- Synthesis of novel angular diazaphenoxazinone derivatives via palladium catalyzed Buchwald-Hartwig amidation protocols
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The synthesis of new amido derivatives of angular diazaphenoxazinone via tandem amidation protocol is reported. This was achieved by the condensation of 4,5-diamino-6-hydroxypyrimidine (7) with 2,3-dichloro-1,4-naphthoquinone (8) in anhydrous basic medium to furnish the key intermediate, 11-amino-6-chloro-8,10-diazabenzo[a]phenoxazin-5-one (9). Palladium catalyzed amidation reaction of 11-amino-6-chloro-8,10-diazabenzo[a]phenoxazin-5-one (9) with different amides (12a-c) (benzamide, acetamide, salicylamide and 4-nitrobenzamide) in the presence of palladium(II) acetate, triphenyl phosphine (PPh3), water and tertiary butanol at 110°C for 3 h gave the new amido derivatives 13a-c. Structures of the new compounds were established by elemental analysis, UV, FTIR, 1H NMR and 13C NMR.
- Odaa,Okoro,Ugwu
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- Design and synthesis of novel 1,3,2-benzoxazaphosphinine-2-one derivatives: an in?vitro biological evaluation and in silico approaches
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A new class of benzoxazaphosphinine-2-one derivatives were synthesized by the reaction of 2-(3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazol-2-yl)phenol with salicylic acid and thionyl chloride (SOCl2) via three-step process, and were obtained in good to excellent yields (77–95%) The designed compounds were evaluated for their in?vitro antioxidant, anti-fungal activities and in silico molecular docking. Amongst all, five compounds exhibited significant anti-fungal activity against F. oxysporum, A. niger and A. foetidus with MIC values displaying from 3.12 to 6.25 μg/mL correlated with standard drug Ketoconazole at 200 μg/mL. Furthermore, four compounds displayed promising antioxidant activity compared with the standard drugs butylated hydroxytoluene (BHT) and ascorbic acid in 1,1-diphenyl-2-picrylhydrazyl (DPPH) and nitric oxide (NO) methods at 25, 50, 75 and 100 μg/mL. Molecular docking results disclosed that all the title compounds shown interesting binding modes with docking scores between ?6.6 and ?7.8 against the target 3MNG protein in comparison with standard drugs BHT (?5.1) and ascorbic acid (?5.5).
- Sivala, Munichandra Reddy,Chintha, Venkataramaiah,Potla, Krishna Murthy,Kerru, Nagaraju,Chinnam, Sivakoteswararao,Devineni, Subba Rao,Salam J. J, Titinchi,Chinnam, Sampath,Chamarthi, Naga Raju
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- Novel derivatives of 5-amino-1-cyclopropyl-7-[(3R,5S)3,5- dimethylpiperazine-1-yl]-6,8-difluoro-4-oxo-quinoline-3-carboxylic acid: Their synthesis, antimicrobial, antifungal, and urease inhibitory studies
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Sparfloxacin (SPFX) or 5-amino-1-cyclopropyl-7-[(3R,5S)3,5- dimethylpiperazine-1-yl]-6,8-difluoro-4-oxo-quinoline-3-carboxylic acid is an orally active synthetic, broad spectrum third generation quinolone, with excellent activity against Gram-positive bacteria with selectivity against anaerobes and atypical pathogens. Three derivatives of SPFX (2, 3, and 4) were synthesized by reacting different aromatic carboxylic acids with SPFX (1). Chemistry involved the formation of amide between reacting species through nucleophilic substitution reactions. The synthesized derivatives were then structurally characterized by IR, NMR, and mass spectroscopic techniques. The antimicrobial activities of these derivatives were evaluated against four Gram-positive, seven Gram-negative bacteria, and six fungi, using SPFX as a reference. Statistical analysis revealed these derivatives as active antimicrobial agents, and 2 was more potent antimicrobial agents than the parent drug as well other fluoroquinolones. Compounds 3 and 4 showed a significant activity against Fusarium solani. Moreover, these three derivatives were evaluated for inhibitory activities against enzyme urease, carbonic anhydrase II, and α-chymotrypsin. Results showed their selectivity against urease enzyme. Based on their nontoxic behavior, these derivatives may be potential agents for further studies.
- Arayne, M. Saeed,Sultana, Najma,Gul, Somia,Khan, Ajmal
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- Novel synthesis of a new surfactant 4-((4-bromophenyl)(dodecyl)amino)-4- oxobutanoic acid containing a benzene ring using a copper catalyst cross-coupling reaction and its properties
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A new surfactant 4-((4-bromophenyl)(dodecyl)amino)-4-oxobutanoic acid with a benzene spacer was synthesized via a novel copper catalyzed cross-coupling reaction. Its structure was confirmed by FTIR, 1H-NMR, 13C-NMR and HRMS; its purity was checked by HPLC. Dynamic light scattering and an atomic force microscope showed that it forms an unusual large-diameter premicellar aggregation below the CMC.
- Chen, Minggui,Hu, Xinqi,Fu, Meilong
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- 6,7-Dimethoxy-2-{2-[4-(1H-1,2,3-triazol-1-yl)phenyl]ethyl}-1,2,3,4-tetrahydroisoquinolines as superior reversal agents for P-glycoprotein-mediated multidrug resistance
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P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a major obstacle for successful cancer chemotherapy. Based on our previous study, 17 novel compounds with the 6,7-dimethoxy-2-{2-[4-(1H-1,2,3-triazol-1-yl)phenyl]ethyl}-1,2,3,4-tetrahydroisoquinoline scaffold were designed and synthesized. Among them, 2-[(1-{4-[2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl]phenyl}-1H-1,2,3-triazol-4-yl)methoxy]-N-(p-tolyl)-benzamide (compound 7h) was identified as a potent modulator of P-gp-mediated MDR, with high potency (EC50 = 127.5 ± 9.1 nM), low cytotoxicity (TI > 784.3), and long duration (> 24 h) in reversing doxorubicin (DOX) resistance in K562/A02 cells. Compound 7h also enhanced the effects of other MDR-related cytotoxic agents (paclitaxel, vinblastine, and daunorubicin), increased the accumulation of DOX and blocked P-gp-mediated rhodamine 123 efflux function in K562/A02 MDR cells. Moreover, 7h did not have any effect on cytochrome (CYP3A4) activity. These results indicate that 7h is a relatively safe modulator of P-gp-mediated MDR that has good potential for further development.
