ОПТИМИЗАЦИЯ СИНТЕЗА 2'- О-α- D-РИБОФУРАНОЗИЛАДЕНОЗИНА ПО МЕТОДУ СИМПЛЕКСНОГО ПЛАНИРОВАНИЯ

Disaccharide nucleosides belong to an important group of natural compounds found in t-RNA and poly(ADPribose). They are also key elements in the structure of antibiotics and other physiologically active compounds. Poly(ADP-ribosylation) is a posttranslational modification of proteins in eukariotic cells catalyzed by poly(ADPribose)-polymerazes. The importance of poly(ADP-ribose) has been established in many cellular processes such as DNA replication, recombination and repair and cellular differentiation. The development of the synthesis of poly(ADP-ribose) and it’s components is still a challenging problem. The synthesis of 2'-O-α-D-ribofuranosyladenosine, a monomeric unit of poly(ADP-ribose) reported earlier has been improved. An important step on this way is the formation of a 2'-O-glycosidic bond between the adenosine and carbohydrate moieties. A new strategy involving glycosylation of 3',5'-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)adenosine has been suggested. Varying of the catalyst (SnCl4), nucleoside and carbohydrate relations by the simplex method allowed improving the yields in the glycosylation step from 35 to 64%. As a result, it made possible to reach a higher overall yield of 2'-O-α-D-ribofuranosyladenosine in comparison with the literature data.С помощью метода симплексного планирования оптимизирован синтез 2'-O-α-D-рибофура-нозиладенозина - мономерного звена поли(АDP-рибозы). Подбор оптимальных соотношений катализатора (SnCl4), нуклеозида и углеводной компоненты позволил повысить выходы на стадии гликозилирования с 35 до 64%

OPTIMIZATION OF 2'-О-α-D-RIBOFURANOSYLADENOSINE SYNTHESIS USING THE SIMPLEX PLANNING METHOD

Disaccharide nucleosides belong to an important group of natural compounds found in t-RNA and poly(ADPribose). They are also key elements in the structure of antibiotics and other physiologically active compounds. Poly(ADP-ribosylation) is a posttranslational modification of proteins in eukariotic cells catalyzed by poly(ADPribose)-polymerazes. The importance of poly(ADP-ribose) has been established in many cellular processes such as DNA replication, recombination and repair and cellular differentiation. The development of the synthesis of poly(ADP-ribose) and it’s components is still a challenging problem. The synthesis of 2'-O-α-D-ribofuranosyladenosine, a monomeric unit of poly(ADP-ribose) reported earlier has been improved. An important step on this way is the formation of a 2'-O-glycosidic bond between the adenosine and carbohydrate moieties. A new strategy involving glycosylation of 3',5'-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)adenosine has been suggested. Varying of the catalyst (SnCl4), nucleoside and carbohydrate relations by the simplex method allowed improving the yields in the glycosylation step from 35 to 64%. As a result, it made possible to reach a higher overall yield of 2'-O-α-D-ribofuranosyladenosine in comparison with the literature data

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

Obtaining and Studying the Properties of Chitosan Films Containing Natural Phytohormones Cytokinins

A promising carrier for the development of polymer systems with controlled release of biologically active compounds is the aminopolysaccharide chitosan. In the present work, we studied the possibility of using chitosan films as a matrix for the N6-benzyladenine (BA), which is the natural cytokinin widely used in tissue culture. The aim of this work was to develop biopolymer carriers containing phytohormones cytokinins that provide its controlled release. As a result of the work, a number of biopolymer carriers containing BA were obtained, and the kinetics of moisture absorption of the resulting complexes and the kinetics of their release of cytokinins were studied. It has been shown that the use of a polymer carrier based on chitosan is a convenient matrix for achieving a prolonged biological effect from cytokinins. The obtained results will make it possible to purposefully design materials with an optimal delivery rate of cytokinins for a biological object

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 α-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)-α-methylbenzyl)adenine (S-MBA), 2-fluoro,N6-((S)-α-methylbenzyl)adenine (S-FMBA) and 2-chloro,N6-((S)-α-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)-α-methylbenzyl)adenosine, 2-amino,N6-((S)-α-methylbenzyl)adenosine) were found to exhibit receptor-specific and chirality-dependent anticytokinin properties