- Structure-based design, docking and binding free energy calculations of a366 derivatives as spindlin1 inhibitors
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The chromatin reader protein Spindlin1 plays an important role in epigenetic regulation, through which it has been linked to several types of malignant tumors. In the current work, we report on the development of novel analogs of the previously published lead inhibitor A366. In an effort to improve the activity and explore the structure–activity relationship (SAR), a series of 21 derivatives was synthesized, tested in vitro, and investigated by means of molecular modeling tools. Docking studies and molecular dynamics (MD) simulations were performed to analyze and rationalize the structural differences responsible for the Spindlin1 activity. The analysis of MD simulations shed light on the important interactions. Our study highlighted the main structural features that are required for Spindlin1 inhibitory activity, which include a positively charged pyrrolidine moiety embedded into the aromatic cage connected via a propyloxy linker to the 2-aminoindole core. Of the latter, the amidine group anchor the compounds into the pocket through salt bridge interactions with Asp184. Different protocols were tested to identify a fast in silico method that could help to discriminate between active and inactive compounds within the A366 series. Rescoring the docking poses with MM-GBSA calculations was successful in this regard. Because A366 is known to be a G9a inhibitor, the most active developed Spindlin1 inhibitors were also tested over G9a and GLP to verify the selectivity profile of the A366 analogs. This resulted in the discovery of diverse selective compounds, among which 1s and 1t showed Spindlin1 activity in the nanomolar range and selectivity over G9a and GLP. Finally, future design hypotheses were suggested based on our findings.
- Luise, Chiara,Robaa, Dina,Regenass, Pierre,Maurer, David,Ostrovskyi, Dmytro,Seifert, Ludwig,Bacher, Johannes,Burgahn, Teresa,Wagner, Tobias,Seitz, Johannes,Greschik, Holger,Park, Kwang-Su,Xiong, Yan,Jin, Jian,Schüle, Roland,Breit, Bernhard,Jung, Manfred,Sippl, Wolfgang
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- Rapid Bis-Coupling Reactivity with Triarylbismuth Reagents: Synthesis of Structurally Diverse Scaffolds and Step-economic Convergent Synthesis of Quebecol
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The cross-coupling study of gem-dibromoesters with triarylbismuths as threefold arylating reagents was investigated under palladium-catalyzed conditions. This study using triarylbismuth reagents explored the cross-coupling reactivity with various functionalized gem-dibromoesters. It furnished a variety of multi-functional trisubstituted acrylates embedded with aryl, alkene and alkyne scaffolds in high yields. The present study in turn, provided easy access to various triarylated acrylates and functionalized 1,3-dienyl and 1,3-enyne esters. Further, the established method applied in the step-economic and convergent synthesis of quebecol natural product in good yield.
- Rao, Maddali L. N.,Murty, Venneti N.,Nand, Sachchida
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p. 1629 - 1636
(2020/03/05)
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- SUBSTITUTED FUSED BI- OR TRI- HETEROCYCLIC COMPOUNDS AS EHMT2 INHIBITORS
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The present disclosure relates to substituted fused bi- or tri- heterocyclic compounds. The present disclosure also relates to pharmaceutical compositions containing these compounds and methods of treating a disorder (e.g., sickle cell anemia) via inhibit
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Paragraph 0444; 0445; 0446; 0447
(2018/04/17)
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- AZAINDOLE COMPOUNDS AS HISTONE METHYLTRANSFERASE INHIBITORS
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The present disclosure provides certain angular tricyclic compounds that are histone methyltransferases G9a and/or GLP inhibitors and are therefore useful for the treatment of diseases treatable by inhibition of G9a and/or GLP such as cancers and hemoglobinopathies (e.g., beta-thalassemia and sickle cell disease). Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
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Page/Page column 76
(2019/01/06)
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- Anti-inflammatory properties of quebecol and its derivatives
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Herein we report our results on the anti-inflammatory activity of quebecol, a polyphenolic compound discovered in maple syrup. Bioassays demonstrated that quebecol has an anti-inflammatory effect on LPS-induced NF-κB activation and inhibits the secretion of two pro-inflammatory cytokines, IL-6 and TNF-α. We also prepared and tested precursors of quebecol and its derivatives corresponding to its substructures of interest, with the aim to study the structure-activity relationships. Comparing the results obtained for all tested compounds allowed the identification of the main moiety responsible for the anti-inflammatory activity of quebecol.
- Cardinal, Sébastien,Azelmat, Jabrane,Grenier, Daniel,Voyer, Normand
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supporting information
p. 440 - 444
(2016/01/09)
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- Rapid Access to Benzofuran-Based Natural Products through a Concise Synthetic Strategy
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A concise strategy is described for the synthesis of ailanthoidol (1), egonol (2), homoegonol (3), demethoxyegonol (4), demethoxyhomoegonol (5), and stemofuran A (6). This approach involves a Pd-catalysed domino cyclization/coupling process using triarylbismuth reagents for the generation of the benzofuran core. Subsequent structural modifications then give the final targets. The high yielding synthesis of the recently isolated natural products egonol-9(Z)-12(Z)-linoleate (2a), 7-demethoxyegonol-9(Z)-12(Z)-linoleate (4a), and 7-demethoxy-egonol-9(Z)-oleate (4b) are also reported.
