- Structure-Activity Study of Nitazoxanide Derivatives as Novel STAT3 Pathway Inhibitors
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We identified nitazoxanide (NTZ) as a moderate STAT3 pathway inhibitor through immunoblot analysis and a cell-based IL-6/JAK/STAT3 pathway activation assay. A series of thiazolide derivatives were designed and synthesized to further validate the thiazolide scaffold as STAT3 inhibitors. Eight out of 25 derivatives displayed potencies greater than that of NTZ, and their STAT3 pathway inhibitory activities were found to be significantly correlated with their antiproliferative activities in HeLa cells. Derivatives 15 and 24 were observed to be more potent than the positive control WP1066, which is under phase I clinical trials. Compared with NTZ, 15 also exhibited much improved in vivo pharmacokinetic parameters in rats and efficacies against proliferations in multiple cancer cell lines, indicating a broad-spectrum effect of these thiazolides as antitumor agents targeted on STAT3.
- Lü, Zirui,Li, Xiaona,Li, Kebin,Wang, Cong,Du, Tingting,Huang, Wei,Ji, Ming,Li, Changhong,Xu, Fengrong,Xu, Ping,Niu, Yan
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supporting information
p. 696 - 703
(2021/05/04)
-
- Cleavage of Carboxylic Esters by Aluminum and Iodine
-
A one-pot procedure for deprotecting carboxylic esters under nonhydrolytic conditions is described. Typical alkyl carboxylates are readily deblocked to the carboxylic acids by the action of aluminum powder and iodine in anhydrous acetonitrile. Cleavage of lactones affords the corresponding ω-iodoalkylcarboxylic acids. Aryl acetylates undergo deacetylation with the participation of the neighboring group. This method enables the selective cleavage of alkyl carboxylic esters in the presence of aryl esters.
- Sang, Dayong,Yue, Huaxin,Fu, Yang,Tian, Juan
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p. 4254 - 4261
(2021/03/09)
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- Discovery of 4-methyl-N-(4-((4-methylpiperazin- 1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-oxy)benzamide as a potent inhibitor of RET and its gatekeeper mutant
-
The receptor tyrosine kinase rearranged during transfection (RET) plays pivotal roles in several cancers, including thyroid carcinoma and non-small cell lung cancer (NSCLC). Currently, there are several FDA-approved RET inhibitors, but their indication is limited to thyroid cancer, and none can overcome their gatekeeper mutants (V804L and V804M). Here, we report the discovery of 9x representing a new chemotype of potent and selective RET inhibitors, using a rational design strategy of type II kinase inhibitors. 9x exhibited both superior antiproliferative activities against NSCLC-related carcinogenic fusions KIF5B-RET and CCDC6-RET and gatekeeper mutant-transformed Ba/F3 cells, with the lowest GI50 of 9 nM, and substantial inhibitory activities against wild-type RET and RET mutant proteins, with the best IC50 of 4 nM. More importantly, 9x also showed nanomole potency against RET-positive NSCLC cells LC-2/ad, but not against a panel of RET-negative cancer cells, such as A549, H3122, A375 or parental Ba/F3 cells, demonstrating its selective ‘on-target’ effect. In mouse xenograft models, 9x repressed tumor growth driven by both wild type KIF5B-RET-Ba/F3 and gatekeeper mutant KIF5B-RET(V804M)-Ba/F3 cells in a dose-dependent manner. Together, these data establish that 9x provides a good starting point for the development of targeted therapeutics against RET-positive cancers, especially NSCLC.
