- Novel amide derivatives of 3-phenylglutaric acid as potent soluble epoxide hydrolase inhibitors
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Abstract: Soluble epoxide hydrolase (sEH) enzyme plays an important role in the metabolism of endogenous chemical mediators, epoxyeicosatrienoic acids, which are involved in the regulation of blood pressure and inflammation. According to the pharmacophoric model suggested for sEH inhibitors, some new amide-based derivatives of 3-phenylglutaric acid were designed, synthesized and biologically evaluated. Docking study illustrated that the amide group as a primary pharmacophore had a suitable distance from the three amino acids of Tyr383, Tyr466 and Asp335 for effective hydrogen binding. Most of the compounds showed moderate to high sEH inhibitory activities in in vitro test in comparison with 12-(3-Adamantan-1-yl-ureido)-dodecanoic acid, as a potent urea-based sEH inhibitor. Compound 6o with phenethyl in R position exhibited the highest activity with IC50 value of 0.5?nM. Graphic abstract: In this study, some new amide-based derivatives of 3-phenylglutaric acid were designed, synthesized and biologically evaluated. Most of the synthesized compounds provided nanomolar range inhibition against sEH enzyme. The best observed IC50 value was 0.5?nM. Incorporating a carboxylic moiety into these structures by forming carboxylate salts would increase the solubility and improving physicochemical properties.[Figure not available: see fulltext.]
- Rezaee, Elham,Amrolah, Somayeh Minaei,Nazari, Maryam,Tabatabai, Sayyed Abbas
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- Hydrogen-Bonding Catalyzed Ring-Closing C?O/C?O Metathesis of Aliphatic Ethers over Ionic Liquid under Metal-Free Conditions
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O-heterocycles have wide applications, and their efficient and green synthesis is very interesting. Herein, we report hydrogen-bonding catalyzed ring-closing metathesis of aliphatic ethers to O-heterocycles over ionic liquid (IL) catalyst under metal- and solvent-free conditions. The IL 1-butylsulfonate-3-methylimidazolium trifluoromethanesulfonate ([SO3H-BMIm][OTf]) is discovered to show outstanding performance, better than the reported catalysts. An interface effect plays an important role in mediating the reaction rate due to the immiscibility between the products and the IL catalyst, and the products can be spontaneously separated. NMR analysis and DFT calculation suggest that a pair of cation and anion of [SO3H-BMIm][OTf] could form three strong H-bonds with an ether molecule, which catalyze the ether transformation via a cyclic oxonium intermediate. A series of O-heterocycles including tetrahydrofurans, tetrahydropyrans, morpholines and dioxane can be obtained from their corresponding ethers in excellent yields (e.g., >99 %). This work opens an efficient and metal-free way to produce O-heterocycles from aliphatic ethers.
- Wang, Huan,Zhao, Yanfei,Zhang, Fengtao,Wu, Yunyan,Li, Ruipeng,Xiang, Junfeng,Wang, Zhenpeng,Han, Buxing,Liu, Zhimin
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supporting information
p. 11850 - 11855
(2020/05/16)
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- A phosphine-free iron complex-catalyzed synthesis of cycloalkanes: Via the borrowing hydrogen strategy
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Herein we report a diaminocyclopentadienone iron tricarbonyl complex catalyzed synthesis of substituted cyclopentane, cyclohexane and cycloheptane compounds using the borrowing hydrogen strategy in the presence of various substituted primary and secondary 1,n diols as alkylating reagents. Deuterium labeling experiments confirm that the diols were the hydride source in this cascade process. This journal is
- Bettoni, Léo,Gaillard, Sylvain,Renaud, Jean-Luc
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supporting information
p. 12909 - 12912
(2020/11/07)
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- Synthesis and biological evaluation of pentanedioic acid derivatives as farnesyltransferase inhibitors
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Structure-based virtual screening of a commercial library identified pentanedioic acid derivatives (6 and 13b) as a kind of novel scaffold farnesyltransferase inhibitors (FTIs). Chemical modifications of the lead compounds, biological assays and analysis of the structure-activity relationships (SAR) were conducted to discover more potent FTIs. Some of them displayed excellent inhibition against FTase, and among them, the most active compound 13n with an IC50 value of 0.0029 μM and SAR analysis might be helpful to the discovery of more potent FTIs. This journal is
- Yang, Liuqing,Liu, Wei,Mei, Hanbing,Zhang, Yuan,Yu, Xiaojuan,Xu, Yufang,Li, Honglin,Huang, Jin,Zhao, Zhenjiang
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p. 671 - 676
(2015/04/27)
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- ALLOSTERIC PROTEIN KINASE MODULATORS
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The invention provides specific small molecule compounds that allosterically regulate the activity or modulate protein-protein interactions of AGC protein kinases and the Aurora family of protein kinases, methods for their production, pharmaceutical compositions comprising same, and their use for preparing medicaments for the treatment and prevention of diseases related to abnormal activities of AGC protein kinases or of protein kinases of the Aurora family.
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Page/Page column 25
(2012/03/10)
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- ALLOSTERIC PROTEIN KINASE MODULATORS
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The invention provides specific small molecule compounds that allosterically regulate the activity or modulate protein-protein interactions of AGC protein kinases and the Aurora family of protein kinases, methods for their production, pharmaceutical compositions comprising same, and their use for preparing medicaments for the treatment and prevention of diseases related to abnormal activities of AGC protein kinases or of protein kinases of the Aurora family.
