- Synthesis, biological evaluation, and docking studies of new pyrazole-based thiourea and sulfonamide derivatives as inhibitors of nucleotide pyrophosphatase/phosphodiesterase
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A series of six compounds (1a-f) possessing pyridine-pyrazole-benzenethiourea or pyridine-pyrazole-benzenesulfonamide scaffold were synthesized. The target compounds were screened to evaluate their inhibitory effect on human nucleotide pyrophosphatase/phosphodiesterase 1 and ?3 (ENPP1 and ENPP3) isoenzymes. Compounds 1c-e were the most potent inhibitors of ENPP1 with sub-micromolar IC50 values (0.69, 0.18, and 0.40 μM, respectively. Moreover, compound 1b was the most potent inhibitor of ENPP3 (IC50 = 0.21 μM). They were much more potent than the reference standard inhibitor, suramin (IC50 values against ENPP1 and ?3 were 7.77 and 0.89 μM, respectively). Furthermore, all the six compounds were investigated for cytotoxic effect against cancerous cell lines (HeLa, MCF-7, and 1321N1) and normal cell line (BHK-21). Compound 1e was active against all the three cancer cell lines, however, showed preferential cytotoxicity against MCF-7 (IC50 = 16.05 μM), which is comparable to the potency of cisplatin. All the tested compounds exhibited low or negligible cytotoxic effect against the normal cells. They have the merit of superior selectivity towards cancer cells than normal cells compared to cisplatin. The relative selectivity and potency of the inhibitors was justified by molecular docking studies. All the docked structures showed considerable binding interactions with amino acids residues of active sites of ENPP isoenzymes.
- Anbar, Hanan S.,El-Gamal, Mohammed I.,Iqbal, Jamshed,Oh, Chang-Hyun,Pelletier, Julie,Sbenati, Rawan M.,Ullah, Saif,Zaib, Sumera,Zaraei, Seyed-Omar,Sévigny, Jean
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- Discovery of a potent p38α/MAPK14 kinase inhibitor: Synthesis, in vitro/in vivo biological evaluation, and docking studies
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This article reports the synthesis of new triarylpyrazole derivatives possessing urea or amide linker, and their biological activities at molecular, cellular, and in vivo levels. Compound 2b was the most potent inhibitor of p38α/MAPK14 kinase (IC50 = 22 nM) among this series. Molecular docking studies were conducted to understand the kinase inhibitory variations and the basis of selectivity. Compound 2b was able to inhibit p38α/MAPK14 kinase inside HEK293 cells in nanoBRET cellular kinase assay with EC50 value of 0.55 μM, comparable to the potency of dasatinib. Compound 2b inhibited TNF-α production in lipopolysaccharide-induced THP-1 cells with IC50 value of 58 nM. In addition, compound 2b showed low potency against hERG. It is 622.38 times less potent than E?4031 against hERG, so the risk of cardiotoxicity of the compound is very minimal. Compound 2b showed also high plasma stability in vitro in human and rat plasmas. The in vivo PK profile of compound 2b is acceptable, and its antiinflammatory effect was comparable to diclofenac with no ulcerogenic side effect on stomach.
- El-Gamal, Mohammed I.,Anbar, Hanan S.,Tarazi, Hamadeh,Oh, Chang-Hyun
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- In situ Generation of Hypervalent Iodine Reagents for the Electrophilic Chlorination of Arenes
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Efficient metal-free methods for the electrophilic chlorination of arenes using PIFA and simple chlorine sources are reported. The in situ formation of PhI(Cl)OCOCF3 from PIFA and KCl is proposed, which resulted in a chlorinating species for moderately activated arenes. Moreover, the in situ formation of PhICl2 from PIFA and TMSCl resulted in an excellent approach for the chlorination of a great variety of arenes (20 examples) in high yields, even when working on a multigram scale.