- Liu, Baomin,Qiu, Qianqian,Zhao, Tianxiao,Jiao, Lei,Li, Yunman,Huang, Wenlong,Qian, Hai
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- Uracil Hydroxybenzamides as Potential Antidiabetic Prodrugs
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A series of N1, N3-bis-hydroxybenzoyl, -acetoxybenzoyl, and -methoxybenzoyl uracil derivatives were synthesized. All compounds were screened for the ability to rupture protein cross links and antiglycating, chelating, and antiaggregant properties, which are most significant for pharmacological treatment of thrombosis and angio-, nephro-, encephalo-, and cardiopathies. 1,3-bis-(4-Methoxybenzoyl)pyrimidine-2,4(1H,3H)-dione was a promising antidiabetic agent with all studied activities.
- Brel’,Spasov,Lisina,Popov,Kucheryavenko,Litvinov,Salaznikova,Rashchenko
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- Design, synthesis, and biological evaluation of 3′,4′,5′-trimethoxy evodiamine derivatives as potential antitumor agents
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A series of compounds bearing 3′,4′,5′-trimethoxy module into the core structure of evodiamine were designed and synthesized. The synthesized compounds were screened in vitro for their antitumor potential. MTT results showed that compounds 14a–14c and 14i–14j had significant effects, with compound 14h being the most prominent, with an IC50 value of 3.3 ± 1.5?μM, which was lower than evodiamine and 5-Fu. Subsequent experiments further confirmed that compound 14h could inhibit cell proliferation and migration, and induce G2/M phase arrest to inhibit the proliferation of HGC-27 cells, which is consistent with the results of the cytotoxicity experiment. Besides, 14h could inhibit microtubule assembly and might kill tumor cells by inhibiting VEGF and glycolysis. All experimental results indicate that compound 14h might be a potential drug candidate for the treatment of gastric cancer and was worthy of further study.
- Peng, Yijiao,Xiong, Runde,Li, Zhen,Peng, Junmei,Xie, Zhi-Zhong,Lei, Xiao-Yong,He, Dongxiu,Tang, Guotao
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p. 1021 - 1032
(2021/02/26)
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- Hydroxybenzoyl Chlorides in the Synthesis of Conjugates with Biologically Active Dipeptides
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Abstract: Conjugates of hydroxy- and acetoxybenzoic acids with dipeptides based on 4-aminobutanoic acid and glycine were synthesized through hydroxy(acetoxy)benzoyl chlorides and 4-[hydroxy(acetoxy)benzoyl-amino]butanoyl chlorides as intermediate products. Acyl chlorides were prepared by treatment of the corre-sponding acids with oxalyl chloride in the presence of dimethylformamide at a ratio of 1:1.1:0.07 in boiling benzene. The target N-[hydroxy(acetoxy)benzoyl] derivatives of dipeptides were obtained with high yields, and no further purification of the products was necessary. The synthesized compounds were evaluated as potential neuroprotective agents.
- Brel, A. K.,Budaeva, Yu. N.,Lisina, S. V.
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p. 540 - 544
(2021/06/02)
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- Novel propargylamine-based inhibitors of cholinesterases and monoamine oxidases: Synthesis, biological evaluation and docking study
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A combination of several pharmacophores in one molecule has been successfully used for multi-target-directed ligands (MTDL) design. New propargylamine substituted derivatives combined with salicylic and cinnamic scaffolds were designed and synthesized as potential cholinesterases and monoamine oxidases (MAOs) inhibitors. They were evaluated in vitro for inhibition of acetyl- (AChE) and butyrylcholinesterase (BuChE) using Ellman's method. All the compounds act as dual inhibitors. Most of the derivatives are stronger inhibitors of AChE, the best activity showed 5-bromo-N-(prop-2-yn-1-yl)salicylamide 1e (IC50 = 8.05 μM). Carbamates (4-bromo-2-[(prop-2-yn-1-yl)carbamoyl]phenyl ethyl(methyl)carbamate 2d and 2,4-dibromo-6-[(prop-2-yn-1-yl)carbamoyl]phenyl ethyl(methyl)carbamate 2e were selective and the most active for BuChE (25.10 and 26.09 μM). 4-Bromo-2-[(prop-2-yn-1-ylimino)methyl]phenol 4a was the most potent inhibitor of MAOs (IC50 of 3.95 and ≈10 μM for MAO-B and MAO-A, respectively) along with a balanced inhibition of both cholinesterases being a real MTDL. The mechanism of action was proposed, and binding modes of the hits were studied by molecular docking on human enzymes. Some of the derivatives also exhibited antioxidant properties. In silico prediction of physicochemical parameters affirm that the molecules would be active after oral administration and able to reach brain tissue.
- Krátky, Martin,Vu, Quynh Anh,?těpánková, ?árka,Maruca, Annalisa,Silva, Tiago Barros,Ambro?, Martin,Pflégr, Václav,Rocca, Roberta,Svr?ková, Katarína,Alcaro, Stefano,Borges, Fernanda,Vin?ová, Jarmila
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- Discovery of Novel Polycyclic Heterocyclic Derivatives from Evodiamine for the Potential Treatment of Triple-Negative Breast Cancer
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Evodiamine (Evo) is a quinazolinocarboline alkaloid found in Evodia rutaecarpa and exhibits moderate antiproliferative activity. Herein, we report using a scaffold-hopping approach to identify a series of novel polycyclic heterocyclic derivatives based on Evo as the topoisomerase I (Top1) inhibitor for the treatment of triple-negative breast cancer (TNBC), which is an aggressive subtype of breast cancer with limited treatment options. The most potent compound 7f inhibited cell growth in a human breast carcinoma cell line (MDA-MB-231) with an IC50 value of 0.36 μM. Further studies revealed that Top1 was the target of 7f, which directly induced irreversible Top1-DNA covalent complex formation or induced an oxidative DNA lesion through an indirect mechanism mediated by reactive oxygen species. More importantly, in vivo studies showed that 7f exhibited potent antitumor activity in a TNBC-patient-derived tumor xenograft model. These results suggest that compound 7f deserves further investigation as a promising candidate for the treatment of TNBC.
