- PDIA4 INHIBITORS AND USE THEREOF FOR INHIBITING ?-CELL PATHOGENESIS AND TREATING DIABETES
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Disulfide-Isomerase A4 (PDIA4) inhibitors and use thereof for inhibiting pancreatic β-cell pathogenesis and treating diabetes are disclosed. Drug candidates that inhibit PDIA4 with IC50 values ranging from 4 μM to 300 nM are identified. The compounds are highly active in augmenting insulin secretion from pancreatic β-cells. The representative compound No. 8 (4,5-dimethoxy-2-propiolamidobenzoic acid), alone or in combination with metformin, is effective in preserving pancreatic β-cell function, treating and/or reversing, returning blood glucose concentration to a normal level in a diabetic.
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Page/Page column 17
(2021/06/11)
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- Synthesis and evaluation of new sesamol-based phenolic acid derivatives with hypolipidemic, antioxidant, and hepatoprotective effects
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The objective of this study is to synthesize a series of sesamol-based phenolic acid derivatives, which were designed by combination principle. The hypolipidemic activity of all these compounds was preliminarily screened by acute hyperlipidemic mice model induced by Triton WR 1339, in which compound T6 exhibited more significant reducing plasma TG and TC than fenofibrate. Compound T6 was also found to obviously decrease TG and TC both in the plasma and hepatic tissue of high-fat-diet-induced hyperlipidemic mice. Moreover, T6 showed hepatoprotective effects, which remarkable amelioration in characteristic liver enzymes was examined and the histopathological observation displayed that compound T6 inhibited lipids accumulation in the hepatic. The levels of PPAR-α receptor related to lipids metabolism in hepatic tissue were upregulated after T6 treatment. Other potent effects of T6 such as antioxidant and anti-inflammatory activity were also observed. On the bases of these findings, compound T6 may serve as an effective hypolipidemic and hepatoprotective agent. [Figure not available: see fulltext.]
- Xie, Yundong,Liu, Jiping,Shi, Yongheng,Bin Wang,Wang, Xiaoping,Wang, Wei,Sun, Meng,Xu, Xinya,He, Shipeng
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p. 1688 - 1702
(2021/07/26)
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- Biological Characterization, Mechanistic Investigation and Structure-Activity Relationships of Chemically Stable TLR2 Antagonists
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Toll-like receptors (TLRs) build the first barrier in the innate immune response and therefore represent promising targets for the modulation of inflammatory processes. Recently, the pyrogallol-containing TLR2 antagonists CU-CPT22 and MMG-11 were reported; however, their 1,2,3-triphenol motif renders them highly susceptible to oxidation and excludes them from use in extended experiments under aerobic conditions. Therefore, we have developed a set of novel TLR2 antagonists (1–9) based on the systematic variation of substructures, linker elements, and the hydrogen-bonding pattern of the pyrogallol precursors by using chemically robust building blocks. The novel series of chemically stable and synthetically accessible TLR2 antagonists (1–9) was pharmacologically characterized, and the potential binding modes of the active compounds were evaluated structurally. Our results provide new insights into structure-activity relationships and allow rationalization of structural binding characteristics. Moreover, they support the hypothesis that this class of TLR ligands bind solely to TLR2 and do not directly interact with TLR1 or TLR6 of the functional heterodimer. The most active compound from this series (6), is chemically stable, nontoxic, TLR2-selective, and shows a similar activity with regard to the pyrogallol starting points, thus indicating the variability of the hydrogen bonding pattern.
- Bermudez, Marcel,Grabowski, Maria,Murgueitio, Manuela S.,Rademann, J?rg,Rudolf, Thomas,Tiemann, Markus,Varga, Péter,Weindl, Günther,Wolber, Gerhard
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- BIODEGRADABLE HYDROGEL AND METHODS FOR USE THEREOF
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The subject matter of this invention relates to hydrogel compositions and, more particularly, to hydrogel compositions comprising block copolymers (BCPs) capable of self-assembly into nanoparticles for the delivery and controlled release of therapeutic ca
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Paragraph 0037
(2020/06/08)
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- NOVEL FLUORINATED 4-ARYLOXYQUINAZOLINE DERIVATIVES AS EGFR INHIBITORS USEFUL FOR TREATING CANCERS
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A novel class of fluorinated derivatives of Formula I have been prepared and found to be useful in the treatment of cancers and other EGFR related disorders. The compounds of Formula I display excellent brain penetration and an improved side effect profil
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Paragraph 00112; 00114
(2019/05/02)
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- NANOPARTICLE
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The present invention relates to polycarbonate-based diblock polymers, nanoparticles comprising the diblock polymers and a therapeutic agent, in particular the therapeutic agent is attached to a magnetic moiety, and methods to prepare the diblock polymers
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Page/Page column 23; 32-33
(2019/04/16)
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- New uses of tetramethylpyrazine derivative in biological nerve protection
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The present invention provides applications of a tetramethylpyrazine derivative having a structure represented by a formula 1, or a salt thereof, or a composition containing a tetramethylpyrazine derivative having a structure represented by the formula 1 or a salt thereof in preparation of drugs for prevention or treatment of nervous system diseases, wherein R1 is any one selected from -H, -OCH3 and -OH, R2 is any one selected from -H, -OCH3 and -OH, R3 is any one selected from -H, -OCH3, -OH and -CH3, and R4 is any one selected from -H and -OCH3. The present invention further provides a tetramethylpyrazine derivative having a structure represented by a formula 2, or a salt thereof, or a composition containing a tetramethylpyrazine derivative having a structure represented by the formula 2 or a salt thereof in preparation of drugs for prevention or treatment of nervous system diseases, wherein R1 is any one selected from -H, -OH and -OCOCH3, R2 is any one selected from -H, -OCH3 and -OH, and R3 is any one selected from -H and -OH. The formulas 1 and 2 are defined in the specification.