- Granados, Albert,Jia, Zhiyu,del Olmo, Marc,Vallribera, Adelina
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p. 2812 - 2818
(2019/04/08)
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- A biocatalytic method for the chemoselective aerobic oxidation of aldehydes to carboxylic acids
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Herein, we present a study on the oxidation of aldehydes to carboxylic acids using three recombinant aldehyde dehydrogenases (ALDHs). The ALDHs were used in purified form with a nicotinamide oxidase (NOx), which recycles the catalytic NAD+ at the expense of dioxygen (air at atmospheric pressure). The reaction was studied also with lyophilised whole cell as well as resting cell biocatalysts for more convenient practical application. The optimised biocatalytic oxidation runs in phosphate buffer at pH 8.5 and at 40 °C. From a set of sixty-one aliphatic, aryl-Aliphatic, benzylic, hetero-Aromatic and bicyclic aldehydes, fifty were converted with elevated yield (up to >99%). The exceptions were a few ortho-substituted benzaldehydes, bicyclic heteroaromatic aldehydes and 2-phenylpropanal. In all cases, the expected carboxylic acid was shown to be the only product (>99% chemoselectivity). Other oxidisable functionalities within the same molecule (e.g. hydroxyl, alkene, and heteroaromatic nitrogen or sulphur atoms) remained untouched. The reaction was scaled for the oxidation of 5-(hydroxymethyl)furfural (2 g), a bio-based starting material, to afford 5-(hydroxymethyl)furoic acid in 61% isolated yield. The new biocatalytic method avoids the use of toxic or unsafe oxidants, strong acids or bases, or undesired solvents. It shows applicability across a wide range of substrates, and retains perfect chemoselectivity. Alternative oxidisable groups were not converted, and other classical side-reactions (e.g. halogenation of unsaturated functionalities, Dakin-Type oxidation) did not occur. In comparison to other established enzymatic methods such as the use of oxidases (where the concomitant oxidation of alcohols and aldehydes is common), ALDHs offer greatly improved selectivity.
- Knaus, Tanja,Tseliou, Vasilis,Humphreys, Luke D.,Scrutton, Nigel S.,Mutti, Francesco G.
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supporting information
p. 3931 - 3943
(2018/09/11)
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- Iron(III)-Catalyzed Chlorination of Activated Arenes
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A general and regioselective method for the chlorination of activated arenes has been developed. The transformation uses iron(III) triflimide as a powerful Lewis acid for the activation of N-chlorosuccinimide and the subsequent chlorination of a wide range of anisole, aniline, acetanilide, and phenol derivatives. The reaction was utilized for the late-stage mono- and dichlorination of a range of target compounds such as the natural product nitrofungin, the antibacterial agent chloroxylenol, and the herbicide chloroxynil. The facile nature of this transformation was demonstrated with the development of one-pot, tandem, iron-catalyzed dihalogenation processes allowing highly regioselective formation of different carbon-halogen bonds. The synthetic utility of the resulting dihalogenated aryl compounds as building blocks was established with the synthesis of natural products and pharmaceutically relevant targets.
- Mostafa, Mohamed A. B.,Bowley, Rosalind M.,Racys, Daugirdas T.,Henry, Martyn C.,Sutherland, Andrew
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p. 7529 - 7537
(2017/07/26)
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- Antiproliferative diarylpyrazole derivatives as dual inhibitors of the ERK pathway and COX-2
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A series of 3,4-diarylpyrazole-1-carboxamide derivatives was designed and synthesized. A selected group of the target compounds was tested for in vitro antiproliferative activities over a panel of 60 cancer cell lines at the National Cancer Institute (NCI, Bethesda, MD, USA) at a single-dose concentration of 10 μm, and the four most active compounds 9a, 9l, 9n, and 10o were further tested in a five-dose testing mode to determine their IC50 values over the 60 cell lines. In addition, a selected group of target compounds were tested for inhibitory effect over cyclooxygenase isozymes. Compounds 9a, 9l, 9n, and 10o were also tested for MEK and ERK kinase inhibitory activity using Western blot assay. Compound 10o was selective toward melanoma cell line subpanel, and its antiproliferative activity may be attributed to selective cyclooxygenase-2 inhibition and ERK pathway inhibition.
- El-Gamal, Mohammed I.,Choi, Hong Seok,Yoo, Kyung Ho,Baek, Daejin,Oh, Chang-Hyun
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p. 336 - 347
(2013/09/12)
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- Design, synthesis, and preliminary cytotoxicity evaluation of new diarylureas and diarylamides possessing 1,3,4-triarylpyrazole scaffold
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A series of new diarylureas and diarylamides possessing 1,3,4-triarylpyrazole scaffold was synthesized and their in vitro antiproliferative activities against A375P human melanoma cell line and NCI-60 cell line panel were tested. Compounds 9, 11, 12, 14, and 17-21 showed superior potency against A375P to Sorafenib. Over the NCI-60 cancer cell line panel, compound 14 possessing a methoxy group, amide linker, and 4-chloro-3- (trifluoromethyl)phenyl terminal ring showed the highest potency and broad-spectrum anticancer activity. Compound 13 showed high selectivity towards leukemia subpanel over other cancer types.