- Chen, Zhe-Sheng,Li, Dahong,Qiu, Yangyi,Wu, Liang,Xu, Jinyi,Xu, Shengtao,Yang, Dong-Hua,Yao, Hong,Zhou, Manzhen
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p. 17346 - 17365
(2021/12/09)
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- Small Molecule Inhibitors of the BfrB-Bfd Interaction Decrease Pseudomonas aeruginosa Fitness and Potentiate Fluoroquinolone Activity
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The iron storage protein bacterioferritin (BfrB) is central to bacterial iron homeostasis. The mobilization of iron from BfrB, which requires binding by a cognate ferredoxin (Bfd), is essential to the regulation of cytosolic iron levels in P. aeruginosa. This paper describes the structure-guided development of small molecule inhibitors of the BfrB-Bfd protein-protein interaction. The process was initiated by screening a fragment library and followed by obtaining the structure of a fragment hit bound to BfrB. The structural insights were used to develop a series of 4-(benzylamino)- A nd 4-((3-phenylpropyl)amino)-isoindoline-1,3-dione analogs that selectively bind BfrB at the Bfd binding site. Challenging P. aeruginosa cells with the 4-substituted isoindoline analogs revealed a dose-dependent growth phenotype. Further investigation determined that the analogs elicit a pyoverdin hyperproduction phenotype that is consistent with blockade of the BfrB-Bfd interaction and ensuing irreversible accumulation of iron in BfrB, with concomitant depletion of iron in the cytosol. The irreversible accumulation of iron in BfrB prompted by the 4-substituted isoindoline analogs was confirmed by visualization of BfrB-iron in P. aeruginosa cell lysates separated on native PAGE gels and stained for iron with Ferene S. Challenging P. aeruginosa cultures with a combination of commercial fluoroquinolone and our isoindoline analogs results in significantly lower cell survival relative to treatment with either antibiotic or analog alone. Collectively, these findings furnish proof of concept for the usefulness of small molecule probes designed to dysregulate bacterial iron homeostasis by targeting a protein-protein interaction pivotal for iron storage in the bacterial cell.
- Hewage, Achala N. D. Punchi,Yao, Huili,Nammalwar, Baskar,Gnanasekaran, Krishna Kumar,Lovell, Scott,Bunce, Richard A.,Eshelman, Kate,Phaniraj, Sahishna M.,Lee, Molly M.,Peterson, Blake R.,Battaile, Kevin P.,Reitz, Allen B.,Rivera, Mario
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supporting information
p. 8171 - 8184
(2019/06/13)
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- Synthesis, Biological Evaluation and Molecular Docking of Deferasirox and Substituted 1,2,4-Triazole Derivatives as Novel Potent Urease Inhibitors: Proposing Repositioning Candidate
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A series of new deferasirox derivatives were synthesized through the reaction of monosubstituted hydrazides with 2-(2-hydroxyphenyl)-4H-benzo[e][1,3]oxazin-4-one. For the first time, deferasirox and some of its derivatives were evaluated for their in vitro inhibitory activity against Jack bean urease. The potencies of the members of this class of compounds are higher than that of acetohydroxamic acid. Two compounds, bearing tetrazole and hydrazine derivatives (bioisoester of carboxylate group), represented the most potent urease inhibitory activity with IC50 values of 1.268 and 3.254 μm, respectively. In silico docking studies were performed to delineate possible binding modes of the compounds with the enzyme, urease. Docking analysis suggests that the synthesized compounds were anchored well in the catalytic site and extending to the entrance of binding pocket and thus restrict the mobility of the flap by interacting with its crucial amino acid residues, CME592 and His593. The overall results of urease inhibition have shown that these target compounds can be further optimized and developed as a lead skeleton for the discovery of novel urease inhibitors.
- Amanlou, Massoud,Azizian, Homa,Balalaie, Saeed,Biglar, Mahmood,Fathi Vavsari, Vaezeh,Mahernia, Shabnam,Sadeghi Alavijeh, Nahid,Salehi Ashani, Razieh,Sheysi, Niloofar
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- Enantioselective Addition of Diethylzinc to Aromatic Aldehydes Using Chiral Oxazoline-Based Ligands
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Abstract: Chiral oxazoline ligands containing an aromatic ring were prepared fromnorephedrine and pyrrole-2-carbonitrile or 2-hydroxybenzoyl chloride. Thesynthesized ligands were used in the copper-catalyzed asymmetric addition ofdiethylzinc to aromatic aldehydes to provide optically active 1-arylpropan-1-olswith high conversion (92%) and enantioselectivity (up to 99% ee).
- Aydin, A. E.
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p. 1304 - 1312
(2020/10/02)
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- Ru-based complexes as heterogeneous potential catalysts for the amidation of aldehydes and nitriles in neat water
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Five novel heterogeneous mononuclear complex-anchored Ru(III) have been efficiently sono-synthesized and characterized by utilizing several analytical techniques. The assembled complexes could be utilized as effective, robust and recyclable (up to eight consecutive runs) catalysts for one-pot transformation of a vast array of nitriles and aldehydes to primary amides in H2O under aerobic conditions. Moreover, some unreported di- and tetra-amide derivatives were obtained also under the optimal conditions. The results of ICP/OES analysis demonstrated that there is no detected leaching of the recycled catalyst, which suggests the real heterogeneity of the present protocol. The present Ru-complexes exhibited superiority compared to other reported catalysts for amide preparation in terms of low catalyst load, short reaction time, low operating temperature, no hazardous additives required, and high values of TON (990) and TOF (1980 h11).
- Arafa, Wael Abdelgayed Ahmed
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supporting information
p. 1056 - 1064
(2020/11/09)
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- L-Type Amino Acid Transporter 1 Enables the Efficient Brain Delivery of Small-Sized Prodrug across the Blood-Brain Barrier and into Human and Mouse Brain Parenchymal Cells
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Membrane transporters have long been utilized to improve the oral, hepatic, and renal (re)absorption. In the brain, however, the transporter-mediated drug delivery has not yet been fully achieved due to the complexity of the blood-brain barrier (BBB). Because L-type amino acid transporter 1 (LAT1) is a good candidate to improve the brain delivery, we developed here four novel LAT1-utilizing prodrugs of four nonsteroidal anti-inflammatory drugs. As a result, all the prodrugs were able to cross the BBB and localize into the brain cells. The brain uptake of salicylic acid (SA) was improved five times, not only across the mouse BBB but also into the cultured mouse and human brain cells. The naproxen prodrug was also transported efficiently into the mouse brain achieving less peripheral exposure, but the brain release of naproxen from the prodrug was not improved. Contrarily, the high plasma protein binding of the flurbiprofen prodrug and the premature bioconversion of the ibuprofen prodrug in the mouse blood hindered the efficient brain delivery. Thus, the structure of the parent drug affects the successful brain delivery of the LAT1-utilizing prodrugs, and the small-sized LAT1-utilizing prodrug of SA constituted a successful model to specifically deliver its parent drug across the mouse BBB and into the cultured mouse and human brain cells.