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Paragraph 0104; 0105
(2016/10/10)
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- Caffeinated compounds and compositions for treatment of amyloid diseases and synucleinopathies
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Compounds and their pharmaceutically acceptable salts for treatment of β-amyloid diseases, such as observed in Alzheimer's disease and synucleinopathies, such as Parkinson's disease.
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Page/Page column 24; 25
(2015/11/09)
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- CAFFEINATED COMPOUNDS AND COMPOSITIONS FOR TREATMENT OF AMYLOID DISEASES AND SYNUCLEINOPATHIES
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Compounds and their pharmaceutically acceptable salts for treatment of Beta-amyloid diseases, such as observed in Alzheimer's disease and synucleinopathies, such as Parkinson's disease
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Page/Page column 35
(2013/05/21)
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- COMPOSITIONS AND METHODS FOR GLUCOSE TRANSPORT INHIBITION
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Glucose deprivation is an attractive strategy in cancer research and treatment. Cancer cells upregulate glucose uptake and metabolism for maintaining accelerated growth and proliferation rates. Specifically blocking these processes is likely to provide new insights to the role of glucose transport and metabolism in tumorigenesis, as well as in apoptosis. As solid tumors outgrow the surrounding vasculature, they encounter microenvironments with a limited supply of nutrients leading to a glucose deprived environment in some regions of the tumor. Cancer cells living in the glucose deprived environment undergo changes to prevent glucose deprivation-induced apoptosis. Knowing how cancer cells evade apoptosis induction is also likely to yield valuable information and knowledge of how to overcome the resistance to apoptosis induction in cancer cells. Disclosed herein are novel anticancer compounds that inhibit basal glucose transport, resulting in tumor suppression and new methods for the study of glucose deprivation in animal cancer research.
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Page/Page column 27-28
(2011/10/13)
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- HIF-1α inhibitors: Synthesis and biological evaluation of novel moracin O and P analogues
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The natural products moracins O and P exhibited potent in vitro inhibitory activity against hypoxia-inducible factor (HIF-1), which is a key mediator during adaptation of cancer cells to tumour hypoxia. Systematic variations of the structures of benzofuran type moracins were made and structure-activity relationship analysis showed the importance of the 2-arylbenzofuran ring and the (R)-configuration of the core scaffold. Further evaluation of the representative compound 5 showed its inhibitory effect on HIF-1α protein accumulation and target gene expression under hypoxia.
