| 1. |
- Klein, Michael, 1971, et al.
(författare)
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Synthesis of chiral 1,4-disubstituted-1,2,3-triazole derivatives from amino acids
- 2009
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Ingår i: Molecules. - : MDPI AG. - 1431-5157 .- 1420-3049. ; 14:12, s. 5124-5143
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Tidskriftsartikel (refereegranskat)abstract
- A versatile method for the synthesis of chiral 1,4-disubstituted-1,2,3-triazole derivatives starting from easily accessible naturally occurring D-or L-amino acids as chiral synthons is described. The amino acids were converted into azido alcohols, followed by copper catalyzed [3+2] cycloaddition reactions between the azido alcohols and methyl propiolate and subsequent ester aminolysis with primary and secondary amines furnished the target compounds, which were obtained in excellent yields with no racemization. Docking of selected target compounds shows that the chiral 1,4-disubstituted-1,2,3-triazoles derivatives has the potential of mimicking the binding mode of known purine analogues.
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| 2. |
- Redwan, Itedale Namro, 1981
(författare)
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Design and Synthesis of Potential Aminoacyl-tRNA Synthetase Inhibitors
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes present in all living organisms, their catalytic activity is involved in the translation of the genetic code into functional proteins and they are potential targets for anti-infective agents. The first step in the biosynthetic pathway catalysed by aaRSs consists of activation of the corresponding amino acid by the reaction with ATP to form an aminoacyl-adenylate (aa-AMP), the key intermediate in the biosynthesis of proteins. As a result stable, analogues of aa-AMP have been identified as potential and valuable lead compounds for the development of potential aaRS inhibitors. This thesis describes the design and synthesis of potential aaRSs inhibitors. The studies involve the development of a novel solution-phase synthetic route to non-hydrolysable sulfamoyl-based aa-AMP analogues. Synthesis includes the development of a protective group strategy that utilises global deprotection under neutral conditions to minimise by-product formation. Optimal reaction conditions for the coupling of different amino acids to the sulfamoyl moiety have also been investigated. A solid-phase synthetic route leading to non-hydrolysable sulfamoyl-based aa-AMP analogues has also been developed. The novel synthetic route enables the possibility for rapid parallel synthesis of structurally diverse compounds in quantities sufficient for biological evaluation. Molecular modelling techniques have been used to gain understanding about the structure–activity relationship of the inhibitors of aaRSs based on non-hydrolysable aa-AMP analogues. A model ligand adopting the putative bioactive conformation was identified based on X-ray data and conformational searches. Novel phosphate bioisosteres of aa-AMP have been designed using the derived model. Molecular docking techniques were used for the design of ribose-free purine-based aa-AMP bioisosteres. The designed compounds were synthesised and evaluated biologically in an assay using aaRS isolated from Escherichia coli. A novel mild method for the activation and recycling of a tritylated solid-phase resin has also been developed. Recycling of recovered resin after the completion of a reaction is considered beneficial since it minimises the associated costs and is environmentally friendly. The method was used for the attachment of primary and secondary alcohols, halogen-containing alcohols and anilines to trityl resin.
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| 3. |
- Redwan, Itedale Namro, 1981, et al.
(författare)
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Investigation, optimization and synthesis of sulfamoyloxy-linked aminoacyl-AMP analogues
- 2012
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Ingår i: Tetrahedron. - : Elsevier BV. - 0040-4020 .- 1464-5416. ; 68, s. 1507-1514
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Tidskriftsartikel (refereegranskat)abstract
- Aminoacyl-tRNA synthetases (aaRSs) constitute a family of enzymes that transfer amino acids to their corresponding tRNA molecules to form aminoacyl-tRNAs and have been validated as potential drug targets. Sulfamoyloxy-linked aminoacyl-AMP analogues are potent inhibitors of aaRSs. In this article, we report the synthesis of several new sulfamoyl analogues of aa-AMP that up to now have been difficult or even impossible to prepare with current synthetic strategies. The developed synthetic strategy relies on performing the synthesis under neutral conditions followed by global deprotection using catalytic hydrogenation affording the desired 5′-O-(N-aminoacyl)sulfamoyladenosine compounds. © 2011 Elsevier Ltd. All rights reserved.
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| 4. |
- Redwan, Itedale Namro, 1981, et al.
(författare)
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Method for Activation and Recycling of Trityl Resins
- 2012
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 77:16, s. 7071-7075
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Tidskriftsartikel (refereegranskat)abstract
- This note describes a rapid and mild strategy for loading of alcohols and anilines onto a polystyrene triphenylmethyl (trityl) resin. High loadings were obtained in a matter of minutes by treating resin-bound trityl chloride with triethyloxonium tetrafluoroborate followed by alcohols or anilines. Yields were comparable or better than known literature methods. Recycling of the recovered resin was also possible using the developed method.
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| 5. |
- Redwan, Itedale Namro, 1981, et al.