- Montaser, Ahmed B.,J?rvinen, Juulia,L?ffler, Susanne,Huttunen, Johanna,Auriola, Seppo,Lehtonen, Marko,Jalkanen, Aaro,Huttunen, Kristiina M.
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p. 4301 - 4315
(2020/12/21)
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- SMARCA INHIBITORS AND USES THEREOF
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The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same for the modulation of one or more SWI/SNF-related matrix associated actin dependent regulator of chromatin subfamily A (SMARCA) and/or polybromo-1 (PB-1) protein via ubiqitination and/or degradation by compounds. The compounds are useful in treatment of cancer.
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Paragraph 0055-0056; 00127-00128; 00139-00140
(2020/12/30)
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- Derivative containing salicylic acid harringtonine, production method and uses thereof
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The invention relates to a compound of a derivative containing salicylic acid harringtonine, wherein the derivative containing salicylic acid harringtonine has the following general formula (I) defined in the specification, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 can be the same or different, and can be hydrogen, carbonyl, hydroxyl or C1-C8 alkyl, alkoxy, acyl alkoxy or C2-C6 alkynyl, alkenyl or C3-C9 cycloalkyl or aralkyl, phenyl, cyano alkyl, nitro alkyl, carboxyl, haloalkyl, monohydroxy or polyhydroxy alkyl, alkylthioalkyl, alkylsulfonylalkyl, acyloxyalkyl, acylalkyl and sulfonic group,and at least one of R1, R2, R3, R4 and R5 is R. According to the present invention, the compound has excellent anticancer pharmacological effects on chronic granulocytic leukemia, acute myeloid leukemia and lupus erythematosus diseases, can meet the requirements of the medical field, and has high treatment effect, and the preparation method is easy, and is suitable for industrial production.
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Paragraph 0090-0092
(2019/01/10)
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- SAR optimization studies on modified salicylamides as a potential treatment for acute myeloid leukemia through inhibition of the CREB pathway
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Disruption of cyclic adenosine monophosphate response element binding protein (CREB) provides a potential new strategy to address acute leukemia, a disease associated with poor prognosis, and for which conventional treatment options often carry a significant risk of morbidity and mortality. We describe the structure-activity relationships (SAR) for a series of XX-650-23 derived from naphthol AS-E phosphate that disrupts binding and activation of CREB by the CREB-binding protein (CBP). Through the development of this series, we identified several salicylamides that are potent inhibitors of acute leukemia cell viability through inhibition of CREB-CBP interaction. Among them, a biphenyl salicylamide, compound 71, was identified as a potent inhibitor of CREB-CBP interaction with improved physicochemical properties relative to previously described derivatives of naphthol AS-E phosphate.
- Chae, Hee-Don,Cox, Nick,Capolicchio, Samanta,Lee, Jae Wook,Horikoshi,Kam, Sharon,Ng, Andrew A.,Edwards, Jeffrey,Butler, Tae-León,Chan, Justin,Lee, Yvonne,Potter, Garrett,Capece, Mark C.,Liu, Corey W.,Wakatsuki, Soichi,Smith, Mark,Sakamoto, Kathleen M.
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supporting information
p. 2307 - 2315
(2019/06/27)
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- Metal-free Synthesis of Spiro-2,2′-benzo[b]furan-3,3′-ones via PhI(OAc)2-Mediated Cascade Spirocyclization
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Treating the benzyl protected 3-hydroxy-1,3-bis(2-hydroxyphenyl)prop-2-en-1-ones solely with PhI(OAc)2 (PIDA) in DCE at room temperature readily furnished the seldom studied spiro-2,2′-benzo[b]furan-3,3′-ones in satisfactory to excellent yields. The hypervalent iodine reagent enables the metal-free cascade spirocyclization resulting in the dual oxidative C?O bond formation. (Figure presented.).
- Xing, Qingyu,Liang, Huiyuan,Bao, Mingmai,Li, Xuemin,Zhang, Jingran,Bi, Tianhao,Zhang, Yilin,Xu, Jun,Du, Yunfei,Zhao, Kang
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supporting information
p. 4669 - 4673
(2019/09/17)
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- Synthesis and antibacterial evaluation of 3,5-Diaryl-1,2,4-oxadiazole derivatives
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This manuscript reports the synthesis of twenty 3,5-diaryl-1,2,4-oxadiazole derivatives, nine of which are novel compounds. The amidoxime reaction with acyl chlorides obtained from substituted benzoic acids was used. All compounds were tested against five standard (American Type Culture Collection (ATCC)) bacteria: Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis, Proteus mirabilis and Staphylococcus aureus. Screening assays were carried out using agar-diffusion technique, in which 100 μM heterocyclic compounds solutions (20percent dimethylsulfoxide/water) were employed. The minimum inhibitory concentrations (MIC) of the active compounds were determined by serial dilutions at decreasing concentrations in microtiter plates. The nitrated derivatives gave the best test results, where MIC = 60 μM (E. coli) was the lowest value found for an ortho-nitrated derivative. The activity of these compounds possibly involves a mechanism via free radicals. S. aureus and P. aeruginosa were resistant to all compounds.
- Cunha, Felipe S.,Nogueira, Joseli M. R.,De Aguiar, Alcino P.
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p. 2405 - 2416
(2018/10/20)
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- Preparation method of oxophenamide glucuronidation product and application thereof
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The invention discloses a preparation method of an oxophenamide glucuronidation product and application thereof in anti-hepatitis B. The preparation method comprises the following steps: (1) couplinga compound C6 and a compound C2 to obtain a compound C7; (2) finally deacetylating the compound C7 to obtain a compound C8 (finished); and (3) enabling the oxophenamide glucuronidation product (C8) tobe used for preparing anti-hepatitis B drugs. According to the method disclosed by the invention, the operations are simplified, the yield is increased, the cost is greatly reduced, and the preparation method is suitable for industrialized enlargement and has actual application value. The structural formula is as shown in the specification.
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Paragraph 0053-0056
(2018/11/22)
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- PHOTOCHEMICALLY STABLE, NON-LEACHING, BRIDGED POLYSILSESQUIOXANE BASED SUNSCREENS
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Bridged polysilsesquioxane based sunscreens prepared as nanoparticles via oil/water microemulsion polymerization, sol-gel polymerizations, or a modified Stober process. Minimized leaching and decreased levels of photo-degradation were achieved with covalent incorporation, with bridged incorporation necessary to ensure isolation of the sunscreen and any photo-products from skin. SPF values of were found to be comparable to existing commercial sunscreens. Furthermore the bridged polysilsesquioxane based sunscreens can be classified as broad-spectrum, and rate from moderate to superior in terms of UVA protective ability.
