- Modulating lipophilicity of rohitukine via prodrug approach: Preparation, characterization, and in vitro enzymatic hydrolysis in biorelevant media
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Rohitukine is a medicinally important natural product which has inspired the discovery of two anticancer clinical candidates. Rohitukine is highly hydrophilic in nature which hampers its oral bioavailability. Thus, herein our objective was to improve the drug-like properties of rohitukine via prodrug-strategy. Various ester prodrugs were synthesized and studied for solubility, lipophilicity, chemical stability and enzymatic hydrolysis in plasma/esterase. All prodrugs displayed lower aqueous solubility and improved lipophilicity compared with rohitukine, which was in accordance with the criteria of compounds in drug-discovery. The stability of synthesized prodrugs was evaluated in buffers at different pH, SGF, SIF, rat plasma and in esterase enzyme. The rate of hydrolysis in all incubation media was dependent primarily on the acyl promoieties. Hexanoyl ester prodrug of rohitukine, 3d, was stable under chemical conditions; however it was completely hydrolyzed to rohitukine, in plasma and in esterase in 4?h. Hexanoate ester 3d appeared to be the most promising prodrug as it remained intact at gastric/intestinal pH and was completely transformed to the parent compound in plasma as desired for an ideal prodrug. The data presented herein, will help in designing prodrugs with desired physicochemical properties in future in structurally similar chemotypes.
- Kumar, Vikas,Bharate, Sonali S.,Vishwakarma, Ram A.
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Read Online
- Structure–activity relationship investigation of tertiary amine derivatives of cinnamic acid as acetylcholinesterase and butyrylcholinesterase inhibitors: compared with that of phenylpropionic acid, sorbic acid and hexanoic acid
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In the present investigation, 48 new tertiary amine derivatives of cinnamic acid, phenylpropionic acid, sorbic acid and hexanoic acid (4d–6g, 10d–12g, 16d–18g and 22d–24g) were designed, synthesized and evaluated for the effect on AChE and BChE in vitro. The results revealed that the alteration of aminoalkyl types and substituted positions markedly influences the effects in inhibiting AChE. Almost of all cinnamic acid derivatives had the most potent inhibitory activity than that of other acid derivatives with the same aminoalkyl side chain. Unsaturated bond and benzene ring in cinnamic acid scaffold seems important for the inhibitory activity against AChE. Among them, compound 6g revealed the most potent AChE inhibitory activity (IC50 value: 3.64 μmol/L) and highest selectivity over BChE (ratio: 28.6). Enzyme kinetic study showed that it present a mixed-type inhibition against AChE. The molecular docking study suggested that it can bind with the catalytic site and peripheral site of AChE.
- Gao, Xiaohui,Tang, Jingjing,Liu, Haoran,Liu, Linbo,Kang, Lu,Chen, Wen
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Read Online
- Enantioselective total synthesis of decytospolide A and decytospolide B using an Achmatowicz reaction
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Enantioselective syntheses of decytospolide A and decytospolide B are described here. The current synthesis highlights an Achmatowicz rearrangement of an optically active furanyl alcohol followed by reduction of the resulting dihydropyranone hemiacetal with BF3·OEt2 and Et3SiH to provide the saturated tetrahydropyranyl alcohol directly. This reduction was investigated with a variety of other Lewis acids. The synthesis also features Noyori asymmetric transfer hydrogenation and Friedel-Crafts acylation. Overall, the synthesis provides ready access to the natural products and may be useful in the preparation of bioactive derivatives.
- Ghosh, Arun K.,Simpson, Hannah M.,Veitschegger, Anne M.
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Read Online
- Stereospecific Synthesis of Glycoside Mimics Through Migita-Kosugi-Stille Cross-Coupling Reactions of Chemically and Configurationally Stable 1-C-Tributylstannyl Iminosugars
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A process for the de novo synthesis of imino-C-glycosides is described. The methodology is based on the reaction of 1-C-stannylated iminosugars with various electrophiles under the conditions of Migita-Kosugi-Stille cross-couplings, which gives 1-C-substituted iminosugar derivatives in a stereoretentive process. The required iminoglycosyl stannanes are obtained by way of the highly stereoselective addition of tributylstannyllithium to (SR)- or (SS)-N-tert-butanesulfinyl glycosylamines, followed by an activation cyclization sequence. Most interestingly, the methodology is tunable: the configuration of the tin adduct is controlled exclusively by the tert-butanesulfinyl auxiliary, thus giving access after ring formation to ‘α’-configured or ‘β’-configured iminoglycosyl stannanes. With the subsequent stereoretentive C?C bond-forming process, the methodology allows the synthesis of pseudo anomers of imino-C-glycosyl compounds in a controlled fashion. (Figure presented.).
- Li, Sizhe,Jaszczyk, Justyna,Pannecoucke, Xavier,Poisson, Thomas,Martin, Olivier R.,Nicolas, Cyril
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Read Online
- Supramolecular cation transporters alter root morphology in the Arabidopsis thaliana plant
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Bibracchial (two-armed) 4,13-diaza-18-crown-6 lariat ether and tris(macrocycle) hydraphile synthetic amphiphiles alter root morphology in Arabidopsis thaliana plants. The effect on root structure and growth depends both on the hydraphile spacer chain length and lariat ether side chain length as well as the concentration of compound in the growth medium. In some cases a correlation to ion transport activity was apparent, but such a correlation is not always manifested. Surprisingly, planar bilayer conductance (BLM) studies showed that lariat ethers and lariat ether amides both exhibited well controlled membrane activity. Pore formation in soybean asolectin membranes occurred readily and the pores were stable and sustained. Low concentrations of active hydraphiles and lariat ethers altered the primary:lateral root density ratio, generally increasing it. The transporter-mediated alterations in lateral root density were suggestive of the activity of plant auxins such as indole-3-acetic acid and 2,4-dichlorophenoxyacetic acid, which are known to depend on cytosolic potassium ion concentrations. The hypothesis that the compounds interfere with the auxin pathway was tested and discounted by using auxin-resistant A. thaliana mutants. Rather than functioning directly as auxin mimics, ionophores affect the ion gradients producing an auxin-like effect on root development.
- Patel, Mohit B.,Negin, Saeedeh,Stavri, Ariel,Gokel, George W.
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Read Online
- One-step Conversion of Amides and Esters to Acid Chlorides with PCl3
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A general and efficient iodine-promoted chlorination of amides and esters with phosphorus trichloride is described. For the first time. Various inactivated amides including secondary and tertiary amides were directly converted to the corresponding acid chlorides in one-step. The substrate scope of methyl esters including aromatic and aliphatic esters was also explored under this system. This method is simple, scalable and wide in scope, which provides an approach to preparation of these acid chlorides.
