- Stereoselective Synthesis, Configurational Assignment and Biological Evaluations of the Lipid Mediator RvD2n-3 DPA
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Herein we report the first total synthesis of RvD2n-3 DPA, an endogenously formed mediator biosynthesized from the omega-3 fatty acid n-3 docosapentaenoic acid. The key steps are the Midland Alpine borane reduction, Sonogashira cross-coupling reactions, and a Z-selective alkyne reduction protocol, yielding RvD2n-3 DPA methyl ester in 13 % yield over 12 steps (longest linear sequence). The physical property data (UV chromophore, chromatography and MS/MS fragmentation) of the synthetic lipid mediator matched those obtained from biologically produced material. Moreover, synthetic RvD2n-3 DPA also carried the potent biological activities of enhancing macrophage uptake of Staphylococcus aureus and zymosan A bioparticles.
- Dalli, Jesmond,De Matteis, Roberta,Hansen, Trond V.,Primdahl, Karoline G.,Reinertsen, Amalie F.
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supporting information
(2022/01/04)
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- First total syntheses of the pro-resolving lipid mediators 7(S),13(R),20(S)-Resolvin T1 and 7(S),13(R)-Resolvin T4
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The first total syntheses of the pro-resolving lipid mediators 7(S),13(R),20(S)-Resolvin T1 [7(S),13(R),20(S)-RvT1] and 7(S),13(R)-Resolvin T4 [7(S),13(R)-RvT4], derived from n-3 docosapentaenoic acid (n-3 DPA), are described. 7(S),13(R),20(S)-RvT1 was prepared from 7(S),13(R)-RvT4 via an enzymatic lipoxidase reaction. 7(S),13(R)-RvT4 was obtained by total synthesis where the chiral centers at C7 and C13 where introduced by a Noyori transfer hydrogenation and a chiral pool strategy respectively. Wittig reactions, Sonogashira coupling and Boland Zn(Cu/Ag) reduction were the key steps in the synthesis.
- Rodriguez, Ana R.,Spur, Bernd W.
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- CATALYTIC CARBOXYLATION OF ACTIVATED ALKANES AND/OR OLEFINS
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The present invention relates to a method of reacting starting materials with an activating group, namely alkanes carrying a leaving group and/or olefins, with carbon dioxide under transition metal catalysis to give carboxyl group-containing products. It is a special feature of the method of the present invention that the carboxylation predominantly takes place at a preferred position of the molecule irrespective of the position of the activating group. The carboxylation position is either an aliphatic terminus of the molecule or it is a carbon atom adjacent to a carbon carrying an electron withdrawing group. The course of the reaction can be controlled by appropriately choosing the reaction conditions to yield the desired regioisomer.
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Page/Page column 64
(2018/02/28)
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- Remote carboxylation of halogenated aliphatic hydrocarbons with carbon dioxide
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Catalytic carbon-carbon bond formation has enabled the streamlining of synthetic routes when assembling complex molecules. It is particularly important when incorporating saturated hydrocarbons, which are common motifs in petrochemicals and biologically relevant molecules. However, cross-coupling methods that involve alkyl electrophiles result in catalytic bond formation only at specific and previously functionalized sites. Here we describe a catalytic method that is capable of promoting carboxylation reactions at remote and unfunctionalized aliphatic sites with carbon dioxide at atmospheric pressure. The reaction occurs via selective migration of the catalyst along the hydrocarbon side-chain with excellent regio- and chemoselectivity, representing a remarkable reactivity relay when compared with classical cross-coupling reactions. Our results demonstrate that site-selectivity can be switched and controlled, enabling the functionalization of less-reactive positions in the presence of a priori more reactive ones. Furthermore, we show that raw materials obtained in bulk from petroleum processing, such as alkanes and unrefined mixtures of olefins, can be used as substrates. This offers an opportunity to integrate a catalytic platform en route to valuable fatty acids by transforming petroleum-derived feedstocks directly.