- Chen, Guyue,Deng, Xianming,Deng, Zhou,Dong, Chao,Hu, Zhiyu,Li, Li,Li, Xiaoyang,Lian, Wenhua,Liu, Xueyan,Su, Jingyi,Wang, Zheng,Xu, Qingyan,Yang, Yanru,Yang, Zaiyou,Zhang, Baoding
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- Histone deacetylases inhibitor and use thereof
-
The present invention relates to a novel histone deacetylase (HDAC) inhibitor and a medical use thereof. More specifically, it is confirmed that a novel aspirin derivative inhibits the activity of HDAC by bonding to a substrate bonding pocket of HDAC and significantly increases the acetylation of intracellular andalpha;-tubulin and histone H3, thereby exhibiting an effect of inhibiting cancer cell proliferation. The novel aspirin derivative is provided as HDAC inhibitors, thereby being able to be provided as a therapeutic agent effective for HDAC-related cancer diseases and central nervous system diseases.COPYRIGHT KIPO 2020
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Paragraph 0066-0069; 0136; 0137
(2019/12/25)
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- Aspirin-inspired acetyl-donating HDACs inhibitors
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Aspirin is one of the oldest drugs for the treatment of inflammation, fever, and pain. It is reported to covalently modify COX-2 enzyme by acetylating a serine amino acid residue. By virtue of aspirin’s acetylating potential, we for the first time developed novel acetyl-donating HDAC inhibitors. In this study, we report the design, synthesis, in silico docking study, and biological evaluation of acetyl-donating HDAC inhibitors. The exposure of MDA-MB-231 cells with compound 4c significantly promotes the acetylation of α-tubulin and histone H3, which are substrates of HDAC6 and HDAC1, respectively. In silico docking simulation also indicates that compound 4c tightly binds to the deep substrate-binding pocket of HDAC6 by coordinating the active zinc ion in a bidentate manner and forming hydrogen bond interactions with Ser531 and His573 amino acid residues. In particular, compound 4c (GI50 = 147?μM) affords the significant enhancement of anti-proliferative effect on MDA-MB-231 cells, compared with its parent compound 2c (GI50 > 1000?μM) and acetyl-donating group deficient compound 6 (GI50 = 554?μM). Overall, compound 4c presents a novel strategy for developing acetyl-donating HDAC inhibitors.
- Lim, Jiah,Song, Yoojin,Jang, Jung-Hee,Jeong, Chul-Ho,Lee, Sooyeun,Park, Byoungduck,Seo, Young Ho
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p. 967 - 976
(2018/06/25)
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- COMPOUNDS FOR TREATING TUBERCULOSIS
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The present invention relates to pyrimidine compounds and compositions for treating tuberculosis. These compounds may be used to target the F1 domain of F-ATP synthase and may be used with bedaquiline or 6-chloro-2-ethyl-N-[[4-[4- [4-(trifluoromethoxy)phenyl]piperidin-1 -yl]phenyl]methyl]imidazo[1,2-a]pyridine-3-carboxamide (Q203) or a combination thereof.
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-
Paragraph 00125
(2018/09/18)
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- Asymmetric Total Synthesis of Brasilicardins
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Brasilicardins, bacterial diterpenoid natural products that display highly potent immunosuppressive activity, are promising immunosuppressant drug candidates. Structurally, they can be described as hybrids of terpenoids, amino acids, and saccharides, and share a characteristic highly strained anti-syn-anti-fused perhydrophenanthrene terpenoid scaffold (ABC-ring system) with two quaternary asymmetric carbon atoms. A unified and stereoselective total synthesis of all four brasilicardins has been designed based on the strategic use of an intramolecular conjugate addition. The ABC-ring system was initially constructed with high stereocontrol by novel intramolecular conjugate additions of Weinreb amides and in situ generated (Z)-vinyl copper species. The late-stage common intermediate was subjected to stereoselective installation of the amino acid component, followed by introduction of the saccharide unit via glycosylation to accomplish the total synthesis of brasilicardins A–D. Our synthesis offers opportunities to synthesize various brasilicardin analogues for biological and pharmacological investigations.
- Yoshimura, Fumihiko,Itoh, Ryusei,Torizuka, Makoto,Mori, Genki,Tanino, Keiji
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supporting information
p. 17161 - 17167
(2018/12/11)
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- (Phosphinito)aryl benzimidazole PCN pincer palladium(II) complexes: Synthesis, characterization and catalytic activity in C–H arylation of azoles with aryl iodides
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The PCN pincer Pd(II) complexes 4a–c with (phosphinito)aryl benzimidazole ligands were conveniently synthesized by one-pot phosphorylation/palladation reaction of a (2-benzimidazolyl)-containing m-phenol derivative 3. The three complexes were well characterized by spectroscopic methods, elemental analysis and their molecular structures were further determined by X-ray single-crystal diffraction. The Pd(II) center in each complex adopts a typical distorted-square-planar geometry. With a catalyst loading of 0.25–0.5 mol%, complex 4a could effectively catalyze C–H arylation of benzothiazole, benzoxazole and thiazole with various aryl iodides in the presence of CuI as a cocatalyst.