- Li, Fangshao,Wu, Xiaofang,Guo, Fengzhe,Tang, Zi-Long,Xiao, Jing
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supporting information
p. 4314 - 4317
(2021/07/16)
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- Synthesis, computational studies and enzyme inhibitory kinetics of benzothiazole-linked thioureas as mushroom tyrosinase inhibitors
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Herein, we report synthesis of a set of benzothiazole-thiourea hybrids with aromatic and aliphatic side chains (BT1 to BT9) using an elegant synthetic strategy. The newly synthesized benzothiazole-thiourea conjugates were subjected to In-vitro tyrosinase inhibition and free radical scavenging activity. Majority of the compounds indicated inhibition considerably improved than the standard; compound (Kojic acid with IC50 = 16.8320 ± 1.1600 μM) BT2 with IC50 = 1.3431 ± 0.0254 μM was found to be the best inhibitor. A non-competitive mode of inhibition of BT2 was disclosed with Ki value of 2.8 μM. In order to study enzyme-inhibitor interactions SAR analysis molecular docking was carried out. The amino groups of thiourea were involved in hydrogen bonding with Glu322 showing the bond length of 1.74 and 2.70 ?, respectively. Moreover, the coupling of π-π was displayed between benzothiazole and benzene rings of His244 and His263, respectively. The outcome of this study might help to develop new inhibitors of melanogenesis, important for cosmetic and food products. Communicated by Ramaswamy H. Sarma.
- Ujan, Rabail,Saeed, Aamer,Ashraf, Saba,Channar, Pervaiz Ali,Abbas, Qamar,Rind, Mahboob Ali,Hassan, Mubashir,Raza, Hussain,Seo, Sung-Yum,El-Seedi, Hesham R.
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p. 7035 - 7043
(2020/08/12)
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- Benzimidazole tethered thioureas as a new entry to elastase inhibition and free radical scavenging: Synthesis, molecular docking, and enzyme inhibitory kinetics
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The porcine pancreatic elastase inhibition and free-radical scavenging play a crucial role in age progression. All the series of 10 newly synthesized benzimidazole thioureas (4a-j) were assessed for elastase inhibition and radical scavenging activity to identify the suitable anti-aging ingredient for cosmetics products. The compounds 4e, 4f, 4g, and 4h showed inhibition better than the standard, while compound 4f showed the most significant elastase inhibition with the IC50 value of 1.318 ± 0.025 μM compared with oleanic acid IC50 13.451 ± 0.014 used ±1.989 and 41.563 ± 0.824, respectively, as standard. Molecular docking studies were performed and the compound 4f showed binding energy of 7.2 kcal/mol. Kinetics studies revealed inhibition of the pancreatic elastase in a competitive manner. The relative binding energy and structure activity relationship (SAR) identified compound 4f as an effective inhibitor of porcine pancreatic elastase. Compounds 4e and 4i showed remarkable free-radical scavenging activity with SC50 values of 26.421.
- Abbas, Qamar,Ashraf, Saba,Channar, Pervaiz Ali,Hassan, Abbas,Hassan, Mubashar,Rafique, Hummera,Raza, Hussain,Rind, Mahboob Ali,Saeed, Aamer,Seo, Sung-Yum,Ujan, Rabail,Ul-Hamid, Anwar
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- Dihydropyrazole MurA enzyme inhibitor molecule as well as preparation method and application thereof
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The invention provides a dihydropyrazole MurA enzyme inhibitor molecule as well as a preparation method and application thereof. The structural formula is shown in the specification, R is a direct-connected alkyl group with the chemical formula of CnH2n+1, and n is equal to 1-7. The preparation method comprises the following steps of by taking acetophenone substances with different substituent groups and 4-(4-methyl piperazinyl) benzaldehyde as raw materials, carrying out aldol condensation reaction under an alkaline condition to obtain an intermediate, and synthesizing a target compound with a structural formula by using the intermediate, hydrazine hydrate and an organic acid with an R-COOH structure. The dihydropyrazole MurA enzyme inhibitor molecule provided by the invention has a bacterial inhibition effect, has an MurA enzyme inhibition effect, and also has an effect of interfering synthesis of bacterial cell walls.
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Paragraph 0039; 0064-0066; 0068; 0087-0089; 0091; 0110-0112
(2021/05/12)
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- Neutrophil-Selective Fluorescent Probe Development through Metabolism-Oriented Live-Cell Distinction
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Human neutrophils are the most abundant leukocytes and have been considered as the first line of defence in the innate immune system. Selective imaging of live neutrophils will facilitate the in situ study of neutrophils in infection or inflammation events as well as clinical diagnosis. However, small-molecule-based probes for the discrimination of live neutrophils among different granulocytes in human blood have yet to be reported. Herein, we report the first fluorescent probe NeutropG for the specific distinction and imaging of active neutrophils. The selective staining mechanism of NeutropG is elucidated as metabolism-oriented live-cell distinction (MOLD) through lipid droplet biogenesis with the help of ACSL and DGAT. Finally, NeutropG is applied to accurately quantify neutrophil levels in fresh blood samples by showing a high correlation with the current clinical method.
- Gao, Min,Lee, Sun Hyeok,Park, Sang Hyuk,Ciaramicoli, Larissa Miasiro,Kwon, Haw-Young,Cho, Heewon,Jeong, Joseph,Chang, Young-Tae
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supporting information
p. 23743 - 23749
(2021/10/14)
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- Conformation, and Charge Tunneling through Molecules in SAMs
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This paper demonstrates that the molecular conformation (in addition to the composition and structure) of molecules making up self-assembled monolayers (SAMs) influences the rates of charge tunneling (CT) through them, in molecular junctions of the form AuTS/S(CH2)2CONR1R2//Ga2O3/EGaIn, where R1 and R2 are alkyl chains of different length. The lengths of chains R1 and R2 were selected to influence the conformations and conformational homogeneity of the molecules in the monolayer. The conformations of the molecules influence the thickness of the monolayer (i.e. tunneling barrier width) and their rectification ratios at ±1.0 V. When R1 = H, the molecules are well ordered and exist predominantly in trans-extended conformations. When R1 is an alkyl group (e.g., R1 H), however, their conformations can no longer be all-trans-extended, and the molecules adopt more gauche dihedral angles. This change in the type of conformation decreases the conformational order and influences the rates of tunneling. When R1 = R2, the rates of CT decrease (up to 6.3×), relative to rates of CT observed through SAMs having the same total chain lengths, or thicknesses, when R1 = H. When R1 H R2, there is a weaker correlation (relative to that when R1 = H or R1 = R2) between current density and chain length or monolayer thickness, and in some cases the rates of CT through SAMs made from molecules with different R2 groups are different, even when the thicknesses of the SAMs (as determined by XPS) are the same. These results indicate that the thickness of a monolayer composed of insulating, amide-containing alkanethiols does not solely determine the rate of CT, and rates of charge tunneling are influenced by the conformation of the molecules making up the junction.
