(2017/01/17)
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- New chiral ebselen analogues with antioxidant and cytotoxic potential
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New chiral camphane-derived benzisoselenazol-3(2H)-ones and corresponding diselenides have been synthetized using a convenient one-pot procedure. Se-N bond was efficiently converted to an Se-Se bond, which could also be easily re-oxidized to the initial benzisoselenazolone moiety. The antioxidant activity of camphor derivatives was evaluated and compared to the reactivity of a series of N-amino acid benzisoselenazol-3(2H)-ones obtained by a modified procedure involving the improved synthesis and isolation of the diseleno bis(dibenzoic) acid. The most efficient peroxide scavengers, N-bornyl and N-leucine methyl ester benzisoselenazol-3(2H)-ones, were further evaluated as cytotoxic agents on four cancer cell lines (MCF-7, HEP G2, HL 6, and DU 145) and normal cell line PNT1A. The highest antiproliferative potential was evaluated for two compounds bearing a 3-methylbutyl carbon chain, N-leucine methyl ester and N-3-methylbutyl benzisoselenazol-3(2H)-ones.
- Pacu?a, Agata J.,Kaczor, Katarzyna B.,Antosiewicz, J?drzej,D?ugosz, Angelika,Janecka, Anna,Janecki, Tomasz,Wojtczak, Andrzej,?cianowski, Jacek,Santi, Claudio,Bagnoli, Luana,Dembinski, Roman
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- Synthesis of new alkylated and methoxylated analogues of ebselen with antiviral and antimicrobial properties
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A series of new mono and disubstituted alkylated and methoxylated benzisoselanzol-3(2H)-ones and bis(2-carbamoylaryl)diselenides were prepared in yields ranging from 55% to 95% starting from anthranilic acid and were evaluated for antiviral and antimicrobial activity. The compounds exhibited antiviral activity against Human herpes virus 1 and Encephalomyocarditis virus as well as antimicrobial activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Candida albicans. (Chemical Equation Presented).
- Pietka-Ottlik, Magdalena,Burda-Grabowska, Ma?gorzata,Wo?na, Marta,Waleńska, Joanna,Kaleta, Rafa?,Zaczyńska, Ewa,Piasecki, Egbert,Giurg, Miros?aw
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p. 546 - 556
(2017/03/14)
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- Benzisoselenazolone quinoline derivative and application thereof in treatment of Alzheimer's disease
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The invention provides a benzisoselenazolone quinoline derivative as shown in a formula I, or pharmaceutically acceptable salts, hydrate, solvates, crystal-form isomers or diastereoisomers thereof, as well as an application of compounds or compositions in
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Paragraph 0047; 0048; 0049
(2017/08/25)
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- PURINE COMPOUNDS AND METHOD FOR THE TREATMENT OF CANCER
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The present disclosure relates to novel compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof; wherein R1, R2, Ra, Rb and Rc are as defined herein, pharmaceutical compositions containing same and methods for the treatment of cancer using same.
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Page/Page column 26-28
(2017/11/14)
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- Reaction of bis[(2-chlorocarbonyl)phenyl] diselenide with phenols, aminophenols, and other amines towards diphenyl diselenides with antimicrobial and antiviral properties ?
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A reaction of bis[(2-chlorocarbonyl)phenyl] diselenide with various mono and bisnucleophiles such as aminophenols, phenols, and amines have been studied as a convenient general route to a series of new antimicrobial and antiviral diphenyl diselenides. The compounds, particularly bis[2-(hydroxyphenylcarbamoyl)]phenyl diselenides and reference benzisoselenazol-3(2H)-ones, exhibited high antimicrobial activity against Gram-positive bacterial species (Enterococcus spp., Staphylococcus spp.), and some compounds were also active against Gram-negative E. coli and fungi (Candida spp., A. Niger). The majority of compounds demonstrated high activity against human herpes virus type 1 (HHV-1) and moderate activity against encephalomyocarditis virus (EMCV), while they were generally inactive against vesicular stomatitis virus (VSV).