- Wang, Cong,Li, Yang,Lu, Beibei,Hao, Xin-Qi,Gong, Jun-Fang,Song, Mao-Ping
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p. 184 - 192
(2017/11/03)
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- Technological method for preparing m-aminophenol
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The invention relates to a technological method for preparing m-aminophenol, belongs to the technical field of chemical material preparation and solves the technical problem of limit caused by utilizing phenyl acetate as a preparation raw material. The technological method disclosed by the invention has the advantages of simpleness in operation, high product yield, reaction easy to control and thelike. The technological method is characterized by comprising the steps: preparing 3-carboxyphenyl phenyl acetate after preparing m-cresyl acetate and utilizing the prepared 3-carboxyphenyl phenyl acetate to prepare the m-aminophenol. The technological method comprises the steps: a, taking a C9H8O4 solvent, adding into an ethyl acetate solution, fully stirring until complete dissolution, dropwiseadding thionyl chloride into a system under the ice water bath condition, thermally insulating 1+/-0.5 hours, warming to 60 DEG C and refluxing; b, under the ice water bath condition, adding triethylamine and hydroxylamine hydrochloride into the system, thermally insulating for 2 hours and warming to a room temperature; c, spin drying the solvent on a rotary evaporator, then adding water and potassium carbonate, warming to 60 to 70 DEG C and hydrolyzing; d, utilizing ethyl acetate to extract the solution, utilizing a thin-layer chromatography to determine whether extraction is complete and obtaining the finished product of the m-aminophenol after the extraction is finished.
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- Technological method for preparing carboxylic phenyl acetate
-
The invention relates to a technological method for preparing carboxylic phenyl acetate, and belongs to the technical field of chemical material preparation, solving the technical problem of limitation of raw materials for preparing phenyl acetate in the prior art. The technological method has the advantages of simplicity in operation, high product yield, easiness in reaction control and the like.The technological method includes preparing cresyl acetate, and preparing the carboxylic phenyl acetate from the obtained cresyl acetate; putting the obtained cresyl acetate in a triangular flask, adding water, fully stirring the water, adding glacial acetic acid, and increasing the system to 60-80 DEG C; weighing potassium permanganate, slowly adding the potassium permanganate into the system insmall quantity repeatedly, and keeping the temperature of the system at 50-80 DEG C for 8-10 hours of reaction after the potassium permanganate is added completely; after purple fades in the system completely, increasing the temperature of the system to 90-110 DEG C, and immediately filtering the generated solution after reaction; c, adjusting the pH of the obtained filtrate to not more than 1 byhydrochloric acid, performing extraction by ethyl acetate, and removing extraction agents in the mixture to obtain a solid carboxylic phenyl acetate product.
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Paragraph 0030; 0031-0034; 0047-0049; 0061-0063
(2018/04/02)
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- (R)- AND (S)-1-(3-(3-N,N-DIMETHYLAMINOCARBONYL)PHENOXYL-4-NITROPHENYL)-1-ETHYL-N,N'-BIS (ETHYLENE)PHOSPHORAMIDATE, COMPOSITIONS AND METHODS FOR THEIR USE AND PREPARATION
-
Provided herein are optically active compounds of the formulae (ii); and (III) and pharmaceutical compositions thereof. Also provided herein are processes of making these compounds and resolving the racemic mixture or the enrichment of same with in one of
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-
Paragraph 0070-0071
(2017/06/12)
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- A method for the preparation of meta-hydroxy acetophenone (by machine translation)
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The invention discloses a method for the preparation of meta-hydroxy acetophenone, comprises the following steps: the hydroxy benzoic acid acetylation by second grade acyloxy benzoic acid, benzoyl chloride is obtained and then the second grade acyloxy acyl, then with malonic acid diethyl ester sodium salt solution reaction to obtain 3 - acetoxy benzoyl c diethyl malonate, finally decarboxylates and gets meta-hydroxy acetophenone. The operation of the invention is simple, and cheap raw material, synthetic easy, less side reaction, with a higher yield. (by machine translation)
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-
Paragraph 0055; 0061; 0067; 0073; 0079; 0085; 0091
(2017/09/18)
-
- Process method for preparing resorcinol
-
The invention relates to a process method for preparing resorcinol and belongs to the technical field of preparation of chemical materials with an aim to solve the technical problem about limitation by taking phenylacetate as a preparation material. The technical scheme of the process method includes: sequentially preparing m-Tolyl acetate, m-carboxyl phenyl acetate and m-aminophenol, and then preparing the resorcinol with the prepared m-aminophenol in a manner of a, drying the obtained m-aminophenol prior to weighing, 1.09g of m-aminophenol, 50ml of water and 2.5ml of concentrated hydrochloric acid, mixing the reaction materials and heating the same to 35DEG C and fully stirring until a solution is clarified; b, weighing, by weight, 0.828g of solid sodium nitrite and solving the same in water; c, under the ice bath condition, dropwise adding a sodium nitrite solution to a system; d, under the ice bath condition, heating the system to 30-40DEG C after full stirring and performing continuous reaction; e, extracting the reacted solution with ethyl acetate, spin-drying a reactant fully extracted by the aid of a rotary evaporator to obtain resorcinol solids. The process method has the advantages of simpleness in operation, high production yield, easy reaction control and the like.
