- A novel synthetic protocol for the synthesis of pulvinones, and naturally occurring Aspulvinone E, molecules of medicinal interest
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A novel two step methodology for readily accessible natural “pulvinone” derivatives in excellent yields has been developed starting from activated precursors, bearing a functionalized 1,3-dioxolane-2,4-diones (OCA’s), as dually protected-activated synthon
- Igglessi-Markopoulou, Olga,Katsamakas, Sotirios,Markopoulos, John,Prousis, Kyriakos C.
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supporting information
(2021/11/22)
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- Evaluation of α-hydroxycinnamic acids as pyruvate carboxylase inhibitors
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Through a structure-based drug design project (SBDD), potent small molecule inhibitors of pyruvate carboxylase (PC) have been discovered. A series of α-keto acids (7) and α-hydroxycinnamic acids (8) were prepared and evaluated for inhibition of PC in two assays. The two most potent inhibitors were 3,3′-(1,4-phenylene)bis[2-hydroxy-2-propenoic acid] (8u) and 2-hydroxy-3-(quinoline-2-yl)propenoic acid (8v) with IC50 values of 3.0 ± 1.0 μM and 4.3 ± 1.5 μM respectively. Compound 8v is a competitive inhibitor with respect to pyruvate (Ki = 0.74 μM) and a mixed-type inhibitor with respect to ATP, indicating that it targets the unique carboxyltransferase (CT) domain of PC. Furthermore, compound 8v does not significantly inhibit human carbonic anhydrase II, matrix metalloproteinase-2, malate dehydrogenase or lactate dehydrogenase.
- Burkett, Daniel J.,Wyatt, Brittney N.,Mews, Mallory,Bautista, Anson,Engel, Ryan,Dockendorff, Chris,Donaldson, William A.,St. Maurice, Martin
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p. 4041 - 4047
(2019/08/26)
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- An Atropos Biphenyl Bisphosphine Ligand with 2,2′-tert-Butylmethylphosphino Groups for the Rhodium-Catalyzed Asymmetric Hydrogenation of Enol Esters
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This is an update of our previous work concerning the development of Atropos biphenyl bisphosphine ligands. An unexpected Atropos structural property was confirmed by single crystal X-ray diffraction and this result is consistent with the computational calculations described in our previous work. This P-stereogenic bisphosphine ligand possessing a biphenyl backbone and 2,2′-tert-butylmethylphosphino groups has been applied to the Rh-catalyzed asymmetric hydrogenation of enol esters, which has not been widely studied and can be used for the synthesis of several important bioactive compounds. Although there is room for further improvement in enantioselectivity, the results reported herein provide a further understanding of such types of ligands. (Figure presented.).
- Jia, Jia,Fan, Dongyang,Zhang, Jian,Zhang, Zhenfeng,Zhang, Wanbin
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supporting information
p. 3793 - 3800
(2018/09/20)
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- 5-(α-Halobenzyl)- and 5-Benzylidene-2,2-dimethyl-1,3-oxazolidin-4-ones in Synthesis of α-Hydroxy Acids
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The reactions of acid hydrolysis of 5-(α-halobenzyl)- and 5-benzylidene-2,2-dimethyl-1,3-oxazolidin-4-ones were studied. A possibility of the synthesis of corresponding α-hydroxy acids was shown.
- Mamedov,Mamedova,Khikmatova,Korshin,Sinyashin
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p. 2801 - 2809
(2018/02/21)
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- Design, synthesis, and biological evaluation of substrate-competitive inhibitors of C-terminal Binding Protein (CtBP)
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C-terminal Binding Protein (CtBP) is a transcriptional co-regulator that downregulates the expression of many tumor-suppressor genes. Utilizing a crystal structure of CtBP with its substrate 4-methylthio-2-oxobutyric acid (MTOB) and NAD+ as a guide, we have designed, synthesized, and tested a series of small molecule inhibitors of CtBP. From our first round of compounds, we identified 2-(hydroxyimino)-3-phenylpropanoic acid as a potent CtBP inhibitor (IC50 = 0.24 μM). A structure-activity relationship study of this compound further identified the 4-chloro- (IC50 = 0.18 μM) and 3-chloro- (IC50 = 0.17 μM) analogues as additional potent CtBP inhibitors. Evaluation of the hydroxyimine analogues in a short-term cell growth/viability assay showed that the 4-chloro- and 3-chloro-analogues are 2-fold and 4-fold more potent, respectively, than the MTOB control. A functional cellular assay using a CtBP-specific transcriptional readout revealed that the 4-chloro- and 3-chloro-hydroxyimine analogues were able to block CtBP transcriptional repression activity. This data suggests that substrate-competitive inhibition of CtBP dehydrogenase activity is a potential mechanism to reactivate tumor-suppressor gene expression as a therapeutic strategy for cancer.
- Korwar, Sudha,Morris, Benjamin L.,Parikh, Hardik I.,Coover, Robert A.,Doughty, Tyler W.,Love, Ian M.,Hilbert, Brendan J.,Royer, William E.,Kellogg, Glen E.,Grossman, Steven R.,Ellis, Keith C.