- Rao, Maddali L. N.,Murty, Venneti N.
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p. 2177 - 2186
(2016/05/09)
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- Dihydropyrrolopyrazol-6-one MCHR1 antagonists for the treatment of obesity: Insights on in vivo efficacy from a novel FLIPR assay setup
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Our investigation of the structure-activity and structure-liability relationships for dihydropyrrolopyrazol-6-one MCHR1 antagonists revealed that off-rate characteristics, inferred from potencies in a FLIPR assay following a 2 h incubation, can impact in
- Devasthale, Pratik,Wang, Wei,Hernandez, Andres S.,Moore, Fang,Renduchintala, Kishore,Sridhar, Radhakrishnan,Pelleymounter, Mary Ann,Longhi, Daniel,Huang, Ning,Flynn, Neil,Azzara, Anthony V.,Rohrbach, Kenneth,Devenny, James,Rooney, Suzanne,Thomas, Michael,Glick, Susan,Godonis, Helen,Harvey, Susan,Cullen, Mary Jane,Zhang, Hongwei,Caporuscio, Christian,Stetsko, Paul,Grubb, Mary,Huang, Christine,Zhang, Lisa,Freeden, Chris,Li, Yi-Xin,Murphy, Brian J.,Robl, Jeffrey A.,Washburn, William N.
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p. 2793 - 2799
(2015/06/08)
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- NOVEL COMPOUND FOR IMAGING TAU PROTEIN ACCUMULATED IN THE BRAIN
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The present invention provides a compound represented by the following formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof. wherein: R1 and R2 are each separately selected from the group consisting of hydrog
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Paragraph 0176
(2014/09/02)
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- Total synthesis of quebecol
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We report here the total synthesis of quebecol, a new polyphenolic compound with potential applications recently isolated from maple syrup and produced during the condensation of the tree acer saccharum's sap. The synthetic approach we developed involves, as key steps, the formation of a dibromoalkene from an α-ketoester precursor followed by a double Suzuki-Miyaura reaction to unite the three aromatic rings of the target compound on a tetrasubstituted olefin precursor. Our methodology is an efficient pathway to the target compound and leads the way for future analogs.
- Cardinal, Sébastien,Voyer, Normand
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supporting information
p. 5178 - 5180
(2013/09/02)
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- PHENOLIC COMPOUNDS WITH ANTIOXIDANT AND ANTI-CANCER PROPERTIES, ANALOGS AND SYNTHESIS THEREOF
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The present document describes a phytochemical isolated from maple syrup and composition comprising the same. More specifically, the document describes an antioxidant phytochemical compound, derivates thereof, and composition comprising the same. The document also describes a process of synthesizing the antioxidant phytochemical compound.
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Page/Page column 50
(2013/02/27)
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- AZOLOPYRROLONE MELANIN CONCENTRATING HORMONE RECEPTOR-1 ANTAGONISTS
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The present application provides compounds, including all stereoisomers, solvates, prodrugs and pharmaceutically acceptable forms thereof according to Formula (I) including all pharmaceutically acceptable salts and stereoisomers thereof: wherein A is a mo
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Page/Page column 78
(2010/05/13)
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- Chiral aromatase and dual aromatase-steroid sulfatase inhibitors from the letrozole template: Synthesis, absolute configuration, and in vitro activity
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To explore aromatase inhibition and to broaden the structural diversity of dual aromatase-sulfatase inhibitors (DASIs), we introduced the steroid sulfatase (STS) inhibitory pharmacophore to letrozole. Letrozole derivatives were prepared bearing bis-sulfamates or mono-sulfamates with or without adjacent substituents. The most potent of the achiral and racemic aromatase inhibitor was 40 (IC50 = 3.0 nM). Its phenolic precursor 39 was separated by chiral HPLC, and the absolute configuration of each enantiomer was determined using vibrational and electronic circular dichroism in tandem with calculations of the predicted spectra. Of the two enantiomers, (R)-phenol (39a) was the most potent aromatase inhibitor (IC50 = 0.6 nM, comparable to letrozole), whereas the (S)-sulfamate, (40b) inhibited STS most potently (IC50 = 553 nM). These results suggest that a new structural class of DASI for potential treatment of hormone-dependent breast cancer has been identified, and this is the first report of STS inhibition by an enantiopure nonsteroidal compound.
- Wood, Paul M.,Woo, L. W. Lawrence,Labrosse, Jean-Robert,Trusselle, Melanie N.,Abbate, Sergio,Longhi, Giovanna,Castiglioni, Ettore,Lebon, France,Purohit, Atul,Reed, Michael J.,Potter, Barry V. L.
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supporting information; scheme or table
p. 4226 - 4238
(2009/06/06)
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- Isoindolone compounds, compositions containing the same, and methods of use thereof for the treatment of viral infections related to the etiology of cancer
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Isoindolone derivatives, compositions containing the same, and methods of use thereof for the treatment or prophylaxis of viral infection are disclosed.