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-
-
- 3-hydroxyacetophenone synthesis method
-
The invention provides a 3-hydroxyacetophenone synthesis method. The method includes the steps that 3-hydroxybenzoic acid is subjected to hydroxyl protection through an esterification or etherification reaction, then a chloroformylation reaction and an alkylation reaction are conducted, finally hydrolysis is conducted, and the 3-hydroxyacetophenone is obtained. According to the method, raw materials are cheap, easy to obtain and wide in source, high-temperature and high-pressure operation does not exist, equipment requirement is low, and equipment investment is low; peroxide, heavy nitride and the like do not exist, and high safety is achieved; compared with a nitration-iron powder reduction-diazotization route commonly adopted in the nation, the synthesis method has huge environment-friendly advantages. Besides, according to the method, the amount of wastewater is less than 5% that of an original process, the total route yield is 90%, and the method has huge technological advantages.
- -
-
Paragraph 0057; 0058
(2017/01/12)
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- Acyl transfer reactions of carbohydrates, alcohols, phenols, thiols and thiophenols under green reaction conditions
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Acyl transfer reactions of various carbohydrates, alcohols, phenols, thiols and thiophenols were achieved at room temperature in high yields and catalytic efficiency in the presence of methane sulfonic acid, a green organic acid, under solvent-free conditions over short time periods. The method is mild enough to allow acid labile substituents such as isopropylidene acetals and trityl ethers on the reacting substrates to be left completely unaffected. Esterification of free mono- and dicarboxylic acids such as acetic acid, cinnamic acid, sialic acid and tartaric acid with alcohols such as menthol, ethanol, methanol or propylene glycol has also been achieved efficiently at room temperature. A comparative study of the method with the silica-sulfuric acid is also reported.
- Giri, Santosh Kumar,Kartha, K. P. Ravindranathan
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p. 11687 - 11696
(2015/02/19)
-
- METHOD OF PRODUCING BENZOIC ACID
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PROBLEM TO BE SOLVED: To provide a novel synthesis method in the production of a benzoic acid, which is an important compound for the synthesis of an organic compound, and an industrially suitable production method using main materials derived from nonfossil resources. SOLUTION: This invention provides a method of producing a benzoic acid with a substituted hydroxyl group, methoxy group, or acetoxy group, comprising the step of the ozonation of a compound represented by formula (I), where R1 is H, a methyl group or an acetyl group; R2 is H or an acetoxy group; R3 is an alkyl group, a carboxy group, a formyl group, an alkoxycarbonyl group, an amide group, an acid chloride group, a halogenation alkyl group, or a hydroxyalkyl group. COPYRIGHT: (C)2015,JPOandINPIT
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- Design, synthesis and evaluation of second generation MurF inhibitors based on a cyanothiophene scaffold
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MurF ligase is a crucial enzyme that catalyses the ultimate intracellular step of bacterial peptidoglycan biosynthesis, and thus represents an attractive target for antibacterial drug discovery. We designed, synthesized and evaluated a new series of cyanothiophene-based inhibitors of MurF enzymes from Streptococcus pneumoniae and Escherichia coli. The target compounds had increased polarity compared to the first generation of inhibitors, with demonstrated enzyme inhibitory potencies in the low micromolar range. Furthermore, the best inhibitors displayed promising antibacterial activities against selected Gram-positive and Gram-negative strains. These results represent an important step towards the development of new antibacterial agents targeting peptidoglycan biosynthesis.
- Hrast, Martina,Anderluh, Marko,Knez, Damijan,Randall, Christopher P.,Barreteau, Hélène,O'Neill, Alex J.,Blanot, Didier,Gobec, Stanislav
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-
- Synthesis and biological evaluation of glucagon-like peptide-1 receptor agonists
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In this study, a series of fused-heterocyclic derivatives were systematically designed and synthesized using an efficient route, and evaluated in terms of GLP-1R agonist activity. We employed short synthetic steps and reactions that are tolerant of the presence of various functional groups and suitable for parallel operations to enable the rapid generation of libraries of diverse and structurally complex small molecules. Of the compounds synthesized, 3-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a] pyridin-2-yl)phenyl methanesulfonate (8e) was the most potent agonist with an EC50 of 7.89 μM, and thus is the compound with the greatest potential for application. These findings represent a valuable starting point for the design and discovery of small-molecule GLP-1R agonists that can be administered orally.
