- Novel 3-(2-Oxo-2H-benzo[b][1,4]oxazin-3-yl)propanoates from dimethyl-2-oxoglutarate and test of their biological activity
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Five novel 3-(2-oxo-2H-benzo[b][1,4]oxazin-3-yl)propanoates were synthesized under mild conditions from 2-aminophenols and dimethyl-2- oxoglutarate. Biological assays of these 1,4-benzoxazinones were conducted with three bacterial strains and one yeast. All compounds were active against a Candida albicans ATCC 10231, whereas only methyl 3-(6-methyl-2-oxo-2H-benzo[b] [1,4]oxazin-3-yl)propanoate showed a general moderate activity against the bacterial strains tested.
- Hachama, Kamel,Khodja, Mohamed,Moulay, Saad,Boutoumi, Hocine,Hennig, Lothar,Sicker, Dieter
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- An efficient synthesis of 4-aryl kainic acid analogs
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A synthesis of 4-aryl kainic acid analogs was achieved using a highly stereoselective Michael addition reaction of dimethyl 2-oxoglutarate with a nitrostyrene. Nitro group reduction, deoxygenation and epimerization complete the synthetic route.
- Maeda, Hiroshi,Selvakumar, Natesan,Kraus, George A.
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- Metabolic fate of depsides and alkaloid constituents in aqueous extracts from Mercurialis perennis L. during fermentation
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Dog's mercury (Mercurialis perennis L.) is an old medicinal plant, nowadays used in complementary medicine. Aqueous fermented extracts of the plant are being mainly applied in remedies to treat external inflammations, but a thorough phytochemical characterization is still lacking. Therefore, the conversion of characteristic compound classes from M. perennis extracts during fermentation and storage was investigated. The microbial transformation of the two main depsides phaselic acid (=(2R)-O-[(E)-caffeoyl]malic acid; 1) and mercurialis acid (=(2R)-[(E)-caffeoyloxy]glutaric acid; 2) was monitored by HPLC-DAD. The degradation followed a second-order kinetic, and the calculated half-life periods of both constituents were 67 and 30 months, respectively. Several depside metabolites were detected by GC/MS in AcOEt extracts as tBuMe2Si (TBDMS) derivatives after derivatization, mainly dihydrocinnamic acids. Moreover, numerous α-hydroxy acids were found, allegedly as degradation products from amino acids or peptides. The microbial alteration of the main alkaloid hermidin was also examined. After three days of fermentation, three novel N-metabolites were formed and thoroughly assigned in CH2Cl2 extracts as a mixture of 3-ethylhermidin, 3-ethylhermidin quinone, and (E/Z)-3-ethylidenehermidin by GC/MS and NMR methods, as well as by means of total synthesis. A mechanism for the formation of these N-metabolites starting from dimeric hermidin oxidation products is proposed. The obtained results reveal the complex pathways plant constituents may undergo during the fermentation of the extracts. Copyright
- Lorenz, Peter,Conrad, Juergen,Stintzing, Florian C.
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- A Br?nsted acidic, ionic liquid containing, heteropolyacid functionalized polysiloxane network as a highly selective catalyst for the esterification of dicarboxylic acids
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A Br?nsted acidic, ionic liquid containing, heteropolyanion functionalized polysiloxane network was formed by self-condensation of dodecatungstophosphoric acid and a zwitterionic organosilane precursor containing both imidazolinium and sulfonate groups. The resulting hybrid material POS-HPA-IL was investigated as a catalyst for the selective esterification of dicarboxylic acids.
- Rajabi, Fatemeh,Wilhelm, Christian,Thiel, Werner R.
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supporting information
p. 4438 - 4444
(2020/08/10)
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- Biotechnological properties of sponges from northeast Brazil: Cliona varians as a Biocatalyst for Enantioselective Reduction of Carbonyl Compounds
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To research the potential ability of whole marine sponges to act as biocatalysts, this paper describes for the first time the employment of whole Cliona varians sponge in the stereoselective reduction of prochiral α-keto esters and isatin to the corresponding chiral alcohols. The addition of D-fructose, D-glucose or sucrose remarkably increased the conversion ratios and stereoselectivities by this marine sponge. Furthermore, in the presence of D-glucose and D-maltose, the reduction of isatin by C. varians afforded the corresponding 3-hydroxyindolin-2-one with high conversions (85-90percent) and good enantioselectivities (60-74percent). These results showed that the marine sponge presents great potential to be used as biocatalyst for stereoselective reduction of carbonyl compounds.
