A role for 3′-O-β-D-ribofuranosyladenosine in altering plant immunity

Our understanding of how, and the extent to which, phytopathogens reconfigure host metabolic pathways to enhance virulence is remarkably limited. Here we investigate the dynamics of the natural disaccharide nucleoside, 3′-O-β-D-ribofuranosyladenosine, in leaves of Arabidopsis thaliana infected with virulent Pseudomonas syringae pv. tomato strain DC3000. 3′-O-β-D-ribofuranosyladenosine is a plant derived molecule that rapidly accumulates following delivery of P. syringae type III effectors to represent a major component of the infected leaf metabolome. We report the first synthesis of 3′-O-β-D-ribofuranosyladenosine using a method involving the condensation of a small excess of 1-O-acetyl-2,3,5-three-O-benzoyl-β-ribofuranose activated with tin tetrachloride with 2′,5′-di-O-tert-butyldimethylsilyladenosine in 1,2-dichloroethane with further removal of silyl and benzoyl protecting groups. Interestingly, application of synthetic 3′-O-β-D-ribofuranosyladenosine did not affect either bacterial multiplication or infection dynamics suggesting a major reconfiguration of metabolism during pathogenesis and a heavy metabolic burden on the infected plant

Comparative Analysis of Enzymatic Transglycosylation Using E. coli Nucleoside Phosphorylases: A Synthetic Concept for the Preparation of Purine Modified 2′-Deoxyribonucleosides from Ribonucleosides

A comparative analysis of the transglycosylation conditions catalyzed by E. coli nucleoside phosphorylases, leading to the formation of 2′-deoxynucleosides, was performed. We demonstrated that maximal yields of 2′-deoxynucleosides, especially modified, can be achieved under small excess of glycosyl-donor (7-methyl-2′-deoxyguanosine, thymidine) and a 4-fold lack of phosphate. A phosphate concentration less than equimolar one allows using only a slight excess of the carbohydrate residue donor nucleoside to increase the reaction’s output. A three-step methodology was elaborated for the preparative synthesis of purine-modified 2′-deoxyribonucleosides, starting from the corresponding ribonucleosides

Regioselective 1-N-Alkylation and Rearrangement of Adenosine Derivatives

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Synthesis of Poly(ADP-ribose) Monomer Containing 2'-O-α-D-Ribofuranosyl Adenosine.

In this article, the earlier reported procedure for the synthesis of 2'-O-β-D-ribofuranosyl nucleosides was extended to the synthesis of 2'-O-α-D-ribofuranosyl adenosine, a monomeric unit of poly(ADP-ribose). It consists in condensation of a small excess of 1-O-acetyl-2,3,5-tri-O-benzoyl-α,β-D-arabinofuranose activated with tin tetrachloride with 3',5'-O-tetra-isopropyldisiloxane-1,3-diyl-ribonucleosides in 1,2-dichloroethane. The following debenzoylation and silylation of arabinofuranosyl residue and inversion of configuration at C-2'' atom of arabinofuranosyl residue and final removal of silyl protective groups gave 2'-O-α-D-ribofuranosyl adenosine in overall 13% to 21% yield. © 2019 by John Wiley & Sons, Inc.status: publishe

Fluorination of naturally occurring N⁶-benzyladenosine remarkably increased its antiviral activity and selectivity

Recently, we demonstrated that the natural cytokinin nucleosides N⁶-isopentenyladenosine (iPR) and N⁶-benzyladenosine (BAPR) exert a potent and selective antiviral effect on the replication of human enterovirus 71. In order to further characterize the antiviral profile of this class of compounds, we generated a series of fluorinated derivatives of BAPR and evaluated their activity on the replication of human enterovirus 71 in a cytopathic effect (CPE) reduction assay. The monofluorination of the BAPR-phenyl group changed the selectivity index (SI) slightly because of the concomitant high cell toxicity. Interestingly, the incorporation of a second fluorine atom resulted in a dramatic improvement of selectivity. Moreover, N⁶-trifluoromethylbenzyladenosines derivatives (9-11) exhibited also a very interesting profile, with low cytotoxicity observed. In particular, the analogue N⁶-(3-trifluoromethylbenzyl)-adenosine (10) with a four-fold gain in potency as compared to BAPR and the best SI in the class represents a promising candidate for further development.status: publishe

Fluorination of Naturally Occurring N6-Benzyladenosine Remarkably Increased Its Antiviral Activity and Selectivity

Recently, we demonstrated that the natural cytokinin nucleosides N6-isopentenyladenosine (iPR) and N6-benzyladenosine (BAPR) exert a potent and selective antiviral effect on the replication of human enterovirus 71. In order to further characterize the antiviral profile of this class of compounds, we generated a series of fluorinated derivatives of BAPR and evaluated their activity on the replication of human enterovirus 71 in a cytopathic effect (CPE) reduction assay. The monofluorination of the BAPR-phenyl group changed the selectivity index (SI) slightly because of the concomitant high cell toxicity. Interestingly, the incorporation of a second fluorine atom resulted in a dramatic improvement of selectivity. Moreover, N6-trifluoromethylbenzyladenosine derivatives (9–11) exhibited also a very interesting profile, with low cytotoxicity observed. In particular, the analogue N6-(3-trifluoromethylbenzyl)-adenosine (10) with a four-fold gain in potency as compared to BAPR and the best SI in the class represents a promising candidate for further development