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Paragraph 0097-0098
(2017/08/21)
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- Oxa or thia- tetradium alkali anti-tumor derivative and its preparation method
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The invention relates to the technical field of medicines and in particular relates to oxa- or thio-evodiamine anti-tumor derivatives as well as a preparation method of the derivatives and application of the derivatives in preparation of topoisomerase inhibitors and anti-tumor drugs. The oxa- or thio-evodiamine anti-tumor derivatives are newly discovered topoisomerase I inhibitors with brand-new structures and have remarkable anti-tumor activity, and the structure of a compound is as shown in a general formula I.
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Paragraph 0078; 0079
(2017/04/21)
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- C-H Functionalization via Remote Hydride Elimination: Palladium Catalyzed Dehydrogenation of ortho-Acyl Phenols to Flavonoids
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Although deprotonation of electron-poor C-H bonds to carbon anions with bases has long been known and widely used in organic synthesis, the hydride elimination from electron-rich C-H bonds to carbon cations or partial carbocations for the introduction of nucleophiles is a comparatively less explored area. Here we report that the carbonyl β-C(sp3)-H bond hydrogens of ortho-acyl phenols could be substituted by intramolecular phenolic hydroxyls to form O-heterocycles, followed by dehydrogenation of the O-heterocycle into flavonoids. The cascade reaction is catalyzed by Pd/C without added oxidants and sacrificing hydrogen acceptors.
- Zhao, Xiaomei,Zhou, Jiabin,Lin, Shuying,Jin, Xukang,Liu, Renhua
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supporting information
p. 976 - 979
(2017/03/14)
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- ADDITIVE FOR IMPARTING ULTRAVIOLET ABSORBENCY AND/OR HIGH REFRACTIVE INDEX TO MATRIX, AND RESIN MEMBER USING SAME
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Provided is an additive for imparting ultraviolet absorbency, or an additive for imparting a high refractive index, which has satisfactory compatibility with a resin serving as a matrix and can maintain high transparency even if added in high concentrations. Also provided is an additive with which the function of imparting both ultraviolet absorbency and a high refractive index can be realized by means of one kind of additive. This additive is represented by the following Formula (I): wherein at least one of R1a to R9a is a monovalent sulfur-containing group represented by the following Formula (i-1) or Formula (i-2): wherein R10a to R12a each represent a divalent hydrocarbon group or the like; and R13a represents a monovalent hydrocarbon group or the like.
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Paragraph 0495
(2017/08/26)
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- INHIBITORS OF CREB-CBP INTERACTION FOR TREATMENT OF LEUKEMIA
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Compounds and methods are provided for inhibiting a CREB-CBP protein-protein interaction in a sample. In some cases, the method includes modulating transcription of CREB in a cell that overexpresses CREB. Also provided are methods of inhibiting the proliferation of a cancer cell. The subject CREB transcription inhibitor compounds include a substituted salicylamide or a prodrug thereof. Methods of alleviating symptoms associated with cancer (e.g., Acute Myeloid Leukemia (AML) or Acute Lymphomblastic Leukemia (ALL)) in a subject in need thereof are also provided. Pharmaceutical compositions including the subject compounds find use in treating cancer. The subject compounds may be formulated or provided to a subject in combination with a second agent, e.g. an anticancer agent.
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Page/Page column 40; 41
(2017/10/06)
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- Isoquinolone derivative as well as preparation method and application thereof
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The invention relates to an isoquinolone derivative as well as a preparation method and application thereof. According to a synthesis method, the isoquinolone derivative is prepared from various substituted acetamides as the raw material and a nonmetal as a catalyst under the action of an initiator. Compared with an existing synthesis method, the synthesis method provided by the invention is more economical and environment-friendly, and use of a metal catalyst is avoided. In addition, the synthesis method also has the advantages of being simple in operation, wide in atom economy and wide in substrate adaptability. Furthermore, the compound has a good application prospect in the aspects, such as tumors, cardiovascular diseases, inflammatory diseases, metabolic diseases and neurodegenerative diseases.
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Sheet 0035-0038
(2017/11/04)
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- Diastereoselective synthesis of trans-3,5-disubstituted dihydrofuran-2(3H)-ones via SmI2-mediated reductive coupling of 2-alkylacrylates of N,N-diisopropyl-2-hydroxybenzamide with aldehydes
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Samarium(II) diiodide has been used to mediate reductive coupling reactions of aldehydes with a variety of substituted acrylates, in both achiral and chiral forms, for accessing substituted dihydrofuran-2(3H)-ones (γ-butyrolactones). Two major issues, concerning with self-dimerization of α-non-branched aliphatic aldehydes and low diastereoselectivity of the products, render limited application of the reductive coupling protocol in total synthesis of natural products. We report here on a novel type of substituted acrylates derived from the 2-amido arenols (HO-Aram) such as N,N-diisopropyl-2-hydroxybenzamide. The acrylates of HO-Aram enable: (a) preferential conjugate reduction of the acrylates than carbonyl reduction of aliphatic aldehydes, leading to diminished aldehyde self-dimerization; and (b) organization of an eight-membered ring among the amide carbonyl oxygen atom and samarium(III) to form a 7/8-bicyclic transition state, resulting in highly diastereoselective protonation of the samarium(III) enolate intermediate. Examples of synthesis of trans-3,5-disubstituted dihydrofuran-2(3H)-ones from 2-alkylacrylates of HO-Aram and aliphatic aldehydes are provided.
- Lai, Yecai,Sun, Lijie,Sit, Man Ki,Wang, Yan,Dai, Wei-Min
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p. 664 - 673
(2016/01/15)
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- PROCESS FOR THE PREPARATION OF DEFERASIROX
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Present disclosure discloses the commercially viable process for the preparation of Deferasirox and its polymorph with. Disclosed process involves the preparation of Deferasirox via metal salt of the corresponding intermediate and deferasirox metal salt.
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Paragraph 0075
(2016/02/18)
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- COMPOSITIONS AND METHODS FOR THE TREATMENT OF INFLAMMATORY BOWEL DISEASE
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The invention relates to the compounds of formula I and formula II or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I or formula II; and methods for treating or preventing inflammatory bowel disease may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of gastrointestinal diseases and inflammation such as inflammatory bowel disease, ulcerative colitis, mild-to-moderate Crohn's disease, rheumatoid arthritis, inflammatory arthritis, psoriatic arthritis, liver cirrhosis and idiopathic urticaria.