- Riatto, Valéria B.,Victor, Mauricio M.,Sousa, Jaqueline F.,Menegola, Carla
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p. 149 - 157
(2018/12/13)
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- Identification and Structure-Activity Relationship of HDAC6 Zinc-Finger Ubiquitin Binding Domain Inhibitors
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HDAC6 plays a central role in the recruitment of protein aggregates for lysosomal degradation and is a promising target for combination therapy with proteasome inhibitors in multiple myeloma. Pharmacologically displacing ubiquitin from the zinc-finger ubiquitin-binding domain (ZnF-UBD) of HDAC6 is an underexplored alternative to catalytic inhibition. Here, we present the discovery of an HDAC6 ZnF-UBD-focused chemical series and its progression from virtual screening hits to low micromolar inhibitors. A carboxylate mimicking the C-terminal extremity of ubiquitin, and an extended aromatic system stacking with W1182 and R1155, are necessary for activity. One of the compounds induced a conformational remodeling of the binding site where the primary binding pocket opens up onto a ligand-able secondary pocket that may be exploited to increase potency. The preliminary structure-activity relationship accompanied by nine crystal structures should enable further optimization into a chemical probe to investigate the merit of targeting the ZnF-UBD of HDAC6 in multiple myeloma and other diseases.
- Ferreira De Freitas, Renato,Harding, Rachel J.,Franzoni, Ivan,Ravichandran, Mani,Mann, Mandeep K.,Ouyang, Hui,Lautens, Mark,Santhakumar, Vijayaratnam,Arrowsmith, Cheryl H.,Schapira, Matthieu
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supporting information
p. 4517 - 4527
(2018/05/31)
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- Identification and quantification of aerosol polar oxygenated compounds bearing carboxylic or hydroxyl groups. 1. Method development
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In this study, a new analytical technique was developed for the identification and quantification of multifunctional compounds containing simultaneously at least one hydroxyl or one carboxylic group, or both. This technique is based on derivatizing first the carboxylic group(s) of the multifunctional compound using an alcohol (e.g., methanol, 1-butanol) in the presence of a relatively strong Lewis acid (BF3) as a catalyst. This esterification reaction quicldy and quantitatively converts carboxylic acids to their ester forms. The second step is based on silylation of the ester compounds using bis(trimethylsilyl) trifluoroacetamide (BSTFA) as the derivatizing agent. For compounds bearing ketone groups in addition to carboxylic and hydroxyl groups, a third step was used based on PFBHA derivatization of the carbonyls. Different parameters including temperature, reaction time, and effect due to artifacts were optimized. A GC/MS in EI and in methane-CI mode was used for the analysis of these compounds. The new approach was tested on a number of multifunctional compounds. The interpretation of their EI (70 eV) and CI mass spectra shows that critical information is gained leading to unambiguous identification of unknown compounds. For example, when derivatized only with BF3-methanol, their mass spectra comprise primary ions at m/z M .+ + 1, M.+ + 29, and M.- - 31 for compounds bearing only carboxylic groups and M.- + 1, M.+ + 29, M.+ - 31, and M+. - 17 for those bearing hydroxyl and carboxylic groups. However, when a second derivatization (BSTFA) was used, compounds bearing hydroxyl and carboxylic groups simultaneously show, in addition to the ions observed before, ions at m/z M.+ + 73, M .+ - 15, M.+ - 59, M.+ - 75, M.+ - 89, and 73. To the best of our knowledge, this technique describes systematically for the first time a method for identifying multifunctional oxygenated compounds containing simultaneously one or more hydroxyl and carboxylic acid groups.
- Jaoui,Kleindienst,Lewandowski,Edney
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p. 4765 - 4778
(2007/10/03)
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- Combination strategy using pure enzymes and whole cells as biocatalysts for the preparation of 2-hydroxyesters and lactones from 2-oxoglutaric acid
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An innovative combination strategy that uses pure enzymes and whole microbial cells in the same process was used to prepare enantiomerically pure 3-carboxyalkyl-γ-butyrolactones and several alkyl esters of 2-hydroxyglutarate from 2-oxoglutaric acid. An innovative combination strategy that uses pure enzymes and whole microbial cells in the same process was used to prepare enantiomerically pure 3-carboxyalkyl-γ-butyrolactones and several alkyl esters of 2-hydroxyglutarates from 2-oxoglutaric acid. The method involves two consecutive biocatalytic steps. The first step, which converts the 2-oxoglutaric acid into the corresponding dialkyl esters, was catalyzed by a lipase. Then in the second step, by microbial reduction of the dialkyl-2-oxoglutarates, it is possible to obtain 3-carboxyalkyl-γ- butyrolactones or 2-hydroxyesters depending on the length of the chain in the alkyl moiety of the esters and on the fresh or lyophilized status of the cells.