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Page/Page column 5
(2010/11/24)
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- An expeditious aqueous Suzuki-Miyaura method for the arylation of bromophenols
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The development of a novel Suzuki-Miyaura method has been achieved to allow the efficient arylation of bromophenols. A range of functionality is tolerated with regard to the boronic acid coupling partner and the reaction exhibits complete chemoselectivity for the Caryl-Br bond versus the Caryl-Cl bond in the aryl halide input. The experimental protocol features a short reaction time of 15 min, utilizes inexpensive Pd/C as a catalyst, and is conducted with water as the solvent.
- Freundlich, Joel S.,Landis, Howard E.
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p. 4275 - 4279
(2007/10/03)
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- Piperazine derivatives
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This invention relates to a compound of formula (I) or pharmaceutically acceptable salts, solvates or derivatives thereof, wherein R1 to R5 are defined in the description, and to processes for the preparation thereof, intermediates used in their preparation, compositions containing them and the uses of such derivatives. The compounds of the present invention inhibit the interaction of gp120 with CD4 and are therefore of use in the treatment of HIV, a retroviral infection genetically related to HIV, or AIDS.
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Page/Page column 39
(2010/02/10)
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- CARBOXYLIC ACID DERIVATIVE AND MEDICINE COMPRISING SALT OR ESTER OF THE SAME
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The present invention provides novel carboxylic acid derivatives useful as an insulin sensitizer, a salt thereof or a hydrate of them, and a medicament comprising the derivative as the active ingredient. Specifically, it provides a carboxylic acid derivative represented by the following formula: (wherein L represents a single bond, or a C1 to C6 alkylene group, a C2 to C6 alkenylene group or a C2 to C6 alkynylene group, each of which may have one or more substituent groups; M represents a single bond, or a C1 to C6 alkylene group, a C2 to C6 alkenylene group or a C2 to C6 alkynylene group, each of which may have one or more substituent groups; T represents a single bond, or a C1 to C3 alkylene group, a C2 to C3 alkenylene group or a C2 to C3 alkynylene group, each of which may have one or more substituent groups; W represents a carboxyl group; X represents a single bond, an oxygen atom, or a group represented by the various substituent groups including -NRX1CQ1O- (wherein Q1 represents an oxygen atom or a sulfur atom; RX1 represents a hydrogen atom, a cyano group, a formyl group, or various groups including a C1 to C6 alkyl group and a C1 to C6 hydroxyalkyl group, each of which may have one or more substituent groups) , ONRX1CQ1-, -NRX1CQ1-, -CQ1NRX1-, -NRX1aCQ1NRX1b-, -Q2SO2- and -SO2Q2-; Y represents a 5 to 14-membered aromatic group which may have one or more substituent groups and one or more hetero atoms, or a C3 to C7 alicyclic hydrocarbon group; and the rings Z and U may be the same as or different from each other and each represents a 5 to 14-membered aromatic group which may have 1 to 4 substituent groups and one or more hetero atoms, and the ring may be partially saturated.), a salt thereof, an ester thereof or a hydrate of them.
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- Iodine (III)-mediated generation of nitrogen-tethered orthoquinol acetates for the construction of oxygenated indole, quinoline, and phenanthridine alkaloid motifs
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Functionalized indole and quinoline derivatives are conveniently prepared from nitrogen-tethered 2-methoxyphenols via phenyliodine(III) diacetate mediated oxidative acetoxylation, followed by a fluoride- or base-induced intramolecular nucleophilic addition reaction. This regioselective Michael-type addition step is further discussed in view of the rearrangement of orthoquinol acetate intermediates into paraquinol acetates that is sometimes observed in situ. Application of this methodology to the synthesis of a functionalized phenanthridine, and its potential for the construction of polyoxygenated lycorine-type alkaloid skeleta are here described.
- Pouysegu, Laurent,Avellan, Anne-Virginie,Quideau, Stephane
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p. 3425 - 3436
(2007/10/03)
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- THE INVENTION OF RADICAL REACTIONS. PART XVI. RADICAL DECARBOXYLATIVE BROMINATION AND IODINATION OF AROMATIC ACIDS
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Thiohydroxamic esters of aromatic carboxylic acids undergo clean decarboxylative bromination or iodination on treatment with bromotrichloromethane, iodoform or diiodomethane in the presence of a radical initiator.
- Barton, Derek H.R.,Lacher, Brigitte,Zard, Samir Z.
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p. 4321 - 4328
(2007/10/02)
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- Arylglycerol Glucosides from Pinus sylvestris
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The 2- and 3-O-β-D-glucopyranosides of 1-(4-hydroxyphenyl)-1,2,3-propanetriol and 1-(4-hydroxy-3-methoxyphenyl)-1,2,3-propanetriol have been isolated from needls of Pinus sylvestris L. and identified.
- Lundgren, Lennart N.,Popoff, Thomas,Theander, Olof
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p. 695 - 700
(2007/10/02)
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