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Page/Page column 53
(2010/04/30)
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- Tandem Knoevenagel-Michael addition of aryl sulfonimines with diethyl malonate for synthesis of arylidene dimalonates
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(Chemical Equation Presented) A highly efficient, one-flask tandem Knoevenagel-Michael addition reaction of sulfonimines with diethyl malonate in the presence of a catalytic amount of base affords the corresponding arylidene dimalonates in good to excellent yields.
- Fan, Renhua,Wang, Weizi,Pu, Dongming,Wu, Jie
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p. 5905 - 5907
(2008/02/10)
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- Three multicomponent reactions of 3,5-dimethyl-4-nitroisoxazole
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The title compound is used to prepare 3-arylglutaric acids, bis-isoxazoles and bis-pyrazoles from commercially available materials. The methodologies described have afforded important synthetic intermediates in high yields and without the use of chromatography.
- Adamo, Mauro F.A.,Konda, Vivekananda R.,Donati, Donato,Sarti-Fantoni, Piero,Torroba, Tomas
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p. 9741 - 9745
(2008/02/12)
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- Enzymatic desymmetrization of 3-arylglutaric acid anhydrides
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Optically active (R)- and (S)-3-arylglutaric acid monoesters 3 were synthesized in quantitative yields and good stereoselectivities by lipase-catalyzed desymmetrization of the corresponding 3-arylglutaric anhydrides 2 with alcohols. It was observed that the stereochemical outcome of the reaction was influenced by the substituents present on the aromatic ring. The influence of the enzyme, alcohol, and solvent was systematically examined. Absolute configurations of the monoesters 3 were assigned by chemical correlation to corresponding lactones 4.
- Fryszkowska, Anna,Komar, Marta,Koszelewski, Dominik,Ostaszewski, Ryszard
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p. 2475 - 2485
(2007/10/03)
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- Synthesis, Screening, and Molecular Modeling of New Potent and Selective Antagonists at the α1d Adrenergic Receptor
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In the present study, more than 75 compounds structurally related to BMY 7378 have been designed and synthesized. Structural variations of each part of the reference molecule have been introduced, obtaining highly selective ligands for the α1d adrenergic receptor. The molecular determinants for selectivity at this receptor are essentially held by the phenyl substituent in the phenylpiperazine moiety. The integration of an extensive SAR analysis with docking simulations using the rhodopsin-based models of the three α1-AR subtypes and of the 5-HT1A receptor provides significant insights into the characterization of the receptor binding sites as well as into the molecular determinants of ligand selectivity at the α1d-AR and the 5-HT1A receptors. The results of multiple copies simultaneous search (MCSS) on the substituted phenylpiperazines together with those of manual docking of compounds BMY 7378 and 69 into the putative binding sites of the α1a-AR, α1b-AR, α1d-AR, and the 5-HT1A receptors suggest that the phenylpiperazine moiety would dock into a site formed by amino acids in helices 3, 4, 5, 6 and extracellular loop 2 (E2), whereas the spirocyclic ring of the ligand docks into a site formed by amino acids of helices 1, 2, 3, and 7. This docking mode is consistent with the SAR data produced in this work. Furthermore, the binding site of the imide moiety does not allow for the simultaneous involvement of the two carbonyl oxygen atoms in H-bonding interactions, consistent with the SAR data, in particular with the results obtained with the lactam derivative 128. The results of docking simulations also suggest that the second and third extracellular loops may act as selectivity filters for the substituted phenylpiperazines. The most potent and selective compounds for α1d adrenergic receptor, i.e., 69 (Rec 26D/038) and 128 (Rec 26D/073), are characterized by the presence of the 2,5-dichlorophenylpiperazine moiety.
- Leonardi, Amedeo,Barlocco, Daniela,Montesano, Federica,Cignarella, Giorgio,Motta, Gianni,Testa, Rodolfo,Poggesi, Elena,Seeber, Michele,De Benedetti, Pier G.,Fanelli, Francesca
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p. 1900 - 1918
(2007/10/03)
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- Folding strain stereocontrol in cyclohexane ring formation by means of an intramolecular ester enolate alkylation reaction
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Diastereoselectivity in the cyclization of ethyl 7-bromo-2-methylheptanoates with an additional substituent at various positions in the chain, by LDA treatment, was investigated in connection with the concept of folding strain stereocontrol. Cyclization of 3-, 4-, and 6-methyl-substituted substrates revealed high selectivity, which demonstrates the prevalence of folding strain stereocontrol and the usefulness of this approach for stereoselective ring construction. In particular, reactions of the latter two substrates resulted in the stereodivergent preparation of diastereomeric 1,3-dimethylcyclohexanecarboxylates. In the case of the 5-methyl-substituted substrate, the selectivity of ring closure was only moderate. 1H and 13C NMR spectroscopic data were useful for determining the conformation of 1-methylcyclohexanecarboxylate derivatives. The origin of the diastereoselectivity was examined through the qualitative comparison of the strain in the diastereomeric folding in the transition state. Various factors that might affect stereoselectivity were examined in the cyclization of 5-substituted substrates to better understand this concept. As predicted, the selectivity increased as the substituent became bulkier: Ph Me ≈ Et ≤ i-Pr t-Bu. The effects of other factors - solvent, base counter cation, and leaving group - on selectivity agree with results predicted from the reactivity-selectivity relationship.
- Tokoroyama, Takashi,Kusaka, Hisashi
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p. 2487 - 2502
(2007/10/03)
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- 1,2,3,4-TETRAAUBSTITUTED ISOQUINOLINE ACETIC ACIDS
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Differentially tetrasubstituted isoquinolines are now conveniently prepared by rearrengement of the readily obtainable indanones.
- Schnur, Rodney C.,Howard, Harry R
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p. 2843 - 2846
(2007/10/02)
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