- Giurg, Miros?aw,Go?ab, Anna,Suchodolski, Jakub,Kaleta, Rafa?,Krasowska, Anna,Piasecki, Egbert,Pietka-Ottlik, Magdalena
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- Selenium containing macrocycles: transformation between Se–N/Se–S/Se–Se bonds
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Macrocycles possess potential applications in supramolecular chemistry and biosystems. Thus development of new kinds of macrocycles is of significance. Herein, novel macrocycles containing Se–Se/Se–S bonds were synthesized via transformation between selenium related dynamic covalent bonds. A monomer containing two ebselen moieties was synthesized (M1). The Se–N bonds in M1 were reduced by dithiothreitol, forming Se–S linked dimer (D1). To realize the transformation from Se–S bonds to Se–Se bonds, guest molecules were added as template, triggering the formation of Se–Se linked dimer (D2). The formation of these two new kinds of macrocycles was determined by 1H NMR and 77Se NMR, and the necessity of guest molecules was also confirmed. The introduction of ebselen moieties and Se–S bonds or Se–Se bonds into macrocycles may endow it with new responsiveness and bioactivities, as well as new types of host-guest chemistry.
- Ji, Shaobo,El Mard, Hicham,Smet, Mario,Dehaen, Wim,Xu, Huaping
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p. 1191 - 1196
(2017/09/18)
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- Synthesis and applications of benzisoselenazolone modified nitrosourea compound
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The present invention relates to a benzisoselenazolone modified nitrosourea compound and applications thereof, wherein the benzisoselenazolone modified nitrosourea compound is represented by a general formula I, has excellent antitumor activity, and can be widely used for preparing antitumor drugs. The general formula I is defined in the specification.
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Paragraph 0082; 0083; 0084; 0085; 0086; 0087; 0088
(2017/08/29)
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- Biomolecular Interaction Assays Identified Dual Inhibitors of Glutaminase and Glutamate Dehydrogenase That Disrupt Mitochondrial Function and Prevent Growth of Cancer Cells
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Glutaminase (KGA/isoenzyme GAC) is an emerging and important drug target for cancer. Traditional methods for assaying glutaminase activity are coupled with several other enzymes. Such coupled assays do not permit the direct and stringent characterization of specific glutaminase inhibitors. Ebselen was identified as a potent 9 nM KGA inhibitor in the KGA/glutamate oxidase (GO)/horse radish peroxidase (HRP) coupled assay but showed very weak activity in inhibiting the growth of glutamine-dependent cancer cells. For rigorous characterization, we developed a direct kinetic binding assay for KGA using bio-layer interferometry (BLI) as the detection method; Ebselen was identified as a GDH inhibitor but not a KGA inhibitor. Furthermore, we designed and synthesized several benzo[d][1,2]selenazol-3(2H)-one dimers which were subjected to SAR analysis by several glutaminolysis specific biochemical and cell based assays. Novel glutamate dehydrogenase (GDH) or dual KGA/GDH inhibitors were discovered from the synthetic compounds; the dual inhibitors completely disrupt mitochondrial function and demonstrate potent anticancer activity with a minimum level of toxicity.
- Zhu, Min,Fang, Jinzhang,Zhang, Jingjing,Zhang, Zheng,Xie, Jianhui,Yu, Yan,Ruan, Jennifer Jin,Chen, Zhao,Hou, Wei,Yang, Gensheng,Su, Weike,Ruan, Benfang Helen
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p. 1689 - 1696
(2017/08/09)
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- Benzisoselenazolone compound metabolite and synthesis method and application thereof
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The invention provides a benzisoselenazolone derivative and pharmacologically acceptable salt thereof (please see the formula I in the specification). R1 and R2 are identical or different, and independently are hydrogen, halogen (such as F and Cl), cyano, nitryl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthiol, N(C1-C6 alkyl)2, NH(C1-C6 alkyl), COOH and SO3H. The invention further provides a medicinal composition containing the compound and application of the composition in preparation of antineoplastic drugs.
