13089-45-7Relevant articles and documents
8-Substituted, syn-Configured Adenosine Derivatives as Potential Inhibitors of the Enzyme IspE from the Non-Mevalonate Pathway of Isoprenoid Biosynthesis
Harder, Michael,Sch?fer, Elisabeth,Kümin, Tobias,Illarionov, Boris,Bacher, Adelbert,Fischer, Markus,Diederich, Fran?ois,Bernet, Bruno
, p. 7276 - 7286 (2015)
The enzymes of the non-mevalonate pathway for isoprenoid biosynthesis are attractive targets for drugs against various diseases, including malaria. We describe herein the structure-based design, synthesis, conformational analysis, and biological evaluation of several 8-brominated or 8-aminated adenosine derivatives with different substituents at C(5′), targeting the ATP-adenine binding site of the IspE protein from the non-mevalonate pathway. An exhaustive conformational analysis of the adenosine derivatives both in solution and in the solid state confirmed the desired syn orientation of the adenine moiety. Despite this favorable pre-organization for binding to the cofactor pocket, biological evaluation of the inhibitors showed only a very modest inhibitory activity.
Kinetic Optimization of Lysine-Targeting Covalent Inhibitors of HSP72
Pettinger, Jonathan,Carter, Michael,Jones, Keith,Cheeseman, Matthew D.
, p. 11383 - 11398 (2019/12/30)
The covalent inhibition mechanism of action, which overcomes competition with high-affinity, high-abundance substrates of challenging protein targets, can deliver effective chemical probes and drugs. The success of this strategy has centered on exposed cy
Structure-activity relationship of adenosine 5′-diphosphoribose at the transient receptor potential melastatin 2 (TRPM2) channel: Rational design of antagonists
Moreau, Christelle,Kirchberger, Tanja,Swarbrick, Joanna M.,Bartlett, Stephen J.,Fliegert, Ralf,Yorgan, Timur,Bauche, Andreas,Harneit, Angelika,Guse, Andreas H.,Potter, Barry V. L.
supporting information, p. 10079 - 10102 (2014/01/17)
Adenosine 5′-diphosphoribose (ADPR) activates TRPM2, a Ca 2+, Na+, and K+ permeable cation channel. Activation is induced by ADPR binding to the cytosolic C-terminal NudT9-homology domain. To generate the first structure-activity relationship, systematically modified ADPR analogues were designed, synthesized, and evaluated as antagonists using patch-clamp experiments in HEK293 cells overexpressing human TRPM2. Compounds with a purine C8 substituent show antagonist activity, and an 8-phenyl substitution (8-Ph-ADPR, 5) is very effective. Modification of the terminal ribose results in a weak antagonist, whereas its removal abolishes activity. An antagonist based upon a hybrid structure, 8-phenyl-2′-deoxy-ADPR (86, IC50 = 3 μM), is more potent than 8-Ph-ADPR (5). Initial bioisosteric replacement of the pyrophosphate linkage abolishes activity, but replacement of the pyrophosphate and the terminal ribose by a sulfamate-based group leads to a weak antagonist, a lead to more drug-like analogues. 8-Ph-ADPR (5) inhibits Ca2+ signalling and chemotaxis in human neutrophils, illustrating the potential for pharmacological intervention at TRPM2.
Total synthesis of a cyclic adenosine 5′-diphosphate ribose receptor agonist
Swarbrick, Joanna M.,Potter, Barry V. L.
experimental part, p. 4191 - 4197 (2012/06/18)
Stable cyclic adenosine 5′-diphosphate ribose (cADPR) analogues are chemical biology tools that can probe the Ca2+ release mechanism and structure-activity relationships of this emerging potent second messenger. However, analogues with an intac
Inhibition of siderophore biosynthesis in Mycobacterium tuberculosis with nucleoside bisubstrate analogues: Structure-activity relationships of the nucleobase domain of 5′-O-[N-(salicyl)sulfamoyl]adenosine
Neres, Jo?o,Labello, Nicholas P.,Somu, Ravindranadh V.,Boshoff, Helena I.,Wilson, Daniel J.,Vannada, Jagadeshwar,Chen, Liqiang,Barry III, Clifton E.,Bennett, Eric M.,Aldrich, Courtney C.