- Zhang, Yu-Juan,Shen, Liu-Lan,Cheon, Hyae-Gyeong,Xu, Yong-Nan,Jeong, Jin-Hyun
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p. 588 - 599
(2014/06/09)
-
- NOVEL TRIAZINE COMPOUNDS
-
The present invention relates to novel triazine compounds of formula (1), methods of their preparation, pharmaceutical compositions containing these compounds and the use of these compounds to treat proliferative disorders such as tumors and cancers and also other conditions and disorders related to or associated with dysregulation of PI3 Kinases, PI3 Kinase pathway, mTOR and/ or the mTOR pathway.
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Page/Page column 68
(2012/08/08)
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- Nickel-catalyzed carboxylation of aryl and vinyl chlorides employing carbon dioxide
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Nickel-catalyzed carboxylation of aryl and vinyl chlorides employing carbon dioxide has been developed. The reactions proceeded under a CO2 pressure of 1 atm at room temperature in the presence of nickel catalysts and Mn powder as a reducing agent. Various aryl chlorides could be converted to the corresponding carboxylic acid in good to high yields. Furthermore, vinyl chlorides were successfully carboxylated with CO2. Mechanistic study suggests that Ni(I) species is involved in the catalytic cycle.
- Fujihara, Tetsuaki,Nogi, Keisuke,Xu, Tinghua,Terao, Jun,Tsuji, Yasushi
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supporting information; experimental part
p. 9106 - 9109
(2012/07/13)
-
- MOLECULARLY IMPRINTED POLYMERS
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The present invention provides methods of designing molecularly imprinted polymers (MIPs) which have applications in extracting bioactive compounds from a range of bioprocessing feedstocks and wastes. The present invention is further directed to MIPs designed by the methods of the present invention.
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- Unsymmetrical chiral PCN pincer palladium(II) and nickel(II) complexes of (imidazolinyl)aryl phosphinite ligands: Synthesis via ligand C-H activation, crystal structures, and catalytic studies
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Six unsymmetrical chiral PCN pincer Pd(II) complexes 3a-f based on (imidazolinyl)aryl phosphinite ligands were easily synthesized from imidazolinyl-containing m-phenol derivatives 2a-e by one-pot phosphorylation/palladation reaction via C-H bond activatio
- Zhang, Ben-Shang,Wang, Wei,Shao, Dan-Dan,Hao, Xin-Qi,Gong, Jun-Fang,Song, Mao-Ping
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experimental part
p. 2579 - 2587
(2010/08/05)
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- The cobalt way to angucyclinones: Asymmetric total synthesis of the antibiotics (+)-rubiginone B2, (-)-tetrangomycin, and ( - ) -8- O-Methyltetrangomycin
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A cobalt(I)-mediated convergent and asymmetric total synthesis of angucyclinones with an aromatic B ring has been developed. In the course of our research, we synthesized three naturally occurring anguclinone derivatives, namely, (+)-rubiginone B2/s
- Kesenheimer, Christian,Kalogerakis, Aris,Meissner, Anja,Groth, Ulrich
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experimental part
p. 8805 - 8821
(2010/10/21)
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- Liquid-phase reactions of isomeric methylphenols with ozone
-
Ozonation of isomeric methylphenols in acetic anhydride was studied. Here, acetic anhydride acts simultaneously as solvent and acylating agent. In the presence of a mineral acid methylphenols were converted into methylphenyl acetates during preparation of solutions for ozonation. The major products in the oxidation of isomeric methylphenyl acetates with ozone were aliphatic peroxides (80-90%); oxidation of the methyl group gave rise to the corresponding acetoxybenzyl acetates (7-14%) and acetoxybenzylidene diacetates (3-6%). A probable scheme for the liquid-phase oxidation of methylphenyl acetates with ozone in acetic anhydride was proposed.
- Galstyan
-
scheme or table
p. 15 - 19
(2010/05/01)
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- Semi-synthesis and proteasome inhibition of D-ring deoxy analogs of (-)-epigallocatechin gallate (EGCG), the active ingredient of green tea extract
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A semi-synthetic route to the D-ring analogs of (-)-epigallocatechin gallate (EGCG) from the relatively abundant (-)-epigallocatechin (EGC), isolated from, green tea leaves, is described. A natural product (13), found in Cistus salvifolius, its acetate (14) and analog (17) were synthesized by this method. Their inhibitory activities against proteasomes were investigated.