(författare)
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Solid-Phase Synthesis of 5 '-O- N-(Acyl)sulfamoyl adenosine Derivatives
- 2012
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Ingår i: European Journal of Organic Chemistry. - : Wiley. - 1434-193X .- 1099-0690. ; 2012:19, s. 3665-3669
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Tidskriftsartikel (refereegranskat)abstract
- The solid-phase synthesis of 5'-O-[N-(acyl)sulfamoyl]adenosine derivatives is described. The use of a Rink amide polystyrene solid support together with an appropriately protected ribo-purine starting material allowed for the development of a highly reliable and practical route for the solid-phase synthesis of 5'-O-[N-(acyl)sulfamoyl]adenosines. The developed procedure enables the efficient parallel synthesis of the target compounds in high yields. These compounds are non-hydrolysable isosteres of acyl-adenylates, which play an important role in a range of different metabolic pathways such as ribosomal and non-ribosomal peptide synthesis, fatty acid oxidation or enzyme regulation; some adenylate-forming enzymes are potential drug targets.
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| 6. |
- Redwan, Itedale Namro, 1981, et al.
(författare)
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Synthesis and photophysical characterization of 1-and 4-(purinyl) triazoles
- 2013
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Ingår i: Tetrahedron. - : Elsevier BV. - 0040-4020. ; 69:42, s. 8857-8864
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Tidskriftsartikel (refereegranskat)abstract
- Fluorescent adenine mimetics are useful tools for studying DNA, RNA and enzyme functions. Herein we describe the synthesis of eight 1-(purinyl)triazoles and two 4-(purinyl)triazoles utilizing the 1,4-regioselective copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction as the key step. The fluorescence properties of five of the synthesized 1-(purinyl)triazoles are also presented. The five measured compounds displayed low quantum yields. The results, when compared to previously published data, suggest a high influence of the substitution pattern of the triazole on the fluorescence properties.
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| 7. |
- Redwan, Itedale Namro, 1981, et al.
(författare)
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Towards the development of chromone-based MEK1/2 modulators
- 2014
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234. ; 85, s. 127-138
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Tidskriftsartikel (refereegranskat)abstract
- Inhibition or allosteric modulation of mitogen-activated protein kinase kinases MEK1 and MEK2 (MEK1/2) represent a promising strategy for the discovery of new specific anticancer agents. In this paper, structure-based design, beginning from the lead compound PD98059, was used to study potential structural modifications on the chromone structure in order to obtain highly potent derivatives that target the allosteric pocket in MEK1. Subsequently, a small series of PD98059 analogs were synthesized to provide a first generation of chromone-based derivatives that inhibit the activation of MEK1 with IC50 values as low as 30 nM in vitro. Complementary cellular studies also showed that two of the compounds in the series inhibit the activity of MEK1/2 with IC50 values in the nanomolar range (73-97 nM). In addition, compounds in this series were found to inhibit the proliferation of a small panel of human cancer cell lines.
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| 8. |
- Sjölander, Johanna J, 1980, et al.
(författare)
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A redox-sensitive thiol in Wis1 modulates the fission yeast MAPK response to H2O2 and is the target of a small molecule.
- 2020
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Ingår i: Molecular and Cellular Biology. - 0270-7306 .- 1098-5549. ; 40:7
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Tidskriftsartikel (refereegranskat)abstract
- Oxidation of a highly-conserved cysteine (Cys) residue located in the kinase-activation loop of mitogen-activated protein kinase kinases (MAPKK) inactivates mammalian MKK6. This residue is conserved in the fission yeast MAPKK Wis1, which belongs to the H2O2-responsive MAPK Sty1 pathway. Here, we show that H2O2 reversibly inactivates Wis1 through this residue (C458) in vitro. We found that C458 is oxidized in vivo and that serine substitution of this residue significantly enhances Wis1 activation upon addition of H2O2 The allosteric MAPKK inhibitor, INR119, which binds in a pocket next to the activation loop and C458 prevented the inhibition of Wis1 by H2O2in vitro, and significantly increased Wis1 activation by low levels of H2O2in vivo We propose that oxidation of C458 inhibits Wis1 and that INR119 cancels out this inhibitory effect by binding close to this residue. Kinase inhibition through the oxidation of a conserved Cys residue in MKK6 (C196) is thus conserved in the S. pombe MAPKK Wis1.
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| 9. |
- Sjölander, Johanna J., et al.
(författare)
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A Redox-Sensitive Thiol in Wis1 Modulates the Fission Yeast Mitogen-Activated Protein Kinase Response to H2O2 and Is the Target of a Small Molecule
- 2020
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Ingår i: Molecular and cellular biology. - 1098-5549 .- 0270-7306. ; 40:7
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Tidskriftsartikel (refereegranskat)abstract
- Oxidation of a highly conserved cysteine (Cys) residue located in the kinase activation loop of mitogen-activated protein kinase kinases (MAPKK) inactivates mammalian MKK6. This residue is conserved in the fission yeast Schizosaccharomyces pombe MAPKK Wis1, which belongs to the H2O2-responsive MAPK Sty1 pathway. Here, we show that H2O2 reversibly inactivates Wis1 through this residue (C458) in vitro We found that C458 is oxidized in vivo and that serine replacement of this residue significantly enhances Wis1 activation upon addition of H2O2 The allosteric MAPKK inhibitor INR119, which binds in a pocket next to the activation loop and C458, prevented the inhibition of Wis1 by H2O2in vitro and significantly increased Wis1 activation by low levels of H2O2in vivo We propose that oxidation of C458 inhibits Wis1 and that INR119 cancels out this inhibitory effect by binding close to this residue. Kinase inhibition through the oxidation of a conserved Cys residue in MKK6 (C196) is thus conserved in the S. pombe MAPKK Wis1.
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