- Belding, Lee,Root, Samuel E.,Li, Yuan,Park, Junwoo,Baghbanzadeh, Mostafa,Rojas, Edwin,Pieters, Priscilla F.,Yoon, Hyo Jae,Whitesides, George M.
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supporting information
p. 3481 - 3493
(2021/03/08)
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- PCl3-mediated transesterification and aminolysis of tert-butyl esters via acid chloride formation
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A PCl3-mediated conversion of tert-butyl esters into esters and amides in one-pot under air is developed. This novel protocol is highlighted by the synthesis of skeletons of bioactive molecules and gram-scale reactions. Mechanistic studies revealed that this transformation involves the formation of an acid chloride in situ, which is followed by reactions with alcohols or amines to afford the desired products.
- Wu, Xiaofang,Zhou, Lei,Li, Fangshao,Xiao, Jing
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p. 491 - 497
(2021/01/20)
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- Direct Decarboxylative Functionalization of Carboxylic Acids via O-H Hydrogen Atom Transfer
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Decarboxylative functionalization via hydrogen atom transfer offers an attractive alternative to standard redox approaches to this important class of transformations. Herein, we report a direct decarboxylative functionalization of aliphatic carboxylic acids using N-xanthylamides. The unique reactivity of amidyl radicals in hydrogen atom transfer enables decarboxylative xanthylation under redox-neutral conditions. This platform provides expedient access to a range of derivatives through subsequent elaboration of the xanthate group.
- Na, Christina G.,Ravelli, Davide,Alexanian, Erik J.
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supporting information
p. 44 - 49
(2020/01/22)
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- A practical chlorination of tert-butyl esters with PCl3 generating acid chlorides
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For the first time, using PCl3, a range of tert-butyl esters is chlorinated successfully, allowing access of both aromatic acid chlorides and aliphatic acid chlorides in good yields. The method features simple reaction conditions and wide substrate scope. Various tert-butyl esters including aryl esters, alkenyl esters, and alkyl esters were tolerated well in the reaction. A plausible mechanism is proposed.
- Wu, Xiaofang,Zhou, Lei,Yang, Ruoqi,Guo, Fengzhe,Tang, Zi-Long,Xiao, Jing
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p. 301 - 304
(2020/01/29)
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- Isoalantolactone derivative, pharmaceutical composition and application thereof
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The invention relates to an isoalantolactone derivative, a pharmaceutical composition and application thereof, especially use of the isoalantolactone derivative shown as formula (I) or a salt pharmaceutical compound thereof in preparation of adjuvant drugs treating cancer, a pharmaceutical composition containing a therapeutically effective amount of isoalantolactone derivative (I) or its salt anda pharmaceutically acceptable carrier or a composition with other anticancer drugs.
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Paragraph 0014
(2019/02/02)
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- Cinnamyl alcohol fatty acid ester derivative and application and preparation method thereof
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The invention relates to a derivative and an application and a preparation method thereof, in particular to a cinnamyl alcohol fatty acid ester derivative and an application and a preparation method thereof. As application of a percutaneous absorption penetration enhancer, a percutaneous administration preparation is prepared, so that the percutaneous absorption of a drug is improved, and the cumulative penetration amount of the drug is increased. The cinnamyl alcohol fatty acid ester derivative is prepared into fatty acyl chloride, and the fatty acyl chloride reacts with cinnamyl alcohol to obtain the cinnamyl alcohol fatty acid ester derivative. The compound can be applied to the percutaneous administration preparation to enhance the drug permeability, can further be used as perfume to cover up the bad smell of the preparation, and has wide potential application prospects.
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Paragraph 0044; 0045
(2019/05/08)
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- An efficient synthesis of benzothiazole using tetrabromomethane as a halogen bond donor catalyst
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An efficient and mild protocol has been developed for the synthesis of 2-substituted benzothiazole under solvent- and metal-free conditions using CBr4 as the catalyst. This process involves the activation of a thioamide through halogen bond formation between the sulphur atom of the thioamide and bromine atom of the CBr4 molecule. The presence of halogen-bonding interaction between N-methylthioamides and tetrabromomethane has been demonstrated with several control experiments, spectroscopic analysis and density functional theory (DFT). This methodology has a wide substrate scope for the synthesis of both 2-alkyl and 2-aryl substituted benzothiazoles.
- Kazi, Imran,Sekar, Govindasamy
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p. 9743 - 9756
(2019/12/02)
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- COMPOUNDS WITH HIV MATURATION INHIBITORY ACTIVITY
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The present invention relates to compound of Formula I or a pharmaceutically acceptable salt thereof (Formula I) wherein R1 is Formula (AA) or Formula (BB) where the squiggly line indicates the point of attachment to the rest of the molecule; R2 is F or Formula (CC) where the squiggly line indicates the point of attachment to the rest of the molecule; R3 is H or CH3; Z is O or is absent; and R4 is -OC1-3alkyl, C1-30alkyl, or -N(CH3)2.
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Page/Page column 14
(2019/11/12)
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- Cobalt-Catalyzed Enantioselective Negishi Cross-Coupling of Racemic α-Bromo Esters with Arylzincs
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The first cobalt-catalyzed enantioselective Negishi cross-coupling reaction, and the first arylation of α-halo esters with arylzinc halides, are disclosed. Employing a cobalt-bisoxazoline catalyst, various α-arylalkanoic esters were synthesized in excellent enantioselectivities and yields (up to 97 % ee and 98 % yield). A diverse range of functional groups, including ether, halide, thioether, silyl, amine, ester, acetal, amide, olefin and heteroaromatics is tolerated by this method. This method was suitable for gram-scale reactions, enabling the synthesis of (R)-xanthorrhizol with high enantiopurity. Radical clock experiments support the intermediacy of radicals.
- Liu, Feipeng,Zhong, Jiangchun,Zhou, Yun,Gao, Zidong,Walsh, Patrick J.,Wang, Xueyang,Ma, Sijie,Hou, Shicong,Liu, Shangzhong,Wang, Minan,Wang, Min,Bian, Qinghua
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supporting information
p. 2059 - 2064
(2018/02/14)
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- IONIZABLE CATIONIC LIPID FOR RNA DELIVERY
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What is described is a compound of formula I consisting of a compound in which R1 is a branched chain alkyl consisting of 10 to 31 carbons; R2 is a linear alkyl, alkenyl, or alkynyl consisting of 2 to 20 carbons; L1 and L2 are the same or different, each a linear alkylene of 1 to 20 carbons or a linear alkenylene of 2 to 20 carbons; X1 is S or O; R3 is a linear or branched alkylene consisting of 1 to 6 carbons; and R4 and R5 are the same or different, each a hydrogen or a linear or branched alkyl consisting of 1 to 6 carbons; or a pharmaceutically acceptable salt thereof.