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Paragraph 0139; 0140
(2016/06/01)
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- Thioester-appended organosilatranes: Synthetic investigations and application in the modification of magnetic silica surfaces
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The present investigation discloses a series of new organosilicon derivatives (3a-k) tailored with substituted benzoic acid modules (1a-k) via thioesterification with 3-mercaptopropylsilatrane (MPS). Product formation was authenticated using elemental analyses and different spectroscopic methods comprising FT-IR, NMR [1H, 13C] and LC-MS (Q-TOF). Thereafter, complete structural elucidation of compounds 3c and 3f was achieved by the single crystal X-ray technique. Photo-electronic inspection of all compounds by UV-Vis spectroscopy revealed their sensitivity towards substitution patterns. In addition, this is the first time that the potential of a silatranyl moiety has been tested for the modification of a silica surface pre-decorated with a magnetite core. The synthesis was achieved through a facile methodology involving chemical bonding at each stage, which proceeded without any external surfactant or template. The course of the reaction was followed by FT-IR, UV-Vis, XRD, TEM, FESEM, EDX and TGA techniques. Furthermore, the hybrid nanomaterial possessed significant sensorial ability toward copper ions, which makes the present protocol favourable for the construction of a new class of chelating ligands with an in-built multifunctional nanodevice.
- Singh, Gurjaspreet,Rani, Sunita,Arora, Aanchal,Aulakh, Darpandeep,Wriedt, Mario
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p. 6200 - 6213
(2016/07/19)
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- Synthesis of Tr?ger's base derived ligands: PHZ-derivatized ligand with pendant donor arms
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A cyclic diamine ligand whose core structure was derived from Tr?ger's base, and included additional pendant arms containing ancillary donor coordination sites was prepared and coordination with transition metals attempted.
- Hampton, Carissa S.,Harmata, Michael
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p. 6064 - 6077
(2016/09/16)
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- Compositions and methods for the treatment of inflammatory bowel disease
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The invention relates to the compounds of formula I and formula II or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I or formula II; and methods for treating or preventing inflammatory bowel disease may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of gastrointestinal diseases and inflammation such as inflammatory bowel disease, ulcerative colitis, mild-to-moderate Crohn's disease, rheumatoid arthritis, inflammatory arthritis, psoriatic arthritis, liver cirrhosis and idiopathic urticaria.
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Page/Page column 45; 46; 47
(2016/12/16)
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- Scaffold Diversity Inspired by the Natural Product Evodiamine: Discovery of Highly Potent and Multitargeting Antitumor Agents
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A critical question in natural product-based drug discovery is how to translate the product into drug-like molecules with optimal pharmacological properties. The generation of natural product-inspired scaffold diversity is an effective but challenging strategy to investigate the broader chemical space and identify promising drug leads. Extending our efforts to the natural product evodiamine, a diverse library containing 11 evodiamine-inspired novel scaffolds and their derivatives were designed and synthesized. Most of them showed good to excellent antitumor activity against various human cancer cell lines. In particular, 3-chloro-10-hydroxyl thio-evodiamine (66c) showed excellent in vitro and in vivo antitumor efficacy with good tolerability and low toxicity. Antitumor mechanism and target profiling studies indicate that compound 66c is the first-in-class triple topoisomerase I/topoisomerase II/tubulin inhibitor. Overall, this study provided an effective strategy for natural product-based drug discovery. (Figure Presented).
- Wang, Shengzheng,Fang, Kun,Dong, Guoqiang,Chen, Shuqiang,Liu, Na,Miao, Zhenyuan,Yao, Jianzhong,Li, Jian,Zhang, Wannian,Sheng, Chunquan
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p. 6678 - 6696
(2015/09/07)
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- Structure-activity relationship study of E6 as a novel necroptosis inducer
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Necroptosis inducers represent a promising potential treatment for drug-resistant cancer. We herein describe the structure modification of E6, which was identified recently as a potent and selective necroptosis inducer. The studies described herein demonstrate for the first time that functionalized biphenyl derivatives possess necroptosis inducer activity. Furthermore, these studies have led to the identification of two promising compounds (5h and 5j) that can be used for further optimization studies as well as mechanism of action investigations.
- Mou, Jianfeng,Park, Ann,Cai, Yu,Yuan, Junying,Yuan, Chengye
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supporting information
p. 3057 - 3061
(2015/06/22)
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- Identification of dual PPARα/γ agonists and their effects on lipid metabolism
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The three peroxisome proliferator-activated receptor (PPAR) isoforms; PPARα, PPARγ and PPARδ, play central roles in lipid metabolism and glucose homeostasis. Dual PPARα/γ agonists, which stimulate both PPARα and PPARγ isoforms to similar extents, are gaining popularity as it is believed that they are able to ameliorate the unwanted side effects of selective PPARα and PPARγ agonists; and may also be used to treat dyslipidemia and type 2 diabetes mellitus simultaneously. In this study, virtual screening of natural product libraries, using both structure-based and ligand-based drug discovery approaches, identified ten potential dual PPARα/γ agonist lead compounds (9-13 and 16-20). In vitro assays confirmed these compounds to show no statistically significant toxicity to cells, with the exception of compound 12 which inhibited cell growth to 74.5% ± 3.5 and 54.1% ± 3.7 at 50 μM and 100 μM, respectively. In support of their potential as dual PPARα/γ agonists, all ten compounds upregulated the expression of cholesterol transporters ABCA1 and ABCG1 in THP-1 macrophages, with indoline derivative 16 producing the greatest elevation (2.3-fold; 3.3-fold, respectively). Furthermore, comparable to the activity of established PPARα and PPARγ agonists, compound 16 stimulated triacylglycerol accumulation during 3T3-L1 adipocyte differentiation as well as fatty acid β-oxidation in HuH7 hepatocytes.
- Gao, Quanqing,Hanh, Jacky,Váradi, Linda,Cairns, Rose,Sj?str?m, Helena,Liao, Vivian W.Y.,Wood, Peta,Balaban, Seher,Ong, Jennifer Ai,Lin, Hsuan-Yu Jennifer,Lai, Felcia,Hoy, Andrew J.,Grewal, Thomas,Groundwater, Paul W.,Hibbs, David E.
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p. 7676 - 7684
(2015/12/23)
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- Antiphlogistic enteropathy and method for treating dermatopathy compsn.
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The invention relates to the compounds of formula I and formula II or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I or formula II; and methods for treating or preventing inflammatory bowel disease may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of gastrointestinal diseases and inflammation such as inflammatory bowel disease, ulcerative colitis, mild-to-moderate Crohn's disease, rheumatoid arthritis, inflammatory arthritis, psoriatic arthritis, liver cirrhosis and idiopathic urticaria.