- Choi, Won-Kyoung,El-Gamal, Mohammed I.,Choi, Hong Seok,Hong, Jun Hee,Baek, Daejin,Choi, Kihang,Oh, Chang-Hyun
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p. 2991 - 2998
(2012/10/30)
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- Design and synthesis of 3-(3-chloro-4-substituted phenyl)-4-(pyridin-4-yl)- 1Hpyrazole- 1-carboxamide derivatives and their antiproliferative activity against melanoma cell line
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Design and synthesis of new 3,4-diarylpyrazole-1-carboxamide derivatives are described. Their antiproliferative activity against A375 human melanoma cell line was tested and the effect of substituents on the diarylpyrazole scaffold was investigated. The pharmacological results indicated that most of the synthesized compounds showed moderate activity against A375, compared with Sorafenib. On the other hand, compounds Ia, Ie, IIb, and IIh were more potent than Sorafenib. In addition, compound IIa was equipotent to Sorafenib. Among all of these derivatives, compound IIb which has diethylamino and phenolic moieties showed the most potent antiproliferative activity against A375 human melanoma cell line. Virtual screening was carried out through docking of the most potent compound IIb into the domain of V600E-b-Raf and the binding mode was studied. Copyright
- El-Gamal, Mohammed I.,Oh, Chang-Hyun
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experimental part
p. 821 - 828
(2012/01/05)
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- Kinetic and chemical characterization of aldehyde oxidation by fungal aryl-alcohol oxidase
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Fungal AAO (aryl-alcohol oxidase) provides H2O2 for lignin biodegradation. AAO is active on benzyl alcohols that are oxidized to aldehydes. However, during oxidation of some alcohols, AAO forms more than a stoichiometric number of H2O2 molecules with respect to the amount of aldehyde detected due to a double reaction that involves aryl-aldehyde oxidase activity. The latter reactionwas investigated using different benzylic aldehydes, whose oxidation to acids was demonstrated by GC-MS. The steady- and presteady state kinetic constants, together with the chromatographic results, revealed that the presence of substrate electron-withdrawing or electron-donating substituents had a strong influence on activity; the highest activity was with p-nitrobenzaldehyde and halogenated aldehydes and the lowest with methoxylated aldehydes. Moreover, activity was correlated to the aldehyde hydration rates estimated by 1H-NMR. These findings, together with the absence in the AAO active site of a residue able to drive oxidation via an aldehyde thiohemiacetal, suggested that oxidation mainly proceeds via the gem-diol species. The reaction mechanism (with a solvent isotope effect, 2H2O kred, of approx. 1.5)would be analogous to that described for alcohols, the reductive half-reaction involving concerted hydride transfer from the a-carbon and proton abstraction from one of the gem-diol hydroxy groups by a base. The existence of two steps of opposite polar requirements (hydration and hydride transfer) explains some aspects of aldehyde oxidation by AAO. Site-directed mutagenesis identified two histidine residues strongly involved in gem-diol oxidation and, unexpectedly, suggested that an active-site tyrosine residue could facilitate the oxidation of some aldehydes that show no detectable hydration. Double alcohol and aldehyde oxidase activities of AAO would contribute to H2O2 supply by the enzyme. The Authors Journal compilation
- Ferreira, Patricia,Hernandez-Ortega, Aitor,Herguedas, Beatriz,Rencoret, Jorge,Gutierrez, Ana,Martinez, Maria Jesus,Jimenez-Barbero, Jesus,Medina, Milagros,Martinez, Angel T.
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scheme or table
p. 585 - 593
(2011/02/24)
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- S1P RECEPTORS MODULATORS
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The invention relates to novel compounds that have S1P receptor modulating activity and, preferably, apoptotic activity and/or anti proliferative activity against cancer cells and other cell types. Further, the invention relates to a pharmaceutical comprising at least one compound of the invention for the treatment of diseases and/or conditions caused by or associated with inappropriate S1P receptor modulating activity or expression, for example, cancer. A further aspect of the invention relates to the use of a pharmaceutical comprising at least one compound of the invention for the manufacture of a medicament for the treatment of diseases and/or conditions caused by or associated with inappropriate S1P receptor modulating activity or expression such as cancer.