- Huo, Congde,Shi, Guoqing,Lam, Wai Har,Chen, Di,Cui, Quizhi Cindy,Dou, Q. Ping,Chan, Tak Hang
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p. 495 - 502
(2008/09/21)
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- 4-amino-thieno[3,2-c] pyridine-7-carboxylic acid derivatives
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The present invention relates to compounds of the formula medicaments containing them and the use of these compounds as pharmaceutically active agents. The compounds exhibit activity as Raf kinase inhibitors and therefore may be useful for the treatment of diseases mediated by said kinases, especially as anticancer agents.
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Page/Page column 14
(2010/11/26)
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- HIV-1 integrase inhibition of biscoumarin analogues
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Nineteen biscoumarins bearing free and modified hydroxyl substituents at benzoyloxyphenyl linker have been synthesized by multiple step synthesis. Among these biscoumarins, thirteen were found to be active molecules against HIV-1 integrase (HIV-1 IN). The structure-activity relationship of the nineteen compounds on HIV IN may be useful for the design of potent therapeutic agents.
- Chang-Xiao,Mouscadet, Jean-Francois,Chiang, Chih-Chia,Tsai, Hou-Jen,Hsu, Ling-Yih
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p. 682 - 686
(2007/10/03)
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- ZnO: A versatile agent for benzylic oxidations
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Zinc oxide catalyzed oxidation of various alkylbenzenes, naphthalene and 1,2,3,4-tetrahydronaphthalene in air using microwave irradiation or conventional heating in the presence of N,N-dimethylformamide is described.
- Gupta, Monika,Paul, Satya,Gupta, Rajive,Loupy, André
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p. 4957 - 4960
(2007/10/03)
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- CATALYSTS COMPRISING CYCLIC ACYLUREA COMPOUNDS AND PROCESSES FOR PRODUCTION OF ORGANIC COMPOUNDS WITH THE SAME
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A catalyst of the invention includes a cyclic acylurea compound having a cyclic acylurea skeleton represented by following Formula (I): wherein R is a hydrogen atom or a hydroxyl-protecting group; n is 1 or 2; G is a carbon atom or a nitrogen atom, where two Gs are the same or different when n is 2. The catalyst may include the cyclic acylurea compound and a metallic compound in combination. In the presence of the catalyst, (A) a compound capable of forming a radical is allowed to react with (B) a radical scavenging compound and thereby yields an addition or substitution reaction product of the compound (A) and the compound (B) or a derivative thereof. This catalyst can produce an organic compound with a high selectivity in a high yield as a result of, for example, an addition or substitution reaction under mild conditions.
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-
- Oxidation of substituted toluenes with molecular oxygen in the presence of N,N′,N″-Trihydroxyisocyanuric acid as a key catalyst
-
N,N′,N″-Trihydroxyisocianuric acid (THICA) was found to be a very efficient catalyst for the oxidation of alkylbenzenes with dioxygen. Thus, a variety of meta- and para-substituted toluenes bearing an electron-withdrawing substituent such as cyanotoluene, chlorotoluene, and toluic acid under O2 (1 atm) in the presence of THICA (5 mol %) and Co(OAc)2 (0.5 mol %) at 100 °C were smoothly oxidized to the corresponding benzoic acids in almost quantitative yields. The aerobic oxidation of toluene by THICA was compared with that by N-hydroxyphthalimide. p-Xylene was efficiently oxidized by THICA to telephthalic acid in high yield (over 95%) under mild conditions.
- Hirai, Naruhisa,Sawatari, Naoko,Nakamura, Norihiro,Sakaguchi, Satoshi,Ishii, Yasutaka
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p. 6587 - 6590
(2007/10/03)
-
- Chalcone derivatives and drugs containing the same
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PCT No. PCT/JP97/01652 Sec. 371 Date Nov. 17, 1998 Sec. 102(e) Date Nov. 17, 1998 PCT Filed May 16, 1997 PCT Pub. No. WO97/44306 PCT Pub. Date Nov. 27, 1997This invention relates to chalcone derivatives represented by the following formula (1): wherein A represents a phenyl group, a quinolyl group or the like, W represents a vinylene group or the like, and R1 to R5 each independently represent a carboxyl, cyano, alkyloxycarbonyl or like group, or salts of the chalcone derivatives, and also to drugs containing them as effective ingredients. These compounds have excellent cys-LT receptor antagonism, and are useful as antiallergic agents or the like.