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Paragraph 0019; 0148; 0149
(2018/07/04)
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- A General Approach to Site-Specific, Intramolecular C?H Functionalization Using Dithiocarbamates
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Intramolecular hydrogen atom transfer is an established approach for the site-specific functionalization of unactivated, aliphatic C?H bonds. Transformations using this strategy typically require unstable intermediates formed using strong oxidants and have mainly targeted C?H halogenations or intramolecular aminations. Herein, we report a site-specific C?H functionalization that significantly increases the synthetic scope and convergency of reactions proceeding via intramolecular hydrogen atom transfer. Stable, isolable N-dithiocarbamates are used as precursors to amidyl radicals formed via either light or radical initiation to efficiently deliver highly versatile alkyl dithiocarbamates across a wide range of complex structures.
- Na, Christina G.,Alexanian, Erik J.
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supporting information
p. 13106 - 13109
(2018/09/21)
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- Copper-Catalyzed Bromination of C(sp3)?H Bonds Distal to Functional Groups
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Selective bromination of γ-methylene C(sp3)?H bonds of aliphatic amides and δ-methylene C(sp3)?H bonds of nosyl-protected alkyl amines are developed using NBS as the brominating reagent and catalytic amount of CuII/phenanthroline complexes as the catalyst. Aryl and benzylic C?H bonds at other locations remain intact during this directed radical abstraction reaction.
- Liu, Tao,Myers, Michael C.,Yu, Jin-Quan
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supporting information
p. 306 - 309
(2016/12/30)
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- Synthesis and biological evaluation of 5-fatty-acylamido-1, 3, 4-thiadiazole-2-thioglycosides
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In the present study, the synthesis of 1, 3, 4-thiadiazole-based thioglycosides were accomplished in good yields with employing a convergent synthetic route. The starting material 5-amino-1, 3, 4-thiadiazole-2-thiol and followed by a series of 5-fatty-acylamido-1, 3, 4-thiadiazole-2-thiols (4a–4j) were synthesized with different fatty acid chlorides. The glycosylation of compounds 4a–4j were achieved with trichloroacetimidate methodology. Antimicrobial and cytotoxicity activities of title compounds were evaluated. Among the entire compounds lauric acid and myristic acid derivatives showed good and moderate antimicrobial activity. In case of cytotoxicity results of compounds 8a–8j and 9a–9j, the acetate protected short chain (C6:0, C8:0, C10:0) compounds and the free hydroxyl long chain saturated (C16:0, C18:0) and unsaturated (C18:1, C22:1) compounds exhibited good activity against different cancer cell lines. Further, the free hydroxyl compounds 9a, 9c–9j did not show any toxicity towards normal CHO-K1 cell line whereas acylated compounds 8a–8j exhibited toxicity.
- Vudhgiri, Srikanth,Koude, Dhevendar,Veeragoni, Dileep Kumar,Misra, Sunil,Prasad,Jala, Ram Chandra Reddy
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supporting information
p. 3370 - 3373
(2017/07/07)
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- d-menthol fatty acid ester derivative, application thereof and preparation method for d-menthol fatty acid ester derivative
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The invention belongs to the technical field of medicines and relates to a d-menthol fatty acid ester derivative, an application thereof and a preparation method for the d-menthol fatty acid ester derivative. The d-terpineol fatty acid ester is prepared through carrying out an esterification reaction on d-menthol and straight-chain fatty acid. The method comprises the steps of firstly, carrying out a reaction on fatty acid and thionyl chloride so as to prepare acyl chloride, and then, subjecting acyl chloride to a reaction with d-menthol, there by preparing the ester. The d-menthol ester is applied to external preparations such as plasters, cataplasm, ointment, gels, sprays and liniment as a penetration enhancer, so that the percutaneous absorption capacity of drugs, particularly, chiral drug enantiomers is increased; and the d-menthol ester is a very good percutaneous absorption penetration enhancer and has a broad application prospect.
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Paragraph 0030
(2017/08/29)
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- Coumarin esterified derivative with effect of inhibiting transcriptional activity of RXRalpha (Retinoid X Receptor) as well as preparation method and application of coumarin esterified derivative
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The invention discloses a coumarin esterified derivative with an effect of inhibiting transcriptional activity of RXRalpha (Retinoid X Receptor) as well as a preparation method and application of the coumarin esterified derivative. The coumarin esterified derivative is a 4-chloromethyl-7-hydroxy coumarin esterified derivative shown by the following general formula. The invention also discloses a preparation method of the 4-chloromethyl-7-hydroxy coumarin esterified derivatives. The preparation method comprises the following steps: preparing 4-chloromethyl-7-hydroxy coumarin under solvent-free conditions by taking anhydrous bismuth chloride as a catalyst; preparing corresponding acyl chloride through different side chain acids; and reacting with the 4-chloromethyl-7-hydroxy coumarin, thereby obtaining the corresponding compound. The coumarin esterified derivative disclosed by the invention has a certain effect of inhibiting the transcriptional activity of RXRalpha and provides a thought for developing medicines taking the RXRalpha as a target. The structural formula is as shown in the specification.
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Paragraph 0040
(2017/09/26)
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- Synthesis, pH dependent, plasma and enzymatic stability of bergenin prodrugs for potential use against rheumatoid arthritis
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Bergenin is a unique C-glycoside natural product possessing anti-inflammatory and anti-arthritic activity. It is hydrophilic molecule and stable under acidic conditions however is unstable at neutral-basic pH conditions. The rate of degradation is directly proportional to the increase in pH which might be one of the reasons for its low oral bioavailability. Thus, herein our objective was to improve its stability using prodrug strategy. Various ester and ether prodrugs were synthesized and studied for lipophilicity, chemical stability and enzymatic hydrolysis in plasma/esterase. The stability of synthesized prodrugs was evaluated in buffers at different pH, in biorelevant media such as SGF, SIF, rat plasma and in esterase enzyme. All prodrugs displayed significantly improved lipophilicity compared with bergenin, which was in accordance with the criteria of drug-like compounds. Acetyl ester 4a2 appeared to be the most promising prodrug as it remained stable at gastric/intestinal pH and was completely transformed to the parent compound bergenin in plasma as desired for an ideal prodrug. The data presented herein, will help in designing stable prodrugs of unstable molecules with desired physicochemical properties in structurally similar chemotypes.
