4412-16-2Relevant academic research and scientific papers
Modulation of antibiotic sensitivity and biofilm formation in Pseudomonas aeruginosa by interspecies signal analogues
An, Shi-qi,Murtagh, Julie,Twomey, Kate B.,Gupta, Manoj K.,O’Sullivan, Timothy P.,Ingram, Rebecca,Valvano, Miguel A.,Tang, Ji-liang
, (2019/06/05)
Pseudomonas aeruginosa, a significant opportunistic pathogen, can participate in inter-species communication through signaling by cis-2-unsaturated fatty acids of the diffusible signal factor (DSF) family. Sensing these signals leads to altered biofilm formation and increased tolerance to various antibiotics, and requires the histidine kinase PA1396. Here, we show that the membrane-associated sensory input domain of PA1396 has five transmembrane helices, two of which are required for DSF sensing. DSF binding is associated with enhanced auto-phosphorylation of PA1396 incorporated into liposomes. Further, we examined the ability of synthetic DSF analogues to modulate or inhibit PA1396 activity. Several of these analogues block the ability of DSF to trigger auto-phosphorylation and gene expression, whereas others act as inverse agonists reducing biofilm formation and antibiotic tolerance, both in vitro and in murine infection models. These analogues may thus represent lead compounds to develop novel adjuvants improving the efficacy of existing antibiotics.
Unexpected AChE inhibitory activity of (2E)α,β-unsaturated fatty acids
Loesche, Anne,Wiemann, Jana,Al Halabi, Zayan,Karasch, Julia,Sippl, Wolfgang,Csuk, René
, p. 3315 - 3319 (2018/09/17)
A small library of (E) α,β-unsaturated fatty acids was prepared, and 20 different saturated and mono-unsaturated fatty acids differing in chain length were subjected to Ellman's assays to determine their ability to act as inhibitors for AChE or BChE. While the compounds were only very weak inhibitors of BChE, seven molecules were inhibitors of AChE holding IC50 = 4.3–12.8 M with three of them as significant inhibitors of this enzyme. The results have shown trans 2-mono-unsaturated fatty acids are better inhibitors for AChE than their saturated analogs. Furthermore, the screening results indicate that the chain length is crucial for obtaining an inhibitory efficacy. The best results were obtained for (2E) eicosenoic acid (14) showing inhibition constants Ki = 1.51 ± 0.09 M and Ki′ = 7.15 ± 0.55 M. All tested compounds were mixed-type inhibitors with a dominating competitive part. Molecular modelling calculations indicate a different binding mode of active/inactive compounds for the enzymes AChE and BChE.
Synthesis and evaluation of analogues of the glycinocin family of calcium-dependent antibiotics
Corcilius, Leo,Liu, Dennis Y.,Ochoa, Jessica L.,Linington, Roger G.,Payne, Richard J.
, p. 5310 - 5320 (2018/08/03)
The glycinocins are a class of calcium-dependent, acidic cyclolipopeptide antibiotics that are structurally related to the clinically approved antibiotic daptomycin. In this article, we describe the synthesis of a small library of glycinocin analogues that differ by variation in the exocyclic fatty acyl substituent. The glycinocin analogues were screened against a panel of Gram-positive bacteria (as well as Gram-negative P. aeruginosa). These analogues exhibited similar calcium-dependent activity to the parent natural products against Gram-positive bacteria but showed no activity against P. aeruginosa. The length of the fatty acid was shown to be important for optimal biological activity, while the hybridisation at the α,β position and branching within the fatty acyl chain had only subtle effects on activity.
Synthesis of α,β-unsaturated aldehydes as potential substrates for bacterial luciferases
Brodl, Eveline,Ivkovic, Jakov,Tabib, Chaitanya R.,Breinbauer, Rolf,Macheroux, Peter
, p. 1487 - 1495 (2017/02/18)
Bacterial luciferase catalyzes the monooxygenation of long-chain aldehydes such as tetradecanal to the corresponding acid accompanied by light emission with a maximum at 490?nm. In this study even numbered aldehydes with eight, ten, twelve and fourteen carbon atoms were compared with analogs having a double bond at the α,β-position. These α,β-unsaturated aldehydes were synthesized in three steps and were examined as potential substrates in vitro. The luciferase of Photobacterium leiognathi was found to convert these analogs and showed a reduced but significant bioluminescence activity compared to tetradecanal. This study showed the trend that aldehydes, both saturated and unsaturated, with longer chain lengths had higher activity in terms of bioluminescence than shorter chain lengths. The maximal light intensity of (E)-tetradec-2-enal was approximately half with luciferase of P. leiognathi, compared to tetradecanal. Luciferases of Vibrio harveyi and Aliivibrio fisheri accepted these newly synthesized substrates but light emission dropped drastically compared to saturated aldehydes. The onset and the decay rate of bioluminescence were much slower, when using unsaturated substrates, indicating a kinetic effect. As a result the duration of the light emission is doubled. These results suggest that the substrate scope of bacterial luciferases is broader than previously reported.