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Paragraph 0100; 0101; 0102
(2017/01/02)
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- Design, synthesis and evaluation of clioquinol-ebselen hybrids as multi-target-directed ligands against Alzheimer's disease
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A novel series of compounds obtained by fusing the metal-chelating agent clioquinol and the antioxidant ebselen were designed, synthesized and evaluated as multi-target-directed ligands against Alzheimer's disease (AD). Specifically, compared with their parent compounds clioquinol and ebselen, these hybrids demonstrated significant potency in inhibiting self- and Cu(ii)-induced amyloid-β (Aβ) aggregation and acted as remarkable antioxidants and biometal chelators. In addition, the hybrids showed considerable improvements in ebselen-related pharmacological properties, including the ability to mimic glutathione peroxidase and scavenge H2O2. Of these molecules, compound 10h was identified as a potential lead compound for AD therapy. Importantly, this compound was found to possess rapid H2O2 scavenging activity and glutathione peroxidase-like (GPx-like) activity. Moreover, compound 10h was able to efficiently disassemble preformed self- and Cu(ii)-induced Aβ aggregates. Furthermore, 10h was able to penetrate the central nervous system (CNS) and did not exhibit any acute toxicity in mice at doses up to 2000 mg kg-1.
- Wang, Zhiren,Li, Wenrui,Wang, Yali,Li, Xiruo,Huang, Ling,Li, Xingshu
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p. 7139 - 7158
(2016/07/12)
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- A Benzisoelenazolone modified pyrrole methyl ester substituted indole ketone compound and use thereof
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The invention discloses a benzisoselenazolone-modified pyrrolyl formate-substituted indolone compound and a use thereof. The invention depends on and claims the priority of a Chinese patent application 201110105248.0 submitted on April 26, 2011. Through reference, all contents of the Chinese patent application 201110105248.0 are incorporated into the invention. The benzisoselenazolone-modified pyrrolyl formate-substituted indolone compound is shown in the general formula I. The 2-indolone compound provided by the invention has excellent antitumor activity and can be widely used for preparation of antitumor drugs.
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Paragraph 0218-0221
(2016/10/08)
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- Identification of methionine aminopeptidase 2 as a molecular target of the organoselenium drug ebselen and its derivatives/analogues: Synthesis, inhibitory activity and molecular modeling study
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A collection of twenty-six organoselenium compounds, ebselen and its structural analogues, provided a novel approach for inhibiting the activity of human methionine aminopeptidase 2 (MetAP2). This metalloprotease, being responsible for the removal of the amino-terminal methionine from newly synthesized proteins, plays a key role in angiogenesis, which is essential for the progression of diseases, including solid tumor cancers. In this work, we discovered that ebselen, a synthetic organoselenium drug molecule with anti-inflammatory, anti-oxidant and cytoprotective activity, inhibits one of the main enzymes in the tumor progression pathway. Using three-step synthesis, we obtained twenty-five ebselen derivatives/analogues, ten of which are new, and tested their inhibitory activity toward three neutral aminopeptidases (MetAP2, alanine and leucine aminopeptidases). All of the tested compounds proved to be selective, slow-binding inhibitors of MetAP2. Similarly to ebselen, most of its analogues exhibited a moderate potency (IC50= 1–12 μM). Moreover, we identified three strong inhibitors that bind favorably to the enzyme with the half maximal inhibitory concentration in the submicromolar range.
- W?glarz-Tomczak, Ewelina,Burda-Grabowska, Ma?gorzata,Giurg, Miros?aw,Mucha, Artur
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p. 5254 - 5259
(2016/11/09)
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- Synthesis and evaluation of 8-hydroxyquinolin derivatives substituted with (benzo[d][1,2]selenazol-3(2H)-one) as effective inhibitor of metal-induced Aβ aggregation and antioxidant
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A series of 8-hydroxyquinolin derivatives substituted with (benzo[d][1,2]selenazol-3(2H)-one) at the 2-position were synthesized and evaluated for treatment of Alzheimer's disease. In vitro assays demonstrated that most of the target compounds exhibit significant inhibition of Cu(II)-induced Aβ1–42aggregation, rapid H2O2scavenging and glutathione peroxidise (GPx)-like catalytic activity. Among these molecules, compound 9a is the most potent peroxide scavenger that possesses the ability to scavenge most H2O2within 200–220 min and possesses GPx-like activity (v0= 106.0 μM·min?1), enabling modulation of metal-induced Aβ aggregation.