- Singh, Rohit,Kumar, Vikas,Bharate, Sonali S.,Vishwakarma, Ram A.
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p. 5513 - 5521
(2017/10/06)
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- Citronellol fatty acid ester derivative and application and preparation method thereof
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The invention relates to a citronellol fatty acid ester derivative and an application and preparation method thereof. The citronellol fatty acid ester derivative is used as a transdermal absorption penetration enhancer for application and used for preparing a transdermal drug delivery preparation so that transdermal absorption of drugs can be improved, and the accumulative penetration amount of the drugs is increased. According to the citronellol fatty acid ester derivative, after reaction with thionyl chloride, fatty acyl chloride is prepared, then the fatty acyl chloride reacts with citronellol, and the citronellol fatty acid ester derivative is obtained. The citronellol fatty acid ester derivative can be applied to the transdermal drug delivery preparation, improves the penetration ability of the drugs, and can also be used as spice to mask the objectionable odor of the preparation.
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Paragraph 0045; 0046
(2017/12/09)
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- Nerol aliphatic ester derivative as well as application and preparation method thereof
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The invention belongs to the technical field of medicine, and relates to a nerol aliphatic ester derivative as well as application and a preparation method thereof. The nerol aliphatic ester is obtained by a esterification reaction between nerol and straight-chain fatty acid and is prepared from the following steps: preparing acyl chloride by reaction between fatty acid and sulfoxide chloride; preparing nerol aliphatic ester. by reaction between acyl chloride and nerol. The nerol aliphatic ester can be used as a penetration enhancer to be applied to external preparation, such as a patch, a cataplasm, an ointment, a gelling agent and a spraying agent, so that the percutaneous absorption of medicine is improved. The nerol aliphatic ester is a good percutaneous absorption enhancer and has a wide application prospect.
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Paragraph 0043; 0044
(2017/11/04)
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- Lavandulol fatty acid ester derivative, application and preparation method thereof
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The invention relates to a derivative, application and a preparation method of the derivative, in particular to a lavandulol fatty acid ester derivative, application and a preparation method thereof. The lavandulol fatty acid ester derivative is prepared by preparing fatty acyl chloride and then carrying out reaction with lavandulol. The lavandulol fatty acid ester derivative can be applied as a transdermal absorption penetration enhancer to prepare transdermal drug delivery preparations, and can improve transdermal absorption of drugs and increase the cumulative penetration amount of drugs. The compound provided by the invention can be applied to transdermal drug delivery preparations to strengthen the penetration performance of drugs, and also can be used as lavender alcohol fatty acid ester derivative, and its application and preparation method. Lavender fatty acid ester derivatives are prepared by preparing fatty acyl chloride and then reacting with lavender. As a percutaneous absorption and penetration enhancer, the transdermal drug preparation is prepared to improve the absorption of the drug and increase the cumulative permeation of the drug. The compounds described in the present invention can be used in the percutaneous drug delivery, enhance the permeation ability of the drug, and can also be used as a spice to cover up the objectionable odor of preparations.
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Paragraph 0006; 0007; 0044; 0045
(2017/12/27)
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- Eugenol fatty acid ester derivative as well as application and preparation method thereof
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The invention discloses a eugenol fatty acid ester derivative as well as application and a preparation method thereof. Eugenol fatty acid ester is obtained by an esterification reaction of eugenol and straight-chain fatty acid. The method comprises the following steps: firstly, preparing acyl chlorine by reacting fatty acid with thionyl chloride; mixing eugenol with an equal mole amount of pyridine or triethylamine; then, dropwise adding the prepared acyl chloride under the cooling action of an ice bath to generate the eugenol fatty acid ester. Eugenol ester can be applied to external preparations such as patches, cataplasm, ointments, gels and spray agents as a penetration enhancer in order to increase the transdermal absorption amount of medicaments, is a very good percutaneous absorption penetration enhancer, and has a wide application prospect.
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Paragraph 0046-0047
(2017/11/18)
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- Linalool fatty acid ester type derivative as well as application and preparation method thereof
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The invention belongs to the technical field of medicines and relates to a linalool fatty acid ester type derivative as well as application and a preparation method thereof. A fatty acid ester is obtained by carrying out esterification reaction on linalool and straight-chain fatty acid; the method comprises the following steps: firstly, taking fatty acid and sulfoxide chloride to react to prepare acyl chloride; taking the acyl chloride and the linalool to react to prepare ester. The linalool is used as a penetration enhancer and is applied to external preparations including patches, cataplasm, ointment, gel, spray, liniments and the like, so that the transdermal absorption amount of drugs, especially chiral drug enantiomers, is improved; the linalool fatty acid ester type derivative is a very good transdermal absorption penetration enhancer and has a wide application prospect.
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Paragraph 0043; 0044
(2018/01/03)
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- Naphthalenedicarboxamide ethylhexoate type compound and application thereof
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The invention discloses an Naphthalenedicarboxamide ethylhexoate type compound with the structure shown as the formula I and a purpose of the compound as a plant growth regulator. The compound shown as the formula I shown as the accompanying drawing has excellent plant growth regulation functions of promoting rooting, increasing the yield and improving the quality; by the modes of seed treatment or root and stem leaf spraying and the like, the compound can be widely applied to rooting, seeding strengthening, yield increase and quality improvement of plants or crops such as grains, cotton, fruit and vegetables, and has the characteristics of use safety, low cost, obvious effect and the like.
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Paragraph 0023; 0024; 0025
(2016/10/17)
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- Synthesis of novel ethyl 1-ethyl-6-fluoro-7-(fatty amido)-1,4-dihydro-4-oxoquinoline-3-carboxylate derivatives and their biological evaluation
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A series of novel ethyl 1-ethyl-6-fluoro-7-(fatty amido)-1,4-dihydro-4-oxoquinoline-3-carboxylate derivatives were prepared through multistep synthesis. The key step in the synthesis was to obtain the C-7 fatty amide derivative. The azide was selectively formed at C-7 position using sodium azide at 60 °C. Subsequently, the azide was reduced under mild conditions using zinc and ammonium chloride to form the corresponding amine. The synthesized derivatives were further subjected to biological evaluation studies like cytotoxicity against a panel of cancer cell lines such as DU145, A549, SKOV3, MCF7 and normal lung cells, IMR-90 as well as with antimicrobial and antioxidant activities. It was observed that the carboxylated quinolone derivatives with hexanoic (8a), octanoic (8b), lauric (8d) and myristic (8e) moieties exhibited promising cytotoxicity against all the tested cancer cell lines. The results also suggested that hexanoic acid-based fatty amide carboxylated quinolone derivative (8a) exhibited promising activity against both bacterial and fungal strains and significant antibacterial activity was observed against Staphylococcus aureus MTCC 96 (MIC value of 3.9 μg/mL). The compound 8a also showed excellent anti-biofilm activity against Staphylococcus aureus MTCC 96 and Bacillus subtilis MTCC 121 with MIC values of 2.1 and 4.6 μg/mL, respectively.