- Juliá-Hernández, Francisco,Moragas, Toni,Cornella, Josep,Martin, Ruben
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- A Fluorescence-Lifetime-Based Binding Assay for Class IIa Histone Deacetylases
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Class IIa histone deacetylases (HDACs) show extremely low enzymatic activity and no commonly accepted endogenous substrate is known today. Increasing evidence suggests that these enzymes exert their effect rather through molecular recognition of acetylated proteins and recruiting other proteins like HDAC3 to the desired target location. Accordingly, class IIa HDACs like bromodomains have been suggested to act as “Readers” of acetyl marks, whereas enzymatically active HDACs of class I or IIb are called “Erasers” to highlight their capability to remove acetyl groups from acetylated histones or other proteins. Small-molecule ligands of class IIa histone deacetylases (HDACs) have gained tremendous attention during the last decade and have been suggested as pharmaceutical targets in several indication areas such as cancer, Huntington's disease and muscular atrophy. Up to now, only enzyme activity assays with artificial chemically activated trifluoroacetylated substrates are in use for the identification and characterization of new active compounds against class IIa HDACs. Here, we describe the first binding assay for this class of HDAC enzymes that involves a simple mix-and-measure procedure and an extraordinarily robust fluorescence lifetime readout based on [1,3]dioxolo[4,5-f]benzodioxole-based ligand probes. The principle of the assay is generic and can also be transferred to class I HDAC8.
- Meyners, Christian,Mertens, Monique,Wessig, Pablo,Meyer-Almes, Franz-Josef
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p. 3107 - 3116
(2017/03/13)
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- Improved antiproliferative activity of 1,3,4-thiadiazole-containing histone deacetylase (HDAC) inhibitors by introduction of the heteroaromatic surface recognition motif
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A series of 1,3,4-thiadiazole-containing hydroxamic acids, in accord with the common pharmacophore of histone deacetylase (HDAC) inhibitors (a Zn2+ binding moiety-a linker-a surface recognition motif), was identified as submicromolar HDAC inhibitors by our group. In this study, we continued our efforts to develop 1,3,4-thiadiazole bearing hydroxamate analogues by modifying the surface recognition motif. We found that 1,3,4-thiadiazoles having a heteroaromatic substituent showed better HDAC inhibitory activity in enzymatic assay and higher antiproliferative potency in cellular assay compared to SAHA.
- Guan, Peng,Wang, Lei,Hou, Xuben,Wan, Yichao,Xu, Wenfang,Tang, Weiping,Fang, Hao
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p. 5766 - 5775
(2015/02/02)
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- Design, synthesis and preliminary bioactivity studies of 1,3,4-thiadiazole hydroxamic acid derivatives as novel histone deacetylase inhibitors
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Histone deacetylase (HDAC) inhibitors have emerged as a new class of anticancer agents, targeting the biological processes including cell cycle, apoptosis and differentiation. In the present study, a series of 1,3,4-thiadiazole based hydroxamic acids were developed as potent HDAC inhibitors. Some of them showed good inhibitory activity in HDAC enzyme assay and potent growth inhibition in some tumor cell lines. Among them, compound 6i (IC50 = 0.089 μM), exhibited better inhibitory effect compared with SAHA (IC50 = 0.15 μM).
- Guan, Peng,Sun, Feng'E,Hou, Xuben,Wang, Feng,Yi, Fan,Xu, Wenfang,Fang, Hao
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experimental part
p. 3865 - 3872
(2012/08/27)
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- Synthesis and SAR requirements of adamantane-colchicine conjugates with both microtubule depolymerizing and tubulin clustering activities
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A series of analogues of conjugate 1, combining an adamantane-based paclitaxel (taxol) mimetic with colchicine was synthesized and tested for cytotoxicity in a cell-based assay with the human lung carcinoma cell line A549. The most active compounds (10 EC50 2 ± 1.0 nM, 23 EC 50 6 ± 1.4 nM, 26 EC50 5 ± 1.8 nM, 28 EC50 11 ± 1.7 nM, 30 EC50 4.8 ± 0.5 nM) were found to interfere with the microtubule dynamics in an interesting manner. Treatment of the cells with these compounds promoted disassembly of microtubules followed by the formation of stable tubulin clusters. Structure-activity relationships for the analogues of 23 revealed the sensitivity of both cytotoxicity and tubulin clustering ability to the linker length. The presence of adamantane (or another bulky hydrophobic and non-aromatic moiety) in 23 was found to play an important role in the formation of tubulin clusters. Structural requirements for optimal activity have been partially explained by molecular modeling.
- Zefirova, Olga N.,Nurieva, Evgeniya V.,Shishov, Dmitrii V.,Baskin, Igor I.,Fuchs, Fabian,Lemcke, Heiko,Schr?der, Fabian,Weiss, Dieter G.,Zefirov, Nikolay S.,Kuznetsov, Sergei A.
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supporting information; experimental part
p. 5529 - 5538
(2011/10/19)
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- Chemical synthesis of exochelins
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A process for the synthetic generation of high affinity, iron binding compounds known as Exochelins, and more particularly, to a synthetic process for making Exochelins and to modifications to these newly synthesized compounds to vary their physiological properties, including applications of these newly synthesized and utile compounds for diagnosing and treating disease in mammals.