Novel group of tyrosyl-DNA-phosphodiesterase 1 inhibitors based on disaccharide nucleosides as drug prototypes for anti-cancer therapy

A new class of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors based on disaccharide nucleosides was identified. TDP1 plays an essential role in the resistance of cancer cells to currently used antitumour drugs based on Top1 inhibitors such as topotecan and irinotecan. The most effective inhibitors investigated in this study have IC50 values (half-maximal inhibitory concentration) in 0.4–18.5 µM range and demonstrate relatively low own cytotoxicity along with significant synergistic effect in combination with anti-cancer drug topotecan. Moreover, kinetic parameters of the enzymatic reaction and fluorescence anisotropy were measured using different types of DNA-biosensors to give a sufficient insight into the mechanism of inhibitor’s action

In Planta, In Vitro and In Silico Studies of Chiral N6-Benzyladenine Derivatives: Discovery of Receptor-Specific S-Enantiomers with Cytokinin or Anticytokinin Activities

Cytokinins, classical phytohormones, affect all stages of plant ontogenesis, but their application in agriculture is limited because of the lack of appropriate ligands, including those specific for individual cytokinin receptors. In this work, a series of chiral N6-benzyladenine derivatives were studied as potential cytokinins or anticytokinins. All compounds contained a methyl group at the &alpha;-carbon atom of the benzyl moiety, making them R- or S-enantiomers. Four pairs of chiral nucleobases and corresponding ribonucleosides containing various substituents at the C2 position of adenine heterocycle were synthesized. A nucleophilic substitution reaction by secondary optically active amines was used. A strong influence of the chirality of studied compounds on their interaction with individual cytokinin receptors of Arabidopsis thaliana was uncovered in in vivo and in vitro assays. The AHK2 and CRE1/AHK4 receptors were shown to have low affinity for the studied S-nucleobases while the AHK3 receptor exhibited significant affinity for most of them. Thereby, three synthetic AHK3-specific cytokinins were discovered: N6-((S)-&alpha;-methylbenzyl)adenine (S-MBA), 2-fluoro,N6-((S)-&alpha;-methylbenzyl)adenine (S-FMBA) and 2-chloro,N6-((S)-&alpha;-methylbenzyl)adenine (S-CMBA). Interaction patterns between individual receptors and specific enantiomers were rationalized by structure analysis and molecular docking. Two other S-enantiomers (N6-((S)-&alpha;-methylbenzyl)adenosine, 2-amino,N6-((S)-&alpha;-methylbenzyl)adenosine) were found to exhibit receptor-specific and chirality-dependent anticytokinin properties

Modification of the length and structure of the linker of N(6)-benzyladenosine modulates its selective antiviral activity against enterovirus 71

Very recently, we demonstrated that N(6)-isopentenyladenosine, a cytokinin nucleoside, exerts a potent and selective antiviral effect on the replication of human enterovirus 71. The present study is devoted to the structure optimization of another natural compound: N(6)-benzyladenosine. We mainly focused on the exploration of the size and nature of the linker between the adenine and the phenyl ring, as well as on the necessity of the D-ribose residue. More than 30 analogues of N(6)-benzyladenosine were prepared and their antiviral properties were evaluated. Two main methodologies were used for preparation: N(6)-acetyl-2',3',5'-tri-O-acetyladenosine can be regioselectively alkylated either by alkyl halides under base promoted conditions or by alcohols in Mitsunobu reactions. After deacylation with 4 M PrNH2 in MeOH at room temperature for one day, the desired products were obtained in overall high yields. Analysis of the structure-activity relationship clearly shows that the optimal size of the linker is limited to 2 or 3 atoms (compounds 4-7). 2'-Deoxyadenosine derivatives did not elicit any inhibitory or cytotoxic effect, while 5'-deoxynucleosides still induced some cell protective antiviral activity. Based on these observations, it can be hypothesized that there may be another mechanism that is at the base of the antiviral activity of these compounds against enterovirus 71 besides a possible 5'-triphosphorylation followed by a putative inhibitory effect on RNA synthesis.publisher: Elsevier articletitle: Modification of the length and structure of the linker of N6-benzyladenosine modulates its selective antiviral activity against enterovirus 71 journaltitle: European Journal of Medicinal Chemistry articlelink: http://dx.doi.org/10.1016/j.ejmech.2016.01.036 content_type: article copyright: Copyright © 2016 Elsevier Masson SAS. All rights reserved.status: publishe