- Venepally, Vijayendar,Prasad,Poornachandra,Kumar, C. Ganesh,Jala, Ram Chandra Reddy
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supporting information
p. 613 - 617
(2016/01/09)
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- Design and Synthesis of 2-Methyl-7-aminobenzoxazole as Auxiliary in the Palladium(II)-Catalyzed Arylation of a beta-Positioned C(sp3)-H Bond
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A palladium(II)-catalyzed direct arylation of methylene C(sp3)-H bonds by 2-methyl-7-aminobenzoxazole as an effective auxiliary is reported. This process exhibited high beta-site selectivity, broad substrate scope, and compatibility with different functional groups with moderate to high yields up to 89%.
- Luo, Feihua,Yang, Jun,Li, Zhengkai,Xiang, Haifeng,Zhou, Xiangge
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supporting information
p. 887 - 893
(2016/04/05)
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- Optimization of amino acid thioesters as inhibitors of metallo-β-lactamase L1
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The emergence of antibiotic resistance caused by metallo-β-lactamases (MβLs) is a global public health problem. Recently, we found amino acid thioesters to be a highly promising scaffold for inhibitors of the MβL L1. In order to optimize this series of inhibitors, nine new amino acid thioesters were developed by modifying the substituents on the N-terminus of the thioesters and the groups representing the amino acid side chain. Biological activity assays indicate that all of them are very potent inhibitors of L1 with an IC50value range of 20–600?nM, lower than those of most of the previously reported inhibitors of this scaffold. Analysis of structure–activity relationship reveals that big hydrophobic substituents on the N-terminus and a methionine amino acid side chain improves inhibitory activity of the thioesters. All these inhibitors are able to restore antibacterial activity of a β-lactam antibiotic against Escherichia coli BL21(DE3) cells producing L1 to that against E. coli cells lacking a β-lactamase. Docking studies reveal that a large N-terminal hydrophobic group results in a slightly different binding mode than smaller hydrophobic groups at the same position.
- Liu, Xiao-Long,Yang, Ke-Wu,Zhang, Yue-Juan,Ge, Ying,Xiang, Yang,Chang, Ya-Nan,Oelschlaeger, Peter
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p. 4698 - 4701
(2016/09/13)
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- New orally active diphenylmethyl-based ester analogues of dihydroartemisinin: Synthesis and antimalarial assessment against multidrug-resistant Plasmodium yoelii nigeriensis in mice
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A new series of ester analogues of artemisinin 8a–f, incorporating diphenylmethyl as pharmacologically privileged substructure, and 8g–j have been prepared and evaluated for their antimalarial activity against multidrug-resistant (MDR) Plasmodium yoelii nigeriensis in Swiss mice via oral route. These diphenylmethyl-based ester analogues 8a–f were found to be 2–4 folds more active than the antimalarial drugs β-arteether 4 and artesunic acid 5. Ester 8a, the most active compound of the series, provided complete protection to the infected mice at 24?mg/kg?×?4?days as well as 12?mg/kg?×?4?days, respectively. In this model β-arteether provided 100% and 20% protection at 48?mg/kg?×?4?days and 24?mg/kg?×?4?days, respectively.
- Chaudhary, Sandeep,Naikade, Niraj K.,Tiwari, Mohit K.,Yadav, Lalit,Shyamlal, Bharti Rajesh K.,Puri, Sunil K.
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p. 1536 - 1541
(2016/07/27)
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- Α-terpineol fatty acid ester derivatives and use
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The invention belongs to the technical field of medicine and discloses alpha-terpineol aliphatic ester and a preparation with the compound. The alpha-terpineol aliphatic ester is formed by alpha-terpineol and fatty acid after esterification reaction. According to a method, first, fatty acid and thionyl chloride react to prepare acyl chloride, and then acyl chloride and alpha-terpineol react to prepare the alpha-terpineol aliphatic ester. The alpha-terpineol ester can be used as penetration enhancers to be used for external preparations of patching agents, Cataplasm, ointment agents, gel agents and the like, accordingly, the percutaneous absorptive amount of medicine is improved, and the alpha-terpineol aliphatic ester is good percutaneous absorptive penetration enhancers and has wide application prospect.
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Paragraph 0045; 0046
(2017/03/18)
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- Safe, selective, and high-yielding synthesis of acryloyl chloride in a continuous-flow system
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Acid chlorides are an important class of compounds and their high reactivity and instability has prompted us to develop a straightforward procedure for their synthesis with ondemand and on-site synthesis possibilities. The focus of this report is acryloyl chloride, mainly important for the acrylate and polymer industry. A continuous-flow methodology was developed for the fast and selective synthesis of the otherwise highly unstable acryloyl chloride. Three routes were investigated in a microreactor setup and all three can potentially be used for its production. The methodology was further expanded to the synthesis of other unstable acid chlorides by both the thionyl chloride and the oxalyl chloride mediated processes. The most sustainable method was the oxalyl chloride mediated procedure under solvent-free conditions, in which nearequimolar amounts of carboxylic acid and oxalyl chloride were used in the presence of catalytic amounts of DMF at room temperature. Within 1 to 3 min, nearly full conversions into the acid chlorides were achieved.
- Movsisyan, Marine,Heugebaert, Thomas S. A.,Dams, Rudy,Stevens, Christian V.
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p. 1945 - 1952
(2018/08/17)
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- Preparation and properties of a novel form-stable phase change material based on a gelator
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A series of gelators (Gm, m is the length of the alkyl tails, m = 2, 4, 6, 8, 10, 12, 14, 16 and 18) containing 4,4′-diaminodiphenylmethane moieties were synthesized. The chemical structures of Gm were confirmed by 1H NMR and MS. The form-stable phase change materials (FSPCMs) were prepared by introducing Gm into paraffin. The minimum gelation concentration (MGC) and gel-to-sol transition temperature (TGS) properties were tested by the "tube-testing method". It found that Gm (m = 2, 4, 6) was insoluble in paraffin, while the MGC and TGS of Gm (m = 8, 10, 12, 14, 16, 18) increased with the increase of alkyl chain. The structure and morphology of the PCMs were systematically investigated by FT-IR, POM, 1D WXAD and SEM. Experimental results revealed that paraffin was restricted because the gelators could self-assemble into three-dimensional netted structures, leading to form the shape-stable PCMs without leakage even above their melting point. The thermal properties were studied by DSC. The research showed that the G18/paraffin FSPCMs exhibited excellent thermal stability and high heat storage density. The shape stability of G18/paraffin was investigated by rheological measurements, indicating that solid hard gel soft gel liquid was observed with the increase of temperature. This work is useful in the comprehensive academic research and industrial application of PCMs.
