- 3,4-Dichloroaniline is detoxified and exported via different pathways in Arabidopsis and soybean
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The metabolic fate of [UL-14C]-3,4-dichloroaniline (DCA) was investigated in Arabidopsis root cultures and soybean plants over a 48 h period following treatment via the root media. DCA was rapidly taken up by both species and metabolised, predominantly to N-malonyl-DCA in soybean and N-glucosyl-DCA in Arabidopsis. Synthesis occurred in the roots and the respective conjugates were largely exported into the culture medium, a smaller proportion being retained within the plant tissue. Once conjugated, the DCA metabolites in the medium were not then readily taken up by roots of either species. The difference in the routes of DCA detoxification in the two plants could be explained partly by the relative activities of the respective conjugating enzymes, soybean containing high DCA-N-malonyltransferase activity, while in Arabidopsis DCA-N-glucosyltransferase activity predominated. A pre-treatment of plants with DCA increased DCA-N-malonyltransferase activity in soybean but not in Arabidopsis, indicating differential regulation of this enzyme in the two plant species. This study demonstrates that DCA can undergo two distinct detoxification mechanisms which both lead to the export of conjugated metabolites from roots into the surrounding medium in contrast to the vacuolar deposition more commonly associated with the metabolism of xenobiotics in plants.
- Lao, Si-Houy,Loutre, Caroline,Brazier, Melissa,Coleman, Julian O.D.,Cole, David J.,Edwards, Robert,Theodoulou, Frederica L.
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- Tackling Pseudomonas aeruginosa Virulence by a Hydroxamic Acid-Based LasB Inhibitor
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In search of novel antibiotics to combat the challenging spread of resistant pathogens, bacterial proteases represent promising targets for pathoblocker development. A common motif for protease inhibitors is the hydroxamic acid function, yet this group has often been related to unspecific inhibition of various metalloproteases. In this work, the inhibition of LasB, a harmful zinc metalloprotease secreted by Pseudomonas aeruginosa, through a hydroxamate derivative is described. The present inhibitor was developed based on a recently reported, highly selective thiol scaffold. Using X-ray crystallography, the lack of inhibition of a range of human matrix metalloproteases could be attributed to a distinct binding mode sparing the S1′ pocket. The inhibitor was shown to restore the effect of the antimicrobial peptide LL-37, decrease the formation of P. aeruginosa biofilm and, for the first time for a LasB inhibitor, reduce the release of extracellular DNA. Hence, it is capable of disrupting several important bacterial resistance mechanisms. These results highlight the potential of protease inhibitors to fight bacterial infections and point out the possibility to achieve selective inhibition even with a strong zinc anchor.
- Kany, Andreas M.,Sikandar, Asfandyar,Yahiaoui, Samir,Haupenthal, J?rg,Walter, Isabell,Empting, Martin,K?hnke, Jesko,Hartmann, Rolf W.
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- MALONAMIDE DERIVATIVES
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The present invention relates to malonamide derivatives of formula (I): A-D-B, the use of the compounds of formula (I) as inhibitors of raf-kinase, the use of the compounds of formula (I) for the manufacture of a pharmaceutical composition and a method of treatment, comprising administering said pharmaceutical composition to a patient.
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- Synthesis and structure-activity relationships of 1,2,3,4- tetrahydroquinoline-2,3,4-trione 3-oximes: Novel and highly potent antagonists for NMDA receptor glycine site
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A series of 1,2,3,4-tetrahydroquinoline-2,3,4-trione 3-oximes (QTOs) was synthesized and evaluated for antagonism of NMDA receptor glycine site. Glycine site affinity was determined using a [3H]DCKA binding assay in rat brain membranes and electrophysiologically in Xenopus oocytes expressing 1a/2C subunits of cloned rat NMDA receptors. Selected compounds were also assayed for antagonism of AMPA receptors in Xenopus oocytes expressing rat brain poly-(A)+ RNA. QTOs were prepared by nitrosation of 2,4- quinolinediols. Structure-activity studies indicated that substitutions in the 5-, 6-, and 7-positions increase potency, whereas substitution in the 8- position causes a decrease in potency. Among the derivatives evaluated, 5,6,7-trichloro-QTO was the most potent antagonist with an IC50 of 7 nM in the [3H]DCKA binding assay and a K(b) of 1-2 nM for NMDA receptors expressed in Xenopus oocytes. 5,6,7-Trichloro-QTO also had a K(b) of 180 nM for AMPA receptors in electrophysiological assays. The SAR of QTOs was compared with the SAR of 1,4-dihydroquinoxaline-2,3-diones (QXs). For compounds with the same benzene ring substitution pattern, QTOs were generally 5-10 times more potent than the corresponding QXs. QTOs represent a new class of inhibitors of the NMDA receptor which, when appropriately substituted, are among the most potent glycine site antagonists known.
- Cai, Sui Xiong,Zhou, Zhang-Lin,Huang, Jin-Cheng,Whittemore, Edward R.,Egbuwoku, Zizi O.,Lü, Yixin,Hawkinson, Jon E.,Woodward, Richard M.,Weber, Eckard,Keana, John F. W.
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p. 3248 - 3255
(2007/10/03)
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- A convenient one-pot synthesis of N-arylmalonamic acid via in-situ generation of malonyl monoacyl chloride
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A convenient one-pot synthesis of N-arylmalonamic acid has been demonstrated based on the in-situ generation of malonyl monoacyl chloride, followed by reaction with aniline.
- Shih, Hsiencheng,Rankin, Gary O.
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p. 833 - 836
(2007/10/03)
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