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- Benzamide analogs useful as PARP (ADP-ribosyltransferase, ADPRT) DNA repair enzyme inhibitors
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A range of 3-oxybenzamide compounds and related quinazolinone compounds are disclosed which can act as potent inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase or PARP enzyme (EC 2.4.2.30), and which thereby can provide useful therapeutic compounds for use in conjunction with DNA-damaging cytotoxic drugs or radiotherapy to potentiate the effects of the latter. The compounds disclosed include 3-benzyloxybenzamides, 3-oxybenzamides in which a chain of 5 or more methylene groups terminate in a halogen atom or in a purin-9-yl moiety, certain benzoxazole-4-carboxamide compounds and certain quinazolinone compounds. In formula X and Y together may form a bride -X-Y- that represents the grouping (a), (b) or (c )wherein R5 is H, alkyl, aryl or aralkyl.
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- Synthesis and structure-activity relationships of carboxylated chalcones: A novel series of CysLT1 (LTD4) receptor antagonists
-
The synthesis and CysLT1 antagonistic activities of a new series of 2- , 3-, and 4-(2-quinolinylmethoxy)- and 3- and 4-[2-(2-quinolinyl)ethenyl]- substituted, 2'-, 3'-, 4'-, or 5'-carboxylated chalcones are described. Structure-activity relationship studies indicate a preference for the presence of a negatively charged (acidic) moiety, although in some cases nitrile or ester analogues also exhibit moderate activity. The quinoline moiety may be substituted at either the 3- or the 4-position. Replacement of this heterocycle by other aromatic groups results in compounds with comparable affinities [2-(7-chloroquinoline), 1-(1-methyl-2-benzimidazole), or 1-(2-benzothiazole)] or substantially lower activities [1-(1- ethoxyethyl)-2-benzimidazole, 2-naphthyl, or phenyl]. The quinoline and chalcone moieties may be connected by either an ethenyl or a methoxy spacer. The acidic moiety at the chalcone B ring may be attached to the 2'-, 3'-, 4'- , or 5'-position, for both the 3- and 4-substituted chalcones. There are no general patterns to specify which substitution positions gave the most potent compounds. The series contains several potent CysLT1 receptor antagonists, with K(D) values approaching the nanomolar range, as measured by the displacement of [3H]LTD4 from guinea pig lung membranes. Antagonism of LTD4-induced contraction of guinea pig ileum, the inhibition of antigen- induced contraction of guinea pig trachea in vitro, and the inhibition of LTD4-induced increase of vascular permeability in vivo are determined for chalcones with high CysLT1 receptor affinities (K(D) values below 0.1μM). 2'-Hydroxy-4-(2-quinolinylmethoxy)-5'-(5-tetrazolyl)chalcone (14, VUF 4819) showed good activity in both in vitro and in vivo assays and has been selected for further evaluation.
- Zwaagstra, Mari?l E.,Timmerman, Hendrik,Tamura, Masahiro,Tohma, Tsutomu,Wada, Yasushi,Onogi, Kazuhiro,Zhang, Ming-Qiang
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p. 1075 - 1089
(2007/10/03)
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- The synthesis of some N-[4-substituted phenyl]-3-acetoxybenzthioamides and their N1,N3-disubstituted amidrazones
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The synthesis of N-[4-substituted phenyl]-3-acetoxythiobenzamides 5 from corresponding carboxyamides 4 is described. The reaction of 5 with hydrazine hydrate gave N1,N3-disubstituted amidrazones. They were characterized by their Nsu
- Jovevska,Anastasova,Aleksic
-
p. 279 - 286
(2007/10/03)
-
- Kinetic and spectroscopic characterization of ternary complexes by numerical fitting methods. Catalysis of acyl-transfer reactions by a macrocyclic azoniacyclophane
-
Spectroscopic and computational procedures are presented for the analysis of highly complex kinetic schemes occurring in acyl-transfer reactions which are catalyzed by an azoniacyclophane (CP66). The results, supported by product identification and inhibition experiments, indicate an acyl transfer from intracavity-bound substrates such as 2,4-dinitronaphthyl acetate (DNNA) to hydroxybenzoic acids which are bound as cosubstrates to the positively charged CP66 by electrostatic association. The kinetic system is represented by 11 single steps, including the hydrolysis via a binary complex with CP66 and a side reaction to Meisenheimer products. Seven constants are determined by separate measurements with different techniques; three parameters for the ternary complex are then identified by curve fitting to the observed saturation kinetics. A newly developed numerical integration and optimization program allows the description of all parallel reaction parameters including fast equilibria.