- Xia, Yan,Jin, Yinglan,Kaur, Navneet,Choi, Yongseok,Lee, Kyeong
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supporting information; experimental part
p. 2386 - 2396
(2011/06/21)
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- Synthesis and characterization of ruthenium(II)-pyridylamine complexes with catechol pendants as metal binding sites
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A novel tris(2-pyridylmethyl)amine (TPA) derivate having two catechol moieties linked by amide linkages at the 6-positions of two pyridyl groups was synthesized. The ligand, N,N-bis[6-{3,4-(dihydroxy)benzamide}-2-pyridyl-methyl]- N-(2-pyridylmethyl)amine (Cat2-TPA; L2), and its precursor, N,N-bis[6-{3,4-bis(benzyloxy)-benzamide}-2-pyridyl-methyl]-N-(2-pyridylmethyl) -amine ((Bn2Cat)2-TPA; L1), formed stable ruthenium(II) complexes, [RuCl(L2)]PF6 (2) and [RuCl(L1)]PF6 (1), respectively. The crystal structure of [RuCl(L2)]Cl (2′) was determined by X-ray crystallography to show two isomers in terms of the orientation of one catechol moiety. In complex 2, the ligand bearing catechols acts as a pentadentate ligand involving coordination of one of the amide oxygen atoms in addition to that of the tetradentate TPA moiety and two metal-free catechol moieties as metal-binding sites. The coordination of L2 results in the preorganization of the two catechols to converge them to undergo intramolecular π-π interactions. The 1H NMR spectrum of 2 in DMSO-d 6 revealed that only one isomer was present in the solution. This selective formation could be ascribed to the formation of an intramolecular hydrogen-bonding network among the hydroxyl groups of the catechol moieties, as suggested by X-ray analysis. This intramolecular hydrogen bonding could differentiate the pKa values of the hydroxy groups of the catechol moieties into three kinds, as indicated by spectroscopic titration with tetramethylammonium hydroxide (TMAOH) in DMF. The complexation of 2 with other metal ions was also examined. The reaction of 2 with [Cu(NO3) 2(TMEDA)] (TMEDA = N,N,N′,N′-tetramethylethylenediamine) in methanol allowed us to observe the selective formation of a binuclear complex, [RuCl(L22-){Cu(TMEDA)}]PF6 (3), which was characterized by ESI-MS, UV-vis, and ESR spectroscopies. Its ESR spectrum in methanol suggested that the coordination of the Cu(II)-TMEDA unit to the converged catechol moieties would be different from conventional κ2-O,O′:η2-coordination: it exhibits a novel bridging coordination mode, bis-κ1-O:η1- coordination, to form the binuclear Ru(II)-Cu(II) complex.
- Kojima, Takahiko,Hirasa, Norihisa,Noguchi, Daisuke,Ishizuka, Tomoya,Miyazaki, Soushi,Shiota, Yoshihito,Yoshizawa, Kazunari,Fukuzumi, Shunichi
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experimental part
p. 3737 - 3745
(2010/06/18)
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- Synthesis, radical scavenging activity, protection during storage, and frying by novel antioxidants
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Novel antioxidants, derivatives of trolox, and selected phenolic acids have been prepared in good yields and fully characterized by 1H NMR, 13C NMR, and MS. Their antioxidant activities have been assessed by DPPH and ORAC assays, and during frying and accelerated storage tests. Novel phenolic compounds exhibited higher radical scavenging activities than both trolox and R-tocopherol. Trolox hydroxybenzoate showed a significantly higher protection than R-tocopherol under storage conditions. All new antioxidants performed better than R-tocopherol under frying conditions. Moreover, their outstanding thermal stability makes them more valuable than R-tocopherol for frying applications.
- Catel, Yohann,Aladedunye, Felix,Przybylski, Roman
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scheme or table
p. 11081 - 11089
(2011/06/21)
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- Direct identification of a siderophore import protein using synthetic petrobactin ligands
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Nice catch! The immobilization of a synthetic petrobactin derivative on agarose was crucial for the isolation and identification of a bacterial siderophore import protein for the first time from crude cell extracts. The biochemical and genetic characteriz
- Bugdahn, Nikolas,Peuckert, Florian,Albrecht, Alexander G.,Miethke, Marcus,Marahiel, Mohamed A.,Oberthuer, Markus
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supporting information; experimental part
p. 10210 - 10213
(2011/03/16)
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- Novel inhibitors of basal glucose transport as potential anticancer agents
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Cancer cells commonly show increased levels of glucose uptake and dependence. A potential strategy for the treatment of cancer may be the inhibition of basal glucose transport. We report here the synthesis of a small library of polyphenolic esters that inhibit basal glucose transport in H1299 lung and other cancer cells. These basal glucose transport inhibitors also inhibit cancer cell growth in H1299 cells, and these two activities appear to be correlated.
- Zhang, Weihe,Liu, Yi,Chen, Xiaozhuo,Bergmeier, Stephen C.
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scheme or table
p. 2191 - 2194
(2010/06/15)
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- First chemical synthesis of three natural depsides involved in flavonol catabolism and related to quercetinase catalysis
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We report here the first chemical synthesis of three depsides related to quercetinase-catalyzed degradation of kaempferol, quercetin, and myricetin. The three depsides were constructed through the coupling of suitably protected phloroglucinol carboxylic acid and hydroxy-perbenzylated, derivatives of gallic, protocatechuic, and 4-hydroxy benzoic acids. The three synthesized target compounds proved to be identical to their natural counterparts, arising from quercetinase action on corresponding flavonols. Copyright Taylor & Francis Group, LLC.
- Tranchimand, Sylvain,Tron, Thierry,Gaudin, Christian,Iacazio, Gilles
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p. 587 - 597
(2007/10/03)
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