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Paragraph 0114; 0115; 0116; 0403; 0404; 0405
(2018/10/19)
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- Intramolecular metal-free oxidative aryl-aryl coupling: An unusual hypervalent-iodine-mediated rearrangement of 2-substituted n-phenylbenzamides
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Hypervalent-iodine-mediated oxidative coupling of the two aryl groups in either 2-acylamino-N-phenyl-benzamides or 2-hydroxy-N-phenylbenzamides, with concomitant insertion of the ortho-substituted N or O atom into the tether, has been described for the first time. This unusual metal-free rearrangement reaction involves an oxidative C(sp2)?C(sp2) aryl-aryl bond formation, cleavage of a C(sp2)?C(O) bond, and a lactamization/lactonization. Furthermore, unsymmetrical diaryl compounds can be easily obtained by removing the tether within the cyclized product.
- Shang, Siyun,Zhang-Negrerie, Daisy,Du, Yunfei,Zhao, Kang
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supporting information
p. 6216 - 6219
(2014/06/23)
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- Modified salicylanilide and 3-phenyl-2 H -benzo[ e ][1,3]oxazine-2,4(3 H)-dione derivatives as novel inhibitors of osteoclast differentiation and bone resorption
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Inhibition of osteoclast formation is a potential strategy to prevent inflammatory bone resorption and to treat bone diseases. In the present work, the purpose was to discover modified salicylanilides and 3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-dione derivatives as potential antiosteoclastogenic agents. Their inhibitory effects on RANKL-induced osteoclastogenesis from RAW264.7 cells were evaluated by TRAP stain assay. The most potent compounds, 1d and 5d, suppressed RANKL-induced osteoclast formation and TRAP activity dose-dependently. The cytotoxicity assay on RAW264.7 cells suggested that the inhibition of osteoclastic bone resorption by these compounds did not result from their cytotoxicity. Moreover, both compounds downregulated RANKL-induced NF-κB and NFATc1 in the nucleus, suppressed the expression of osteoclastogenesis-related marker genes during osteoclastogenesis, and prevented osteoclastic bone resorption but did not impair osteoblast differentiation in MC3T3-E1. Therefore, these modified salicylanilides and 3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-diones could be potential lead compounds for the development of a new class of antiresorptive agents.
- Chen, Chun-Liang,Liu, Fei-Lan,Lee, Chia-Chung,Chen, Tsung-Chih,Ahmed Ali, Ahmed Atef,Sytwu, Huey-Kang,Chang, Deh-Ming,Huang, Hsu-Shan
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p. 8072 - 8085
(2014/12/10)
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- NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF CYSTIC FIBROSIS
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The present invention discloses compounds according to Formula (I), wherein R1, R2, R3, L, and the subscript m are as defined herein. The present invention relates to compounds and their use in the treatment of cystic fibrosis, methods for their production, pharmaceutical compositions, and methods of treatment using the same, for the treatment of cystic fibrosis by administering a compound of the invention.
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Paragraph 00291
(2014/12/09)
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- 2-Hydroxybenzoic acid esters: Synthesis, complexes with Tb(III), and their luminescence characteristics
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New esters of 2-hydroxybenzoic acid and 4-(4-alkoxybenzoyloxy)phenols, forming liquid crystals, were synthesized. These compounds in solution form complexes with Tb(III), exhibiting photoluminescence properties.
- Kondrat'Eva,Novikova,Meshkova,Topilova,Doga
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p. 786 - 792
(2015/03/03)
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- Asymmetric Henry reactions catalyzed by metal complexes of chiral oxazoline based ligands
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Chiral oxazolines have been synthesized from norephedrine and pyrrole nitrile or benzoyl chloride and applied to the catalytic asymmetric Henry reactions of p-nitro aldehydes with nitromethane to provide β-hydroxy nitroalkanols in high conversion (up to 92%). The reaction was then optimized in terms of the metal, solvent, temperature, and amount of chiral ligand. The corresponding catalyst with Cu(OTf)2 and isopropanol as the solvent gave the best enantioselectivities (up to 84% ee) of the corresponding β-nitroalkanol for p-nitrobenzaldehyde.
- Ebru Aydin,Yuksekdanaci, Seda
-
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- Diaryl-1,2,4-oxadiazole antioxidants: Synthesis and properties of inhibiting the oxidation of DNA and scavenging radicals
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Six 1,2,4-oxadiazole derivatives were prepared in order to compare their abilities to protect DNA against radical-mediated oxidation and to scavenge radicals. These derivatives had a structure based on disubstituted 1,2,4-oxadiazole, in which a vanillin group (A ring) and a substituted benzene group (B ring) were the substituents. The functional group at B ring was assigned as ortho- or meta-hydroxylbenzene group, ortho-chlorobenzene group, no group contained, and pyridine group or vanillin group at B ring. It was found that the compound with two vanillin groups attaching to oxadiazole can trap 2.05 radicals in protecting DNA against 2,2′-azobis(2-amidinopropane hydrochloride) (AAPH)-induced oxidation, and the compound with an ortho-hydroxylbenzene group at B ring can trap 1.78 radicals. The compound with an ortho-chlorobenzene group at B ring exhibited the highest ability to inhibit ·OH-induced oxidation of DNA, while the compound with a meta-hydroxylbenzene group at B ring inhibited Cu2+/glutathione (GSH)-induced oxidation of DNA efficiently. The ortho- and para-hydroxylbenzene groups at B ring made the compounds possess the highest rate constant (k) in scavenging 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS+.) and 2,2′-diphenyl-1-picrylhydrazyl radical (DPPH). Therefore, only a few hydroxyl groups can markedly enhance the activity of the core-branched antioxidant, which may be a novel structural feature in designing antioxidant.
- Zhao, Chao,Liu, Zai-Qun
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p. 842 - 849
(2013/04/24)
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- β-Hydroxyamide derivatives of salicylic acid as organocatalysts for enantioselective reductions of prochiral ketones
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In order to find the most effective catalyst for the enantioselective reduction of a prochiral ketone, a series of novel β-hydroxyamide derivatives of salicylic acid and chiral amino alcohols were synthesized. Different substituted prochiral ketones have been reduced in high yield (up to 99%) and the corresponding secondary alcohols are formed with good enantiomeric excess (up to 86%). The mechanism of this type of catalyst can be explained by considering the reaction mechanism for the CBS catalyst.