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Page/Page column 51; 52
(2010/04/30)
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- Chlorometabolite production by the ecologically important white rot fungus Bjerkandera adusta
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Two strains of the basidiomycete, Bjerkandera adusta (DAOM 215869 and BOS55) produce in static liquid culture, phenyl, veratryl, anisyl and chloroanisyl metabolites (CAM's) (alcohols, acids and aldehydes) as well as a series of compounds not previously known to be produced by Bjerkandera species: 1-phenyl, 1-anisyl, 1-(3-chloro-4-methoxy) and 1-(3,5-dichloro-4-methoxy) propan-1,2-diols, predominantly as erythro diastereomers with 1R, 2S absolute configurations. 1-Anisyl-propan-1,2-diol and 1-(3,5-dichloro-4-methoxy)-propan-1,2-diol are new metabolites for which the names Bjerkanderol A and B, respectively, are proposed. Experiments with static liquid cultures supplied with 13C66- and 13C9-L-phenylalanine showed that all identified aromatic compounds (with the exception of phenol) can be derived from L-phenylalanine. For the aryl propane diols, the 13C label appeared only in the phenyl ring and the benzylic carbon, suggesting a stereoselective re-synthesis from a C7 and a C2-unit, likely aromatic aldehyde and decarboxylated pyruvate, respectively. Other compounds newly discovered to be derived from phenylalanine by this white rot fungus include phenylacetaldehyde and phenylpyruvic, phenylacetic, phenyllactic, mandelic and phenyl glyoxylic (benzoyl formic) acids. For both strains, cultures supplied with Na37Cl showed incorporation of 37Cl in all identified chlorometabolites. Veratryl alcohol and the CAM alcohols, which occur in both strains and can be derived from L-phenylalanine (all 13C-labelled), have reported important physiological functions in this white rot fungus. Possible mechanisms for their formation through the newly discovered compounds are discussed.
- Silk,Aubry,Lonergan,Macaulay
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p. 1603 - 1616
(2007/10/03)
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- Evaluation of isomeric 4-(chlorohydroxyphenyl)-1,2,3,4-tetrahydroisoquinolines as dopamine D-1 antagonists
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The isomeric 4-(3-chloro-4-hydroxyphenyl)- and 4-(4-chloro-3-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinolines, the N-methyl derivative of the 4-(4-chloro-3-hydroxyphenyl)isomer, and 4-(3-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline were synthesized and evaluated for dopamine D-1 antagonist activity. The 4-(3-chloro-4-hydroxyphenyl) and the 4-(3-hydroxyphenyl) isomer possessed similar potencies as D-1 antagonists. Introduction of the N-methyl group enhanced potency about twofold. The 'pharmacophore' for selective dopamine D-1 antagonist activity appears to be a tertiary 2-(3-hydroxyphenyl)-2-phenethylamine.
- Riggs,Nichols,Foreman,Truex
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p. 1887 - 1891
(2007/10/02)
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- Steric Enhancement of Resonance-Evidence from Kinetic Study on some Acetophenones
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The kinetics of oxidation of some mono-, di- and tri-substituted acetophenones by alkaline hexacyanoferrate(III) in 50percent (v/v) methanol-water mixture at constant ionic strength and at 20, 30 and 40 deg have been studied spectrophotometrically and the rate constants determined by least-squares analysis.Electron-withdrawing groups in the ring facilitate the oxidation of the acetyl function while electron-releasing groups retard the rate.The rate constant values for the oxidation of 3-substituted-4-alkoxy-acetophenones are computed based on the principle of additivity of group effects.The observed rate constants are significantly lower than the calculated values.This is attributed to the phenomenon of steric enhancement of resonance (SER). 3,5-Disubstituted-4-methoxyacetophenones have higher observed rate constant values than the calculated ones.The steric inhibition of resonance (SIR) operates in these systems.In the case of 3-halogeno-4-methoxyacetophenones, the importance of SER increases with increase in the bulkiness of the 3-substituents.The difference between the calculated and observed multiple substituent constants of 3-substituted-4-methoxyacetophenones also lends support for SER.
- Pillay, M. Krishna,Palanivelu, S.
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p. 1055 - 1059
(2007/10/02)
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- Design and synthesis of a hapten for the radioimmunoassay of bupropion
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The synthesis of a hapten useful in the radioimmunoassay of bupropion is described. Since bupropion has no functional group that can be easily derivatized, a hydroxypropyl group was incorporated into the molecule. Studies in cross-reactivity with possible metabolites required the synthesis of the 4'-hydroxy analogue of bupropion. This synthesis is also described.
- Mehta,Musso
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p. 410 - 412
(2007/10/02)
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- Pharmaceutical compositions and methods of producing coronary vasodilation
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Pharmaceutical compositions and methods of producing coronary vasodilation by administering substituted benzofurans, for example 2-n-butyl-3-[4' -(2-hydroxy-3-isopropylamino)propoxybenzoyl] benzofuran.
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