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p. 2707 - 2715
(2016/06/08)
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- Structure-activity relationship study of 4EGI-1, small molecule eIF4E/eIF4G protein-protein interaction inhibitors
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Abstract Protein-protein interactions are critical for regulating the activity of translation initiation factors and multitude of other cellular process, and form the largest block of untapped albeit most challenging targets for drug development. 4EGI-1, (E/Z)-2-(2-(4-(3,4-dichlorophenyl)thiazol-2-yl) hydrazono)-3-(2-nitrophenyl)propanoic acid, is a hit compound discovered in a screening campaign of small molecule libraries as an inhibitor of translation initiation factors eIF4E and eIF4G protein-protein interaction; it inhibits translation initiation in vitro and in vivo. A series of 4EGI-1-derived thiazol-2-yl hydrazones have been designed and synthesized in order to delineate the structural latitude and improve its binding affinity to eIF4E, and increase its potency in inhibiting the eIF4E/eIF4G interaction. Probing a wide range of substituents on both phenyl rings comprising the 3-phenylpropionic acid and 4-phenylthiazolidine moieties in the context of both E- and Z-isomers of 4EGI-1 led to analogs with enhanced binding affinity and translation initiation inhibitory activities.
- Takrouri, Khuloud,Chen, Ting,Papadopoulos, Evangelos,Sahoo, Rupam,Kabha, Eihab,Chen, Han,Cantel, Sonia,Wagner, Gerhard,Halperin, Jose A.,Aktas, Bertal H.,Chorev, Michael
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p. 361 - 377
(2014/04/17)
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- Synthesis of novel cinnamanilides as potential immunosuppressive agents
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A series of new cinnamanilides (6-40) were synthesized and their immunosuppressive activity and cytotoxicity were evaluated. Most of the cinnamanilides showed good immunosuppressive activity. Among the synthesized compounds, (Z)-N-(4-bromophenyl)-2-methox
- Shi, Lei,Wang, Lu,Wang, Zhi,Zhu, Hai-Liang,Song, Qiao
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experimental part
p. 585 - 593
(2012/02/14)
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- New 3- and 4-hydroxyfuranones as anti-oxidants and anti-inflammatory agents
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Two series of new furanones substituted by methylsulfonylphenyl or methylsulfamidophenyl moieties were found to protect against oxidation damage by inhibiting or quenching free radicals and reactive oxygen species in in vitro experiments. The effect on lipid peroxidation was also examined. In addition, we investigated the activity of products in two models of inflammation: phorbol ester-induced ear edema in mice and carrageenan-induced paw edema in rat. The most powerful compounds and with reducing activity against DPPH (IC50 = 1779 and 57 μM, respectively), superoxide anion quenching capacity (IC50 = 511 and 49 μM, respectively), lipid peroxidation inhibitory effect and anti-inflammatory properties (about 50-65% inhibition of edema at 200 mg/kg ip in both tests used) were selected for further pharmacological and toxicological tests because of their attractive profile for the treatment of inflammatory diseases.
- Weber, Valerie,Rubat, Catherine,Duroux, Eliane,Lartigue, Claire,Madesclaire, Michel,Coudert, Pascal
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p. 4552 - 4564
(2007/10/03)
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- Enantioselective synthesis of non-natural amino acids using phenylalanine dehydrogenases modified by site-directed mutagenesis
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The substrate scope of three mutants of phenylalanine dehydrogenase as biocatalysts for the transformation of a series of 2-oxo acids, structurally related to phenylpyruvic acid, to the analogous -amino acids, non-natural analogues of phenylalanine, has been investigated. The mutant enzymes are more tolerant than the wild type enzyme of the non-natural substrates, especially those with substituents at the 4-position on the phenyl ring. Excellent enantiocontrol resulted in all cases.
- Busca, Patricia,Paradisi, Francesca,Moynihan, Eamonn,Maguire, Anita R.,Engel, Paul C.
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p. 2684 - 2691
(2007/10/03)
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- Synthesis and biological evaluation of analogues of butyrolactone I and molecular model of its interaction with CDK2.
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A series of analogues of butyrolactone I, a natural product isolated from Aspergillus terreus that selectively inhibits the CDK2 and CDK1 kinases and that has been found to exhibit an interesting antiproliferative activity, have been synthesized. Its anti
- Brana, Miguel F,Garcia, M Luisa,Lopez, Berta,de Pascual-Teresa, Beatriz,Ramos, Ana,Pozuelo, Jose M,Dominguez, M Teresa
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p. 1864 - 1871
(2007/10/03)
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- Chemocontrolled reduction of aromatic α-ketoesters by NaBH4: Selective synthesis of α-hydroxy esters or 1,2-diols
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α-Hydroxyesters 5a-g or diols 6a-g have been obtained in high yields by reduction of aromatic α-ketoesters 4 once or twice respectively by using NaBH4 as the reducer under suitable conditions. The use of a solvent that does not interact with the reagent allowed the double reduction to occur with only a slight excess of borohydride in very mild conditions.
- Dalla, Vincent,Cotelle, Philippe,Catteau, Jean Pierre
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p. 1577 - 1580
(2007/10/03)
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