Cobalt-Catalyzed Allylic C(sp3)-H Carboxylation with CO2
Michigami, Kenichi,Mita, Tsuyoshi,Sato, Yoshihiro
, p. 6094 - 6097 (2017/05/08)
Catalytic carboxylation of the allylic C(sp3)-H bond of terminal alkenes with CO2 was developed with the aid of a Co/Xantphos complex. A wide range of allylarenes and 1,4-dienes were successfully transformed into the linear styrylacetic acid and hexa-3,5-dienoic acid derivatives in moderate to high yields, with excellent regioselectivity. The carboxylation showed remarkable functional group tolerability, so that selective addition to CO2 occurred in the presence of other carbonyl groups such as amide, ester, and ketone. Since styrylacetic acid derivatives can be readily converted into optically active γ-butyrolactones through Sharpless asymmetric dihydroxylation, this allylic C(sp3)-H carboxylation showcases a facile synthesis of γ-butyrolactones from simple allylarenes via short steps.
Allyl-Palladium-Catalyzed α,β-Dehydrogenation of Carboxylic Acids via Enediolates
Zhao, Yizhou,Chen, Yifeng,Newhouse, Timothy R.
supporting information, p. 13122 - 13125 (2017/09/13)
A highly practical and step-economic α,β-dehydrogenation of carboxylic acids via enediolates is reported through the use of allyl-palladium catalysis. Dianions underwent smooth dehydrogenation when generated using Zn(TMP)2?2 LiCl as a base in the presence of excess ZnCl2, thus avoiding the typical decarboxylation pathway of these substrates. Direct access to 2-enoic acids allows derivatization by numerous approaches.
An Unusual Iron-Dependent Oxidative Deformylation Reaction Providing Insight into Hydrocarbon Biosynthesis in Nature
Ellington, Benjamin R.,Paul, Bishwajit,Das, Debasis,Vitek, Andrew K.,Zimmerman, Paul M.,Marsh, E. Neil G.
, p. 3293 - 3300 (2016/07/06)
The development of new pathways for next-generation biofuel production has spurred recent investigations into the mechanisms of enzymes that biosynthesize hydrocarbons. One widely distributed group of enzymes, aldehyde decarbonylases, catalyze unusual deformylation reactions in which long-chain fatty aldehydes are converted to alkanes. These enzymes are all iron-dependent and in insects are represented by a cytochrome P450 enzyme that releases the aldehyde carbon as CO2. Here we describe a novel nonenzymatic reaction of an α-cyclopropyl-substituted aldehyde that mimics the enzyme reaction. This aldehyde is oxidatively deformylated in the presence of aqueous iron(II) salts and oxygen to yield an alkyl-substituted cyclopropane and CO2, in a reaction that competes with the more conventional oxidation of the aldehyde to the carboxylic acid. Like the enzymatic reaction, the reaction occurs with retention of the aldehyde proton in the alkane product and probably proceeds through an iron-peroxo species. Computational reaction discovery tools were used to search for potential reaction pathways and investigate their energetic feasibility. These identified a plausible reaction pathway leading to the experimentally observed products and reproduced the transfer of the aldehyde proton to the cyclopropane product. These studies provide further insight into how enzymes may control reactive iron-oxo species to catalyze the diverse range of iron-dependent oxidative transformations observed in biology.
MANUFACTURING METHOD OF α,β-UNSATURATED CARBOXYLIC ACID
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Paragraph 0050-0052, (2018/10/16)
PROBLEM TO BE SOLVED: To provide a manufacturing method which can get α,β-unsaturated carboxylic acid at a high yield by liquid phase oxidation of α,β-unsaturated aldehyde by oxygen or air with a handy metal catalyst under a mild reaction condition. SOLUTION: Preferably under a presence of organic solvent, α,β-unsaturated carboxylic acid is manufactured by oxidation of α,β-unsaturated aldehydes and oxygen or air under a presence of an iron salt catalyst and a catalyst of alkali metal salt of carboxylic acid. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT
A Continuous, Fluorogenic Sirtuin 2 Deacylase Assay: Substrate Screening and Inhibitor Evaluation
Galleano, Iacopo,Schiedel, Matthias,Jung, Manfred,Madsen, Andreas S.,Olsen, Christian A.
supporting information, p. 1021 - 1031 (2016/02/23)
Sirtuins are important regulators of lysine acylation, which is implicated in cellular metabolism and transcriptional control. This makes the sirtuin class of enzymes interesting targets for development of small molecule probes with pharmaceutical potential. To achieve detailed profiling and kinetic insight regarding sirtuin inhibitors, it is important to have access to efficient assays. In this work, we report readily synthesized fluorogenic substrates enabling enzyme-economical evaluation of SIRT2 inhibitors in a continuous assay format as well as evaluation of the properties of SIRT2 as a long chain deacylase enzyme. Novel enzymatic activities of SIRT2 were thus established in vitro, which warrant further investigation, and two known inhibitors, suramin and SirReal2, were profiled against substrates containing ε-N-acyllysine modifications of varying length.