- Wu, Dang,Wen, Wen,Chen, Sheng,Zhang, Hailiang
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supporting information
p. 2589 - 2600
(2015/02/19)
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- Rational Development of a Potent 15-Lipoxygenase-1 Inhibitor with in Vitro and ex Vivo Anti-inflammatory Properties
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Human 15-lipoxygenase-1 (h-15-LOX-1) is a mammalian lipoxygenase and plays an important role in several inflammatory lung diseases such as asthma, COPD, and chronic bronchitis. Novel potent inhibitors of h-15-LOX-1 are required to explore the role of this enzyme further and to enable drug discovery efforts. In this study, we applied an approach in which we screened a fragment collection that is focused on a diverse substitution pattern of nitrogen-containing heterocycles such as indoles, quinolones, pyrazoles, and others. We denoted this approach substitution-oriented fragment screening (SOS) because it focuses on the identification of novel substitution patterns rather than on novel scaffolds. This approach enabled the identification of hits with good potency and clear structure-activity relationships (SAR) for h-1-5-LOX-1 inhibition. Molecular modeling enabled the rationalization of the observed SAR and supported structure-based design for further optimization to obtain inhibitor 14d that binds with a Ki of 36 nM to the enzyme. In vitro and ex vivo biological evaluations of our best inhibitor demonstrate a significant increase of interleukin-10 (IL-10) gene expression, which indicates its anti-inflammatory properties.
- Eleftheriadis, Nikolaos,Neochoritis, Constantinos G.,Leus, Niek G. J.,Van Der Wouden, Petra E.,D?mling, Alexander,Dekker, Frank J.
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p. 7850 - 7862
(2015/10/20)
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- Prodrugs of NH-acidic compounds
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The invention provides a method of sustained delivery of a lactam, imide, amide, sulfonamide, carbamate or urea containing parent drug by administering to a patient an effective amount of a prodrug compound of the invention wherein upon administration to the patient, release of the parent drug from the prodrug is sustained release. Prodrug compounds suitable for use in the methods of the invention are labile conjugates of parent drugs that are derivatized through carbonyl linked prodrug moieties. The prodrug compounds of the invention can be used to treat any condition for which the lactam, imide, amide, sulfonamide, carbamate or urea containing parent drug is useful as a treatment.
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Page/Page column 424
(2015/11/16)
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- Synthesis of pyrazoles based on functionalized allenoates
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Regiospecific synthesis of pyrazole-3-carboxylate derivatives by 1,3-dipolar cycloaddition of diazomethane with allenoates in presence of triethylamine is demonstrated. Reaction of allenoates with stearic acid moiety containing diazoketone is explored under ultrasonic conditions. Novel derivatives of pyrazole were achieved in excellent yields.
- Sakhautdinov, Ilshat M.,Gumerov, Aynur M.,Batyrshin, Ilnur R.,Fatykhov, Akhnaf A.,Suponitsky, Kyrill Yu.,Yunusov, Marat S.
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p. 641 - 651
(2014/04/03)
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- Synthesis, characterization and biological evaluation of novel diesters of 4,4'-dihydroxy azoxy benzene with long chain carboxylic acids
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Synthesis of novel symmetrical azoxy diesters have been prepared by the reaction of 4,4'-dihydroxyazoxy benzene with aliphatic acid halides of varying chain lengths. The synthesized compounds have been characterized by spectral and analytical data. These symmetrical azoxy diesters exhibit good antifungal activity against six fungal strains (Mucor species, Aspergillus niger, Aspergillus flavus, Alternaria solani, Fusarium solani and Aspergillus fumigatus) and antitumor activities while no significant antibacterial activity has been observed. These synthesized compounds are also potent free radical scavengers.
- Shehzadi, Sumaira,Siddiqi, Humaira Masood,Qasim, Malik Muhammed,Fawad, Musfirah,Manan, Abdul,Khan, Naeema,Saleem, Samreen,Bashir, Farah,Mirza, Bushra
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p. 462 - 472
(2014/08/05)
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- Cobalt-bisoxazoline-catalyzed asymmetric kumada cross-coupling of racemic α-bromo esters with aryl grignard reagents
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The first cobalt-catalyzed asymmetric Kumada cross-coupling with high enantioselectivity has been developed. The reaction affords a unique strategy for the enantioselective arylation of α-bromo esters catalyzed by a cobalt-bisoxazoline complex. A variety of chiral α-arylalkanoic esters were prepared in excellent enantioselectivity and yield (up to 97% ee and 96% yield). The arylated products were transformed into α-arylcarboxylic acids and primary alcohols without erosion of ee. The new enantioenriched α-arylpropionic esters synthesized herein are potentially useful in the development of nonsteroidal anti-inflammatory drugs. This method was conducted on gram-scale and applied to the synthesis of highly enantioenriched (S)-fenoprofen and (S)-ar-turmerone.
- Mao, Jianyou,Liu, Feipeng,Wang, Min,Wu, Lin,Zheng, Bing,Liu, Shangzhong,Zhong, Jiangchun,Bian, Qinghua,Walsh, Patrick J.