- Wang, Bo,Wang, Zhiren,Chen, Hong,Lu, Chuan-Jun,Li, Xingshu
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p. 4741 - 4749
(2016/09/09)
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- Organoselenocyanates and symmetrical diselenides redox modulators: Design, synthesis and biological evaluation
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Abstract Oxidative stress (OS) and disturbed intracellular redox balance have been predominantly observed in different types of cancer, including hepatocellular carcinoma (HCC). Agents which can stop OS multi-stressor events and modulate the intracellular redox state are becoming a major focus in HCC prevention. Among them, compounds with glutathione peroxidase (GPx)-like activity are of particularly concern. We herein report the synthesis of novel series of organoselenocyanates and symmetrical diselenide antioxidants, inspired by the natural redox enzyme, GPx and the synthetic organoselenium ebselen antioxidants. Their cytotoxic activity was evaluated against Hep G2 cells and their antimicrobial activities were evaluated against Candida albicans (C. albicans) fungus as well as against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), gram-negative and gram-positive bacteria, respectively. These compounds were also tested for their antioxidant activities using 2,2-diphenyl-1-picrylhydrazyl (DPPH), GPx-like activity and bleomycin dependent DNA damage assays and a basic structure-activity relationship was subsequently established. The physicochemical parameters and drug-likeness were computed employing the Molinspiration online property calculation toolkit and MolSoft software. Interestingly, some compounds proved to be more cytotoxic than ebselen and the known anticancer drug 5-Fu and in the same time they showed similar, sometime even more, antifungal activity than the reference antifungal drugs. Among these compounds, compound 16 was considered to be the most interesting with free radical-scavenging activity comparable to ascorbic acid and a GPx-like activity similar to ebselen. As most of these compounds comply with Lipinski's Rule of Five, they promise good bioavailability, which needs to be studied as part of future investigations.
- Shaaban, Saad,Negm, Amr,Sobh, Mohamed A.,Wessjohann, Ludger A.
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p. 190 - 201
(2015/05/20)
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- Synthesis and biological evaluation of 2-picolylamide-based diselenides with non-bonded interactions
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In this paper, we report the synthesis and biological evaluation of picolylamide-based diselenides with the aim of developing a new series of diselenides with O???Se non-bonded interactions. The synthesis of diselenides was performed by a simple and efficient synthetic route. All the products were obtained in good yields and their structures were determined by 1H-NMR, 13C-NMR and HRMS. All these new compounds showed promising activities when tested in different antioxidant assays. These amides exhibited strong thiol peroxidase-like (TPx) activity. In fact one of the compounds showed 4.66 times higher potential than the classical standard i.e., diphenyl diselenide. The same compound significantly inhibited iron (Fe)-induced thiobarbituric acid reactive species (TBARS) production in rat's brain homogenate. In addition, the X-ray structure of the most active compound showed non-bonded interaction between the selenium and the oxygen atom that are in close proximity and may be responsible for the increased antioxidant activity. The present study provides evidence about the possible biochemical influence of nonbonding interactions on organochalcogens potency.
- Rafique, Jamal,Saba, Sumbal,Canto, Rmulo Faria Santos,Frizon, Tiago Elias Allievi,Hassan, Waseem,Waczuk, Emily Pansera,Jan, Maryam,Back, Davi Fernando,Rocha, Joo Batista Teixeira Da,Braga, Antonio Luiz
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p. 10095 - 10109
(2015/08/06)
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- Synthesis of functionalized organoselenium materials: Selenides and diselenides containing cholesterol
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Abstract A simple and efficient procedure for the synthesis of three new series of chalcogen liquid crystals, based on selenides and diselenides, containing cholesterol in their structure, is described. Thermal and liquid crystalline properties were investigated by POM, DSC, TGA and XRD scattering. Six of the nine molecules synthesized showed liquid crystal properties, with smectic mesomorphism. All the compounds presented good thermal stability. The smectic mesomorphism was confirmed through XRD analysis. The morphology of the surface of the films was investigated by using atomic force microscopy (AFM). All prepared diselenides showed good glutathione peroxidase like activity and one of the diselenides was 3.3 times more active than the standard Ebselen.