- Rustoy, Eduardo M.,Pereyra, Elba N.,Moreno, Silvia,Baldessari, Alicia
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p. 3763 - 3768
(2007/10/03)
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- Synthesis and in vitro pharmacology of substituted quinoline-2,4-dicarboxylic acids as inhibitors of vesicular glutamate transport
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The vesicular glutamate transport (VGLUT) system selectively mediates the uptake of L-glutamate into synaptic vesicles. Uptake is linked to an H+-ATPase that provides coupling among ATP hydrolysis, an electrochemical proton gradient, and glutamate transport. Substituted quinoline-2,4-dicarboxylic acids (QDCs), prepared by condensation of dimethyl ketoglutaconate (DKG) with substituted anilines and subsequent hydrolysis, were investigated as potential VGLUT inhibitors in synaptic vesicles. A brief panel of substituted QDCs was previously reported (Carrigan et al. Bioorg. Med. Chem. Lett. 1999, 9, 2607-2612)1 and showed that certain substituents led to more potent competitive inhibitors of VGLUT. Using these compounds as leads, an expanded series of QDC analogues were prepared either by condensation of DKG with novel anilines or via aryl-coupling (Suzuki or Heck) to dimethyl 6-bromoquinolinedicarboxylate. From the panel of almost 50 substituted QDCs tested as inhibitors of the VGLUT system, the 6-PhCH=CH-QDC (Ki = 167 μM), 6-PhCH2CH2-QDC (Ki = 143 μM), 6-(4′-phenylstyryl)-QDC (Ki = 64 μM), and 6-biphenyl-4-yl-QDC (Ki=41 μM) were found to be the most potent blockers. A preliminary assessment of the key elements needed for binding to the VGLUT protein based on the structure-activity relationships for the panel of substituted QDCs is discussed herein. The substituted QDCs represent the first synthetically derived VGLUT inhibitors and are promising templates for the development of selective transporter inhibitors.
- Carrigan, Christina N.,Bartlett, Richard D.,Esslinger, C. Sean,Cybulski, Kimberly A.,Tongcharoensirikul, Pakamas,Bridges, Richard J.,Thompson, Charles M.
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p. 2260 - 2276
(2007/10/03)
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- Synthesis of the angiotensin-converting enzyme inhibitors (-)-A58365A and (-)-A58365B from a common intermediate
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(-)-A58365A (1) and (-)-A58365B (2), which are inhibitors of angiotensin-converting enzyme, were synthesized from the subunits 9 and 10. These were coupled, and the resulting individual amides 17a,b were converted by ozonolysis into aldehydes 18a,b, which underwent cyclodehydration to the enamides 19a,b. Treatment with a stannane served to generate the vinyl stannanes 20a,b, from which ketones 22a,b were produced by protodestannylation and ozonolysis. Base treatment and hydrogenolysis then afforded (-)-A58365A (1). The intermediates 17a,b were also converted into aldehydes 26a,b by hydroboration and oxidation, and a similar sequence to that used for (-)-A58365A was then applied in order to complete the first enantiospecific synthesis of the congener, (-)-A58365B (2).
- Clive, Derrick L. J.,Coltart, Don M.,Zhou, Yuanxi
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p. 1447 - 1454
(2007/10/03)
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- Enantiomerically pure tetrahydro-5-oxo-2-furancarboxylic esters from dialkyl 2-oxoglutarates
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Enantiomerically pure tetrahydro-5-oxo-2-furancarboxylic esters can be prepared either by enzymatic resolution of the racemic γ-lactones themselves or by bioreduction with baker's yeast of dialkyl 2-oxoglutarates and subsequent cyclization of the resulting dialkyl 2-hydroxyglutarates. The best results were obtained by the former route, by which the desired compounds were isolated in high enantiomeric excess. Bioreductions were less satisfactory. In fact the hydroxyester intermediates were initially formed as racemic mixtures and their final enantiomeric enrichment was reached by asymmetric destruction, occurring in the bioreaction medium, however at the same time large amounts of alkyl 4-hydroxybutanoates were formed as side products.
- Drioli, Sara,Nitti, Patrizia,Pitacco, Giuliana,Tossut, Laura,Valentin, Ennio
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p. 2713 - 2728
(2007/10/03)
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- The synthesis of oxa-analogs of the kainoid family
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In an effort to mimic the anthelmintic and insecticidal activities of kainic acid (1) and domoic acid (2) with compounds of simpler structure and much easier accessibility, the highly functionalised isoxazolidines (4) and (20) were prepared.