- Turgut, Yilmaz,Azizoglu, Murat,Erdogan, Asli,Arslan, Nevin,Hosgoren, Halil
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p. 853 - 859
(2013/08/23)
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- Novel TypeII Fatty Acid Biosynthesis (FAS II) Inhibitors as Multistage Antimalarial Agents
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Malaria is a potentially fatal disease caused by Plasmodium parasites and poses a major medical risk in large parts of the world. The development of new, affordable antimalarial drugs is of vital importance as there are increasing reports of resistance to the currently available therapeutics. In addition, most of the current drugs used for chemoprophylaxis merely act on parasites already replicating in the blood. At this point, a patient might already be suffering from the symptoms associated with the disease and could additionally be infectious to an Anopheles mosquito. These insects act as a vector, subsequently spreading the disease to other humans. In order to cure not only malaria but prevent transmission as well, a drug must target both the blood- and pre-erythrocytic liver stages of the parasite. P.falciparum (Pf) enoyl acyl carrier protein (ACP) reductase (ENR) is a key enzyme of plasmodial typeII fatty acid biosynthesis (FASII). It has been shown to be essential for liver-stage development of Plasmodium berghei and is therefore qualified as a target for true causal chemoprophylaxis. Using virtual screening based on two crystal structures of PfENR, we identified a structurally novel class of FAS inhibitors. Subsequent chemical optimization yielded two compounds that are effective against multiple stages of the malaria parasite. These two most promising derivatives were found to inhibit blood-stage parasite growth with IC50 values of 1.7 and 3.0μM and lead to a more prominent developmental attenuation of liver-stage parasites than the gold-standard drug, primaquine.
- Schrader, Florian C.,Glinca, Serghei,Sattler, Julia M.,Dahse, Hans-Martin,Afanador, Gustavo A.,Prigge, Sean T.,Lanzer, Michael,Mueller, Ann-Kristin,Klebe, Gerhard,Schlitzer, Martin
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p. 442 - 461
(2013/08/25)
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- PHARMACEUTICAL COMPOSITION OF SALICYLANILIDE-DERIVED SMALL MOLECULES AND PREPARATION AND APPLICATION THEREOF
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The present invention provides a pharmaceutical composition of salicylanilide-derived small molecules include: (a) a compound which structure is selected from formula I or formula II: (b) a pharmaceutically acceptable salt and excipient. The present invention also provides the synthesis method of the pharmaceutical composition and the application thereof.
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Paragraph 0050; 0066
(2013/11/05)
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- PROCESS FOR THE PRODUCTION OF DEFERASIROX
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A new process is described for the preparation of deferasirox, 4-[(3Z,5E)-3,5-bis(6- oxo-1 -cyclohexa-2,4-dienylidene)-1,2,4-triazolidin-1 -yl]benzoic acid, having the following structural formula (I).
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Page/Page column 7
(2012/10/18)
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- New tricks for an Old natural product: Discovery of highly potent evodiamine derivatives as novel antitumor agents by systemic structure-activity relationship analysis and biological evaluations
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Evodiamine is a quinazolinocarboline alkaloid isolated from the fruits of traditional Chinese herb Evodiae fructus. Previously, we identified N13-substituted evodiamine derivatives as potent topoisomerase I inhibitors by structure-based virtual screening and lead optimization. Herein, a library of novel evodiamine derivatives bearing various substitutions or modified scaffold were synthesized. Among them, a number of evodiamine derivatives showed substantial increase of the antitumor activity, with GI50 values lower than 3 nM. Moreover, these highly potent compounds can effectively induce the apoptosis of A549 cells. Interestingly, further computational target prediction calculations in combination with biological assays confirmed that the evodiamine derivatives acted by dual inhibition of topoisomerases I and II. Moreover, several hydroxyl derivatives, such as 10-hydroxyl evodiamine (10j) and 3-amino-10-hydroxyl evodiamine (18g), also showed good in vivo antitumor efficacy and low toxicity at the dose of 1 mg/kg or 2 mg/kg. They represent promising candidates for the development of novel antitumor agents.
- Dong, Guoqiang,Wang, Shengzheng,Miao, Zhenyuan,Yao, Jianzhong,Zhang, Yongqiang,Guo, Zizhao,Zhang, Wannian,Sheng, Chunquan
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p. 7593 - 7613
(2012/10/29)
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- Discovery and structure-activity relationships of modified salicylanilides as cell permeable inhibitors of poly(ADP-ribose) glycohydrolase (PARG)
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The metabolism of poly(ADP-ribose) (PAR) in response to DNA strand breaks, which involves the concerted activities of poly(ADP-ribose) polymerases (PARPs) and poly(ADP-ribose) glycohydrolase (PARG), modulates cell recovery or cell death depending upon the level of DNA damage. While PARP inhibitors show high promise in clinical trials because of their low toxicity and selectivity for BRCA related cancers, evaluation of the therapeutic potential of PARG is limited by the lack of well-validated cell permeable inhibitors. In this study, target-related affinity profiling (TRAP), an alternative to high-throughput screening, was used to identify a number of druglike compounds from several chemical classes that demonstrated PARG inhibition in the low-micromolar range. A number of analogues of one of the most active chemotypes were synthesized to explore the structure-activity relationship (SAR) for that series. This led to the discovery of a putative pharmacophore for PARG inhibition that contains a modified salicylanilide structure. Interestingly, these compounds also inhibit PARP-1, indicating strong homology in the active sites of PARG and PARP-1 and raising a new challenge for development of PARG specific inhibitors. The cellular activity of a lead inhibitor was demonstrated by the inhibition of both PARP and PARG activity in squamous cell carcinoma cells, although preferential inhibition of PARG relative to PARP was observed. The ability of inhibitors to modulate PAR metabolism via simultaneous effects on PARPs and PARG may represent a new approach for therapeutic development.
- Steffen, Jamin D.,Coyle, Donna L.,Damodaran, Komath,Beroza, Paul,Jacobson, Myron K.
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experimental part
p. 5403 - 5413
(2011/10/02)
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- PROCESSES FOR THE PREPARATION OF DEFERASIROX, AND DEFERASIROX POLYMORPHS
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The present invention relates to processes for the preparation of deferasirox, an oral iron chelator developed to treat iron overload due to e.g. multiple blood transfusions. The present invention further provides novel deferasirox pseudopolymorphs and a novel amorphous form of deferasirox, processes for their preparation, as well as pharmaceutical compositions comprising same, and use thereof in treating iron overload.
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Page/Page column 61
(2011/06/26)
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