- Frizon, Tiago E.,Rafique, Jamal,Saba, Sumbal,Bechtold, Ivan H.,Gallardo, Hugo,Braga, Antonio L.
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supporting information
p. 3470 - 3476
(2015/06/08)
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- Computer-assisted designed "selenoxy-chinolin": A new catalytic mechanism of the GPx-like cycle and inhibition of metal-free and metal-associated Aβ aggregation
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Using support from rational computer-assisted design, a novel series of hybrids (selenoxy-chinolin) designed by fusing the metal-chelating agent CQ and the antioxidant ebselen were synthesized and evaluated as multitarget-directed ligands. Most of the hybrids demonstrated significant ability to mimic GPx, which is highly consistent with the prediction results of DFT studies for the selenenyl sulfide intermediates in the computational design. Using 77Se, 1H and 13C NMR spectroscopy and high-resolution mass spectroscopy (HRMS), a novel catalytic mechanism, including a new selenium quinone active species, was first demonstrated. 2D NMR studies indicated that the typical hybrid has an effective interaction with Aβ. In addition, the optimal compound 12k was found to possess an excellent ability to scavenge peroxide and to inhibit self- and metal-induced Aβ aggregation, and an ability to disassemble preformed self- and metal-induced Aβ aggregates effectively. Furthermore, 12k was able to penetrate the central nervous system (CNS) and did not exhibit any acute toxicity in mice at doses up to 2000 mg kg-1. Overall, we demonstrated that hybrid 12k, through rational structure-based computational design, shows a potential for development as a therapeutic agent in AD.
- Wang, Zhiren,Wang, Yali,Li, Wenrui,Liu, Zhihong,Luo, Zonghua,Sun, Yang,Wu, Ruibo,Huang, Ling,Li, Xingshu
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p. 20913 - 20925
(2015/12/11)
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- Glutathione S-transferase pi expression regulates the Nrf2-dependent response to hormetic diselenides
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Glutathione S-transferase pi (GSTP), a phase II gene downstream of the nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant-responsive element (ARE)/electrophile response element (EpRE) transcription pathway, plays a key role in both the signali
- Bartolini,Commodi,Piroddi,Incipini,Sancineto,Santi,Galli
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p. 466 - 480
(2016/06/06)
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- Xerogel-sequestered silanated organochalcogenide catalysts for bromination with hydrogen peroxide and sodium bromide
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While H2O22 is a powerful oxidant, decomposing into environmentally benign H2O and O2, a catalyst is often required for reactions with H2O2 to proceed at synthetically useful rates. Organotellurium and organoselenium compounds catalyze the oxidation of ha
- Gatley, Caitlyn M.,Muller, Lisa M.,Lang, Meredith A.,Alberto, Eduardo E.,Detty, Michael R.
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p. 9616 - 9639
(2015/08/06)
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- Design and synthesis of a mitochondria-targeted mimic of glutathione peroxidase, mitoebselen-2, as a radiation mitigator
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Ionizing radiation (IR) triggers mitochondrial overproduction of H2O2 and accumulation of lipid hydroperoxides leading to the induction of apoptotic and necroptotic cell death pathways. Given the high catalytic efficiency of the seleno-enzyme glutathione peroxidase (Gpx) toward reduction of lipid hydroperoxides and H2O2, we tested the potential of mitochondria-targeted derivatives of ebselen to mitigate the deleterious effects of IR. We report that 2-[[2-[4-(3-oxo-1,2-benzoselenazol-2-yl)phenyl]acetyl]amino]ethyl-triphenyl-phosphonium chloride (MitoPeroxidase 2) was effective in reducing lipid hydroperoxides, preventing apoptotic cell death, and, when administered 24 h postirradiation, increased the survival of mice exposed to whole body γ-irradiation.