- Baumgartner, Hansruedi,O'Sullivan, Anthony C.,Schneider, Josef
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p. 1537 - 1549
(2007/10/03)
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- Organic Syntheses Based on 2-Oxoglutaric Acid. II. On the Synthesis of Heterocycles by Reactions of Dimethyl 3-bromo-2-oxoglutarate with Binucleophiles
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Reactions of dimethyl 3-bromo-2-oxoglutarate 2 with binucleophiles to form heterocycles proceed on two different pathways depending on the type of reactant.Thus, strong S-nucleophiles like thioureas and thiocarbohydrazide substitute initially the bromine atom and form 2-aminothiazoles 3 - 7 and the 1,3,4-thiadiazine 8.However, o-phenylendiamines reacted to form the brominated quinoxaline-2(1H)-one derivatives 9 and 10, resp.
- Hartenstein, H.,Blitzke, T.,Sicker, D.,Wilde, H.
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p. 176 - 180
(2007/10/02)
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- DDQ Oxidations in the Indole Area. Synthesis of 4-Alkoxy-β-carbolines Including the Natural Products Crenatine and 1-Methoxycanthin-6-one
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The seven-step synthesis of the cytotoxic, antileukemic alkaloid 1-methoxycanthin-6-one (2b) is described.The pivotal steps are represented by the oxidation (DDQ, aqueous THF, room temperature) of 1-(methoxycarbonyl)-1,2,3,4-tetrahydro-β-carboline (10) to provide the 4-oxo-substituted derivative 14 in 78percent yield, and conversion of the 4-oxo analogue 7 into 4-methoxy-1-alkyl-β-carboline (23) via a methoxylation-oxidation process .This four-step, one-pot reaction has been shown to be general; 4-oxo-1,2,3,4-tetrahydro-β-carboline (18) was converted into the corresponding 4-methoxy-, 4-ethoxy-, 4-(allyloxy)-, and 4-(benzyloxy)-β-carbolines (19a-d, respectively) on heating in the appropriate alcohol in the presence of pTSA and a trialkyl orthoformate (Table II).The proposed mechanism for this intriguing transformation is outlined in Scheme IV.Execution of this process has also resulted in a four-step preparation of crenatine (1a), a 4-methoxy-1-ethyl-β-carboline alkaloid.Finally, steric and electronic parameters have also been successfully manipulated to direct the DDQ oxidation of 1,2,3,4-tetrahydro-β-carbolines to position 1, regiospecifically.The conversion of tetrahydro-β-carboline 25 into 2-acylindole 38 and benzamide 26 into 1-oxotetrahydro-β-carboline 27 (Table I), respectively, is in agreement with the proposed mechanism for this process.
- Hagen, Timothy J.,Narayanan, Krishnaswamy,Names, Jeffrey,Cook, James M.
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p. 2170 - 2178
(2007/10/02)
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- CONVENIENT SYNTHESIS AND REACTION OF VARIOUS KINDS OF α-DEHYDROGLUTAMIC ACID DERIVATIVES
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Various conversions of methyl γ-methyl-α-(N-benzyloxycarbonyl)-α-dehydroglutamate, derived by the condensation of methyl γ-methyl-α-oxoglutarate with benzyl carbamate, gave the corresponding five more different and interesting α-dehydroglutamic acid and a quasi-pyrodehydroglutamic acid derivatives.
- Shin, Chung-gi,Yonezawa, Yasuchika,Watanabe, Etsuko
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- NEW METHODS AND REAGENTS IN ORGANIC SYNTHESIS. 14. A SIMPLE EFFICIENT PREPARATION OF METHYL ESTERS WITH TRIMETHYLSILYLDIAZOMETHANE (TMSCHN2) AND ITS APPLICATION TO GAS CHROMATOGRAPHIC ANALYSIS OF FATTY ACIDS
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Trimethylsilyldiazomethane (TMSCHN2), known as a stable and safe substitute for highly toxic and explosive diazomethane in the Arndt-Eistert synthesis and homologation of carbonyl compounds, has smoothly reacted with various carboxylic acids in methanolic benzene solution to give the corresponding methyl esters in excellent yields.Keyords: trimethylsilyldiazomethane; carboxylic acid; methyl ester; esterification; fatty acid; gas chromatographic analysis
- Mashimoto, Norio,Aoyama, Toyohiko,Shioiri, Takayuki
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p. 1475 - 1478
(2007/10/02)
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- Syntheses en serie indolique. VII. Synthese et transformation chimiques de l'enchainement tetracyclique commun aux alcaloides a chromophore ester anilinoacrylique
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The anilinoacrylic ester 1 was prepared in six steps from tryptamine and dimethyl 2-oxoglutarate.It was condensed with vindolinine via the chloro-indolenine 22a to yield, after reduction, compounds 24a and 24b, which are structurally related to vinblastine.Oxidation and rearrangement of 1 gave, although with vindoline via the chloro-indolenine 22a to yield, after 31a, 16-epivincamine 31b and apovincamine 32, respectively.
- Maindreville, Michele Doe de,Levy, Jean
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p. 179 - 184
(2007/10/02)
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