- Schneider, Hans-J?rg,Kramer, Rüdiger,Rammo, J?rg
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p. 8980 - 8984
(2007/10/02)
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- Cobalt(II)-Catalyzed Reaction of Aldehydes with Acetic Anhydride under an Oxygen Atmosphere: Scope and Mechanism
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The reaction of aldehydes with acetic anhydride in the presence of catalytic cobalt(II) chloride under an oxygen atmosphere at ambient temperature is dependent upon the reaction medium.Aliphatic aldehydes react in acetonitrile to give 1,2-diones whereas the aromatic aldehydes are acylated to yield the corresponding acylals.On the other hand, carboxylic acids are obtained from aliphatic and aromatic aldehydes by conducting the reaction in dichloroethane or benzene.Cobalt(II) chloride in acetonitrile catalyzes the conversion of aliphatic aldehydes to the correspondinganhydrides in the absence of acetic anhydride whereas aromatic aldehydes remain largely unaffected under these conditions.A preliminary mechanistic study in three different solvents (i.e. acetonitrile, dichloroethane, and DMF) has revealed that in acetonitrile and in the presence of acetic anhydride, aliphatic aldehydes behave differently than aromatic aldehydes.Some trapping experiments using methyl acrylate and stilbene have been conducted to demonstrate the occurence of an acyl cobalt and peroxyacyl cobalt intermediate during these reactions.
- Bhatia, Beena,Punniyamurthy, T.,Iqbal, Javed
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p. 5518 - 5523
(2007/10/02)
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- Polyelectrolyte-Catalyzed Acetyl Transfer Reactions. Structure-Reactivity Relationships in the Aminolysis of Phenyl Acetates by Poly(ethyleneimine) and Glycylglycine.
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The aminolysis of a wide series of substituted phenyl acetates by poly(ethyleneimine) (PEI) is studied.Saturation kinetics are observed and the ester-polyamine association equilibrium constants, as well as the rates of decomposition of the resulting intracomplexes, are determined.Unlike the association constants, the rate constants for the reaction of the intracomplex are found to depend on the acidity of the leaving groups.Two Broensted-type relationships are found for anionic and neutral esters having different intercepts but proximate slopes -0.73 and -0.77 respectively, which decrease to lower values with very reactive phenyl acetates.Only one broken Broensted relationship is found for the bimolecular aminolysis by glycylglycine.The results are consistent with the formation of a tetrahedral intermediate by the amino groups of PEI, with a change in the rate-determining step for very reactive esters from the breakdown to the formation of the tetrahedral intermediate.The higher reactivity of PEI, which is more relevant with substrates containing anionic groups, is principally ascribed to the electrostatic polyelectrolyte-substrate binding.A minor role is played by the increase in the acidity of the conjugate acid of the leaving group, i.e. of its leaving ability, caused by the association of the ester with PEI: values of effective molarity in the range of 10 to 15 mol cm-3 are found.
- Arcelli, Antonio,Concilio, Carlo
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p. 201 - 226
(2007/10/02)
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- Cobalt (II) catalyzed oxidation of aldehydes to carboxylic acid with molecular oxygen
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A variety of aromatic and some aliphatic aldehydes are efficiently transformed to the corresponding carboxylic acid in presence of catalytic amount of Cobalt (II) chloride, molecular oxygen and acetic anhydride at room temperature. Phenolic aldehydes undergo acylative oxidation to give the corresponding acylated carboxylic acid.
- Bhatia, Beena,Iqbal, Javed
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p. 7961 - 7964
(2007/10/02)
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- H-bonded oxyhemoglobin models with substituted picket-fence porphyrins: The model compound equivalent of site-directed mutagenesis
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Iron(II) complexes of picket-fence-type porphyrins having one of the four pivalamide pickets replaced by a substituent capable of H-bonding have been synthesized as models for oxyhemoglobin. This synthetic approach is analogous to site-directed mutagenesis of the distal residues in oxygen-binding hemoproteins. Rate and equilibrium data for dioxygen binding have been determined to evaluate the effect of the H-bonding substituent and to make comparisons with more passive substituents. The effect of H-bonding on the dioxygen affinity under standard conditions (25 °C, toluene solvent, 1,2-dimethylimidazole as axial ligand) is best illustrated by the ca. 10-fold increase observed when one pivalamide substituent of picket-fence porphyrin is replaced by a phenylurea substituent. Other substituents influence dioxygen adduct stability in a variety of ways to reveal that even with an apparently straightforward systematic approach, there can be considerable difficulty in partitioning the various factors that influence O2 affinity. This applies to both model compounds and mutant proteins.
- Wuenschell, Gerald E.,Tetreau, Catherine,Lavalette, Daniel,Reed, Christopher A.
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p. 3346 - 3355
(2007/10/02)
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