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Page column 7
(2008/06/13)
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- Chemical synthesis of exochelins
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A process for the synthetic generation of high affinity, iron binding compounds known as Exochelins, and more particularly, to a synthetic process for making Exochelins and to modifications to these newly synthesized compounds to vary their physiological properties, including applications of these newly synthesized and utile compounds for diagnosing and treating disease in mammals.
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- Enzyme-assisted Preparation of Pure Alkanedicarboxylic Acid Monoesters: Chain-length Dependence of Porcine Liver Esterase (PLE)-catalysed Hydrolyses
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Porcine liver esterase (PJE)-catalysed hydrolyses of alkanedicarboxylic esters MeO2C-(CH2)n-CO2Me lead exclusively to pure monoesters if n 8.Using the active site model for PLE an interpretation of these surprising observations is attempted.
- Lobell, Mario,Schneider, Manfred P.
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p. 1713 - 1714
(2007/10/02)
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- Synthesis of Tetrahydrofuranic Acids Substituted in Position 2 and 5
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A synthesis of the 3,6-epoxyalkane diacids 9a-d previously detected in human urine is described.
- Kern, Werner,Spiteller, Gerhard
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p. 1168 - 1174
(2007/10/02)
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- SELECTIVE MONOMETHYL ESTERIFICATION OF DICARBOXYLIC ACIDS BY USE OF MONOCARBOXYLATE CHEMISORPTION ON ALUMINA.
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The application of alumina as a solid support affords a new procedure for selective reactions. Although it is difficult to obtain monoesters in the esterification of dicarboxylic acids by conventional methods, dicarboxylic acids adsorbed on alumina selectively form the monoesters. Terephthalic acid (1), isophthalic acid, cis- and trans-1,4-cyclohexanedicarboxylic acids, and aliphatic dicarboxylic acids give the corresponding monomethyl esters quantitatively with diazomethane. On the basis of these results, the authors suggest that dicarboxylic acids are adsorbed on alumina through one of their carboxyl groups, and the carboxyl group not adsorbed on the alumina is esterified selectively. Selective monomethyl esterification of phthalic acid is not successful on alumina, probably as a consequence of the close proximity of the two carboxyl groups and the forced orientation of the second group when one is adsorbed.
- Ogawa,Chihara,Taya
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p. 1365 - 1369
(2007/10/02)
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- Regioselective Functionalization of Non-Activated CH-bonds, 2. Photochemical Functionalization of the Myristoyl Group in 1,2-Alkanediyl and o-Phenylene 1-(4-Benzoylbenzoate) 2-Myristates
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Myristic acid (1a) was linked with ethylene glycol (2a), trans-1,2-cyclohexanediol (2b), and catechol (2c) to 4-benzoylbencoic acid to form the diesters 4a-c.These cyclize by photolysis to the carbinols 12, which are converted into the methyl 7- to 13-oxomyristates (5a).The ketofunctionalization of the remote CH2-groups in 1a is more selective than in the corresponding benzoylbenzoic esters 13 without the 1,2-alkanediyl or o-phenylene link.Additionally the maximum of the functionalization is shifted from the end towards the middle of the chain.The latter observation can be explained by a higher population of gauche conformations at the beginning of the chain.In CCl4 the selectivity increases slightly from 4a to 4b, c with increasing rigidity of the link.The polarity of the solvent has only a small effect on the selectivity.
- Dors, Bernhard,Luftmann, Heinrich,Schaefer, Hans J.
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p. 761 - 776
(2007/10/02)
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- Conjugate, Homoconjugate, and 1,2-Additions of Acetylene Nucleophiles and their Application to Prostaglandin Synthesis
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1-Acylcyclopent-1-enes (10) and (11) undergo 1,4- and 1,2-addition reactions with various alkynylalane reagents at ambient temperatures.Homoconjugate additions of alkynylalanes to endo-3-t-butyldimethylsilyloxytricyclo2,7>heptan-6-one (12) occur to give 7-anti-alkynylbicycloheptanones (24) and (25). 1-Lithioalk-1-ynes can undergo conjugate additions when the reagent is solvated with hexamethylphosphoric triamide. These reactions, designed to provide an approach to prostanoic acid derivatives and their intermediates, avoid the use of low temperatures for conjugate additions.
- Newton, Roger F.,Reynolds, Derek P.,Greenwood, John,Scheinmann, Feodor
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p. 2346 - 2352
(2007/10/02)
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