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supporting information
p. 17662 - 17668
(2015/02/02)
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- Novel capsaicin analogues as potential anticancer agents: Synthesis, biological evaluation, and in silico approach
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A novel class of benzo[d][1,3]dioxol-5-ylmethyl alkyl/aryl amide and ester analogues of capsaicin were designed, synthesized, and evaluated for their cytotoxic activity against human and murine cancer cell lines (B16F10, SK-MEL-28, NCI-H1299, NCI-H460, SK-BR-3, and MDA-MB-231) and human lung fibroblasts (MRC-5). Three compounds (5f, 6c, and 6e ) selectively inhibited the growth of aggressive cancer cells in the micromolar (mM) range. Furthermore, an exploratory data analysis pointed at the topological and electronic molecular properties as responsible for the discrimination process regarding the set of investigated compounds. The findings suggest that the applied designing strategy, besides providing more potent analogues, indicates the aryl amides and esters as well as the alkyl esters as interesting scaffolds to design and develop novel anticancer agents. 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
- Damio, Mariana C. F. C. B.,Pasqualoto, Kerly F. M.,Ferreira, Adilson K.,Teixeira, Sarah F.,Azevedo, Ricardo A.,Barbuto, Jos A. M.,Palace-Berl, Fanny,Franchi-Junior, Gilberto C.,Nowill, Alexre E.,Tavares, Maurcio T.,Parise-Filho, Roberto
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p. 885 - 895
(2015/02/19)
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- Chemical and microbial semi-synthesis of tetrahydroprotoberberines as inhibitors on tissue factor procoagulant activity
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To discover new inhibitors on tissue factor procoagulant activity, 21 tetrahydroprotoberberines were screened on the model of human THP-1 cells stimulated by lipopolysaccharide. Among these tetrahydroprotoberberines, several unique compounds were synthesized through microbial transformation: compound 6 (l-corydalmine) was obtained through regio-selective demethylation by Streptomyces griseus ATCC 13273, whereas compounds 4a, 4b, 5h, and 5i were microbial glycosylation products by Gliocladium deliquescens NRRL1086. The bioassay results showed that compounds 3 (tetrahydroberberine), 10 (tetrahydroberberrubine), and 5f (cinnamyl ester of 5) and 5i (glycosidic product of 5), exhibited the most potential effects, with IC50 values of 8.35, 6.75, 3.75, and 8.79 nM, respectively. The preliminary structure and activity relationship analysis revealed that the 2,3-methylenedioxy group of the A ring was essential for the strong inhibitory effects, and the R configuration of the chiral center C-14 showed higher activity than S-form products. The formation of fatty acid or aromatic acid esters of compound 5, except the cinnamyl esters, would weaken its effects. It is also interesting to note that the glycosylation of tetrahydroprotoberberines will maintain and even enhance the inhibitory effects. Because of the importance of glycochemistry in new drug discovery and development, this deserves further exploration and may provide some guide on the semi-synthesis of tetrahydroprotoberberines as tissue factor pathway inhibitors. Our findings also provide some potential leading compounds for tissue factor-related diseases, such as cancer and cardiovascular diseases.
- Ge, Hai-Xia,Zhang, Jian,Chen, Ling,Kou, Jun-Ping,Yu, Bo-Yang
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- Discovery of a series of thiazole derivatives as novel inhibitors of metastatic cancer cell migration and invasion
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Effective inhibitors of cancer cell migration and invasion can potentially lead to clinical applications as a therapy to block tumor metastasis, the primary cause of death in cancer patients. To this end, we have designed and synthesized a series of thiazole derivatives that showed potent efficacy against cell migration and invasion in metastatic cancer cells. The most effective compound, 5k, was found to have an IC50 value of 176 nM in the dose-dependent transwell migration assays in MDA-MB-231cells. At a dose of 10 μM, 5k also blocked about 80% of migration in HeLa and A549 cells and 60% of invasion of MDA-MB-231 cells. Importantly, the majority of the derivatives exhibited no apparent cytotoxicity in the clonogenic assays. The low to negligible inhibition of cell proliferation is a desirable property of these antimigration derivatives because they hold promise of low toxicity to healthy cells as potential therapeutic agents. Mechanistic studies analyzing the actin cytoskeleton by microscopy demonstrate that compound 5k substantially reduced cellular f-actin and prevented localization of fascin to actin-rich membrane protrusions. These results suggest that the antimigration activity may result from impaired actin structures in protrusions that are necessary to drive migration.
- Zheng, Shilong,Zhong, Qiu,Jiang, Quan,Mottamal, Madhusoodanan,Zhang, Qiang,Zhu, Naijue,Burow, Matthew E.,Worthylake, Rebecca A.,Wang, Guangdi
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supporting information
p. 191 - 196
(2013/03/28)
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- A facile route for synthesis of (±)-dinoprost, (±)-carboprost and its analogs
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A general synthetic approach was developed for (±)-dinoprost (1), (±)-carboprost (2) and their analogs (3-5) through a key intermediate (6). Compound 6 can be converted into the target compounds in two or three steps. Diastereomeric separation was accomplished easily for obtaining (±) dinoprost. Separation of diastereomers was difficult for (±) carboprost and their analogs. Key intermediate 6 was obtained, in turn, from (±)-corey lactone.
- Shankar,Mohan, H. Rama,Prasad, U. Viplava,Krishna, M. Hari,Rao, P. Mareswar,Lakshmikumar,Subbaraju, Gottumukkala V.
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p. 913 - 920
(2013/06/04)
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- Bioresponsive deciduous-charge amphiphiles for liposomal delivery of DNA and siRNA
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Purpose: Biolabile cationic lipids were developed for efficient intracellular delivery of DNA and siRNA. Methods: The compounds have been designed starting from the membrane lipid DOPC in a way they may loose their cationic charge when exposed to an acidic and/or enzymatic stimulus, such as those met during the journey of a lipoplex in biological media. Results: They demonstrated remarkable efficiency to deliver DNA in various cell lines (BHK-21, Calu-3, NCI-H292, and A549), with no significant cytotoxicity. Furthermore, two of the compounds (carbonate-based DOPC derivatives) revealed able to deliver small interfering RNA in U87Luc and A549Luc cancer cells and to mediate a selective 70-80% knockdown of the stably transfected luciferase gene. Conclusions: The results show that the described bioresponsive cationic lipids have high DNA and siARN delivery activity which is encouraging in view of delivering a therapeutic nucleic acid to pulmonary tissues in vivo.
- Pierrat, Philippe,Kereselidze, Dimitri,Wehrung, Patrick,Zuber, Guy,Pons, Francoise,Lebeau, Luc
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p. 1362 - 1379
(2013/06/27)
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- Design and synthesis of conformationally restricted capsaicin analogues based in the 1, 3, 4-thiadiazoleheterocycle reveal a novel family of transient receptor potential vanilloid 1 (TRPV1) antagonists
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4-hydroxy-3-methoxybenzaldehyde was used as starting material to obtain a number of 1, 3, 4-thiadiazole alkylamide derivatives. The pharmacological properties of these conformationally restricted capsaicin analogues were evaluated on HEK-293T cells transiently expressing TRPV1 receptor. By means of a highthroughput calcium imaging assay we find that 1, 3, 4-thiadiazoles (compounds 8-15) act as potent antagonists of the capsaicin receptor, inhibiting both, the capsaicin- and temperature-dependent activation. Docking studies suggested a different binding orientation on the vanilloid binding site when compared with capsaicin analogues, such as 5-iodononivamide. Overall, our studies suggest that 1, 3, 4-thiadiazoles interact with capsaicin 's binding region of the receptor, although using a different set of interactions within the vanilloid binding pocket.
- Rebolledo, Carolyne Lespay,Sotelo-Hitschfeld, Pamela,Brauchi, Sebastián,Olavarría, Miguel Zárraga
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p. 193 - 203
(2013/10/01)
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