experimental part, p. 5349 - 5370 (2009/07/01)
5′-O-[N-(salicyl)sulfamoyl]adenosine (Sal-AMS) is a prototype for a new class of antitubercular agents that inhibit the aryl acid adenylating enzyme (AAAE) known as MbtA involved in biosynthesis of the mycobactins. Herein, we report the structure-based design, synthesis, biochemical, and biological evaluation of a comprehensive and systematic series of analogues, exploring the structure-activity relationship of the purine nucleobase domain of Sal-AMS. Significantly, 2-phenyl-Sal-AMS derivative 26 exhibited exceptionally potent antitubercular activity with an MIC99 under iron-deficient conditions of 0.049 μM while the N-6-cyclopropyl-Sal-AMS 16 led to improved potency and to a 64-enhancement in activity under iron-deficient conditions relative to iron-replete conditions, a phenotype concordant with the designed mechanism of action. The most potent MbtA inhibitors disclosed here display in vitro antitubercular activity superior to most current first line TB drugs, and these compounds are also expected to be useful against a wide range of pathogens that require aryl-capped siderphores for virulence.
Antibacterial Agents
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Page/Page column 51-52, (2009/01/20)
The invention provides compounds of formula (I) and salts thereof: R1-L-R2—B wherein R1, L, R2, and B have any of the values defined herein, as well as compositions comprising such compounds, and therapeutic methods comprising the administration of such compounds or salts. The compounds block siderophore production in bacteria and are useful as antibacterial agents.
The elusive 8-fluoroadenosine: a simple non-enzymatic synthesis and characterization
Butora, Gabor,Schmitt, Christoph,Levorse, Dorothy A.,Streckfuss, Eric,Doss, George A.,MacCoss, Malcolm
, p. 3782 - 3789 (2008/02/01)
The only successful synthesis of 8-fluoroadenosine reported until now relied on an enzymatic removal of the acetate protecting groups using thermally resistant hydrolases. In the present communication we describe the first non-enzymatic synthesis of 8-fluoroadenosine. According to this, the C8-fluorine atom was introduced in a halogen-exchange process performed at elevated temperature. The chief obstacle in the synthesis of 8-fluoroadenosine, the removal of the protecting groups in the presence of the labile C8-F bond, was addressed by judicious choice of acid-labile protecting groups. Their deprotection in the presence of C8-F is described. Using this newly developed procedure, significant quantities of 8-fluoroadenosine were synthesized and, for the first time, its physicochemical properties including pH-dependent stability, examined in detail. The intermediate generation of 8-fluoroadenosines as a tool to increase the reaction rates of nucleophilic substitutions was briefly examined and successfully demonstrated with the example of 8-cyanoadenosine. The presented procedure is applicable to the synthesis of various adenosine analogs with potential pharmacological significance.
N3,5′-Cycloxanthosine, the first natural occurrence of a cyclonucleoside
Capon, Robert J.,Trotter, Nicholas S.
, p. 1689 - 1691 (2008/09/17)
An Eryus sp. of marine sponge from the Great Australian Bight has yielded the first reported natural occurrence of a cyclonucleoside, N 3,5'-cycloxanthosine. The structure of N3,5'- cycloxanthosine was confirmed by detailed spectroscopic analysis and total synthesis. 2005 American Chemical Society and American Society of Pharmacognosy.
ATP-lipids - Protein anchor and energy source in two dimensions
Schmitt, Lutz,Tampé, Robert
, p. 5532 - 5543 (2007/10/03)
The ubiquitous function of ATP as energy equivalent in nature has resulted in a common folding pattern of ATP-binding proteins. Their binding pocket tolerates modifications of the adenine ring to some extend, whereas those of the triphosphate group strong