- Stoyanovsky, Detcho A.,Jiang, Jianfei,Murphy, Michael P.,Epperly, Michael,Zhang, Xiaolan,Li, Song,Greenberger, Joel,Kagan, Valerian,Bayr, Hülya
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supporting information
p. 1304 - 1307
(2015/01/09)
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- Synthesis and biological evaluation of a new series of ebselen derivatives as glutathione peroxidase (GPx) mimics and cholinesterase inhibitors against Alzheimer's disease
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A series of ebselen derivatives were designed, synthesised and evaluated as inhibitors of cholinesterases (ChEs) and glutathione peroxidase (GPx) mimics. Most of the compounds were found to be potent against AChEs and BuChE, compounds 5e and 5i, proved to be the most potent against AChE with IC50 values of 0.76 and 0.46 μM, respectively. Among these hybrids, most of the compounds were found to be good GPx mimics compare with ebselen. The selected compounds 5e and 5i were also used to determine the catalytic parameters and in vitro hydrogen peroxide scavenging activity. The results indicate that compounds 5e and 5i may be excellent multifunctional agents for the treatment of AD.
- Luo, Zonghua,Liang, Liang,Sheng, Jianfei,Pang, Yanqing,Li, Jianheng,Huang, Ling,Li, Xingshu
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p. 1355 - 1361
(2014/03/21)
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- Synthesis and antiproliferative activity of selenoindirubins and selenoindirubin-N-glycosides
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Selenoindirubins and selenoindirubin-N-glycosides were prepared by the reaction of isatins and isatin-N-glycosides with 3-acetoxy-benzo[b]selenophene, respectively. While selenoindirubin-N-glycosides have not been reported before, three non-glycosylated s
- Erben, Friedrich,Kleeblatt, Dennis,Sonneck, Marcel,Hein, Martin,Feist, Holger,Fahrenwaldt, Thomas,Fischer, Christine,Matin, Abdul,Iqbal, Jamshed,Pl?tz, Michael,Eberle, Jürgen,Langer, Peter
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p. 3963 - 3978
(2013/07/11)
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- A fluorescent probe for rapid detection of thiols and imaging of thiols reducing repair and H2O2 oxidative stress cycles in living cells
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A diselenide containing fluorescent probe based on a fluorescein scaffold for thiols was developed. The fluorescent probe exhibited rapid response, high selectivity and reversibility. Confocal fluorescence microscopy was used to visualize the redox change
- Lou, Zhangrong,Li, Peng,Sun, Xiaofei,Yang, Songqiu,Wang, Bingshuai,Han, Keli
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p. 391 - 393
(2013/02/22)
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- DIPHOSPHONATE COMPOUND AND A METHOD FOR PREPARING THE SAME AND AN APPLICATION OF THE SAME
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The present disclosure relates to a new diphosphonate compound, and the method to prepare the above new diphosphonate compound. The new diphosphonate compound exhibits an activity in inhibiting osteoclast equivalent to alendronate sodium, and a higher activity in affecting the proliferation of osteoplast than the positive control compounds, but the positive control exhibits a weaker effect on osteoblast proliferation. In experimental examples, an administration schedule for the diphosphonate compound is provided.
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Paragraph 0106; 0107; 0108; 0109
(2013/08/28)
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- DIPHOSPHONATE COMPOUNDS AND PREPARATION METHOD AND USE THEREOF
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The present invention relates to a new diphosphonate compound, and the method to prepare the above new diphosphonate compound. The new diphosphonate compound provided in this present invention exhibits an activity in inhibiting osteoclast equivalent to alendronate sodium, and a higer activity in affecting the proliferation of osteoplast than the positive control compounds, but the positive control exhibits a weaker effect on osteoblast proliferation. In experimental examples, an administration schedule for the diphosphonate compound of the present invention is provided.
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Paragraph 0049-0052
(2013/09/26)
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- Synthesis and evaluation of multi-target-directed ligands against Alzheimer's disease based on the fusion of donepezil and ebselen
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A novel series of compounds obtained by fusing the cholinesterase inhibitor donepezil and the antioxidant ebselen were designed as multi-target-directed ligands against Alzheimer's disease. An in vitro assay showed that some of these molecules did not exhibit highly potent cholinesterase inhibitory activity but did have various other ebselen-related pharmacological effects. Among the molecules, compound 7d, one of the most potent acetylcholinesterase inhibitors (IC50 values of 0.042 μM for Electrophorus electricus acetylcholinesterase and 0.097 μM for human acetylcholinesterase), was found to be a strong butyrylcholinesterase inhibitor (IC50 = 1.586 μM), to possess rapid H2O2 and peroxynitrite scavenging activity and glutathione peroxidase-like activity (ν0 = 123.5 μM min-1), and to be a substrate of mammalian TrxR. A toxicity test in mice showed no acute toxicity at doses of up to 2000 mg/kg. According to an in vitro blood-brain barrier model, 7d is able to penetrate the central nervous system.
- Luo, Zonghua,Sheng, Jianfei,Sun, Yang,Lu, Chuanjun,Yan, Jun,Liu, Anqiu,Luo, Hai-Bin,Huang, Ling,Li, Xingshu
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p. 9089 - 9099
(2014/01/06)
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- Novel tacrine-ebselen hybrids with improved cholinesterase inhibitory, hydrogen peroxide and peroxynitrite scavenging activity
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A series of tacrine-ebselen hybrids were synthesised and evaluated as possible multifunctional anti-Alzheimer's disease (AD) agents. Compound 6i, which is tacrine linked with 5,6-dimethoxybenzo[d][1,2]selenazol-3(2H)-one by a six-carbon spacer, was the most potent acetylcholinesterase (AChE) and butylcholinesterase (BuChE) inhibitor, with IC50 values of 2.55 and 2.80 nM, respectively. Furthermore, this compound demonstrated similar hydrogen peroxide and peroxynitrite scavenging activity as ebselen by horseradish peroxidase assay and peroxynitrite scavenging activity assay, indicating that this hybrid is a good multifunctional drug candidate for the treatment of AD.
- Mao, Fei,Chen, Jianwen,Zhou, Qi,Luo, Zonghua,Huang, Ling,Li, Xingshu
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supporting information
p. 6737 - 6742
(2014/01/06)
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- Inhibition of thioredoxin reductase by a novel series of bis-1,2-benzisoselenazol-3(2H)-ones: Organoselenium compounds for cancer therapy
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Thioredoxin reductase (TrxR) is critical for cellular redox regulation and is involved in tumor proliferation, apoptosis and metastasis. Its C-terminal redox-active center contains a cysteine (Cys497) and a unique selenocysteine (Sec498), which are exposed to solvent and easily accessible. Thus, it is becoming an important target for anticancer drugs. Selective inhibition of TrxR by 1,2-(bis-1,2-benzisoselenazol-3(2H)-one)ethane (4a) prevents proliferation of several cancer cell lines both in vivo and in vitro. Using the structure of 4a as a starting point, a series of novel bis-1,2-benzisoselenazol-3(2H)-ones was designed, prepared and tested to explore the structure-activity relationships (SARs) for this class of inhibitor and to improve their potency. Notably, 1,2-(5,5′-dimethoxybis(1,2-benzisoselenazol-3(2H)-one))ethane (12) was found to be more potent than 4a in both in vitro and in vivo evaluation. Its binding sites were confirmed by biotin-conjugated iodoacetamide assay and a SAR model was generated to guide further structural modification.
- He, Jie,Li, Dongdong,Xiong, Kun,Ge, Yongjie,Jin, Hongwei,Zhang, Guozhou,Hong, Mengshi,Tian, Yongliang,Yin, Jin,Zeng, Huihui
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experimental part
p. 3816 - 3827
(2012/08/27)
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