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An Expedient Synthesis of Flexible Nucleosides through Enzymatic Glycosylation of Proximal and Distal Fleximer Bases.

ABSTRACT: The structurally unique "fleximer" nucleosides were originally designed to investigate how flexibility in a nucleobase could potentially affect receptor-ligand recognition and function. Recently they have been shown to have low-to-sub-micromolar levels of activity against a number of viruses, including coronaviruses, filoviruses, and flaviviruses. However, the synthesis of distal fleximers in particular has thus far been quite tedious and low yielding. As a potential solution to this issue, a series of proximal fleximer bases (flex-bases) has been successfully coupled to both ribose and 2'-deoxyribose sugars by using the N-deoxyribosyltransferase?II of Lactobacillus leichmannii (LlNDT) and Escherichia coli purine nucleoside phosphorylase (PNP). To explore the range of this facile approach, transglycosylation experiments on a thieno-expanded tricyclic heterocyclic base, as well as several distal and proximal flex-bases were performed to determine whether the corresponding fleximer nucleosides could be obtained in this fashion, thus potentially significantly shortening the route to these biologically significant compounds. The results of those studies are reported herein.

SUBMITTER: Vichier-Guerre S

PROVIDER: S-EPMC7228337 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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An Expedient Synthesis of Flexible Nucleosides through Enzymatic Glycosylation of Proximal and Distal Fleximer Bases.

Vichier-Guerre Sophie S Ku Therese C TC Pochet Sylvie S Seley-Radtke Katherine L KL

Chembiochem : a European journal of chemical biology 20200227 10

The structurally unique "fleximer" nucleosides were originally designed to investigate how flexibility in a nucleobase could potentially affect receptor-ligand recognition and function. Recently they have been shown to have low-to-sub-micromolar levels of activity against a number of viruses, including coronaviruses, filoviruses, and flaviviruses. However, the synthesis of distal fleximers in particular has thus far been quite tedious and low yielding. As a potential solution to this issue, a se ...[more]

PMID: 31899839

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Project description:A comparative study of the possibilities of using ribokinase → phosphopentomutase → nucleoside phosphorylase cascades in the synthesis of modified nucleosides was carried out. Recombinant phosphopentomutase from Thermus thermophilus HB27 was obtained for the first time: a strain producing a soluble form of the enzyme was created, and a method for its isolation and chromatographic purification was developed. It was shown that cascade syntheses of modified nucleosides can be carried out both by the mesophilic and thermophilic routes from D-pentoses: ribose, 2-deoxyribose, arabinose, xylose, and 2-deoxy-2-fluoroarabinose. The efficiency of 2-chloradenine nucleoside synthesis decreases in the following order: Rib (92), dRib (74), Ara (66), F-Ara (8), and Xyl (2%) in 30 min for mesophilic enzymes. For thermophilic enzymes: Rib (76), dRib (62), Ara (32), F-Ara (<1), and Xyl (2%) in 30 min. Upon incubation of the reaction mixtures for a day, the amounts of 2-chloroadenine riboside (thermophilic cascade), 2-deoxyribosides (both cascades), and arabinoside (mesophilic cascade) decreased roughly by half. The conversion of the base to 2-fluoroarabinosides and xylosides continued to increase in both cases and reached 20-40%. Four nucleosides were quantitatively produced by a cascade of enzymes from D-ribose and D-arabinose. The ribosides of 8-azaguanine (thermophilic cascade) and allopurinol (mesophilic cascade) were synthesized. For the first time, D-arabinosides of 2-chloro-6-methoxypurine and 2-fluoro-6-methoxypurine were synthesized using the mesophilic cascade. Despite the relatively small difference in temperatures when performing the cascade reactions (50 and 80 °C), the rate of product formation in the reactions with Escherichia coli enzymes was significantly higher. E. coli enzymes also provided a higher content of the target products in the reaction mixture. Therefore, they are more appropriate for use in the polyenzymatic synthesis of modified nucleosides.

Project description:High tibial osteotomy is a common procedure to address unicompartment knee osteoarthritis and other conditions. Regarding the specific surgical methods, medial open wedge osteotomy and lateral close wedge osteotomy are the most used. Both methods have a common disadvantage in that they are not so suitable to correct a severe deformity. Thus, we would like to introduce an anterior proximal-to-posterior distal oblique proximal tibial osteotomy technique, which is especially suitable to correct severe tibial deformity. The most critical point of this technique is to create an osteotomy plane from the most proximal posterior site of the tibial tubercle posteriorly and distally to the posterior cortex of the tibia, with each horizontal osteotomy maneuver in the coronal plane. Combined fibular osteotomy is always needed, and better results can be obtained when it is combined with arthroscopic debridement of the knee. We consider the introduction of this technique will provide a useful option when tibial osteotomy is needed to preserve the knee, especially for a great deformity correction. Technique Video Video 1 Anterior proximal-to-posterior distal oblique proximal tibial osteotomy. This procedure is performed in the right knee. Arthroscopy is performed to confirm the osteoarthritis status of the medial compartment and the healthier status of the lateral compartment. Debridement and other indicated arthroscopic procedures are performed. A K-wire is drilled in the coronal plane from the medial to the lateral side of the tibia at a level approximately 1 cm distal to the joint line, parallels the joint line as far as possible, and is used as a proximal reference wire. Another K-wire is drilled into the tibia also in the coronal plane at a level in the distal one third of the leg and used as a distal reference wire. The angle between the 2 reference wires is controlled being equal to the to-be-corrected angle of the tibia as far as possible. A longitudinal incision is made over the midline of the medial surface of the tibia. The pes anserinus is peeled off from its tibial insertion. A K-wire is placed at the most proximal and posterior site of the tibial tubercle and an osteotomy line is marked posterodistally to the posteromedial ridge of the tibia with 30° angulation to the tibial axis. The posterior osteofascial compartments are opened at the distal end of the osteotomy line. A 2.5-mm K-wire is used to drill through the medial tibial cortex along the osteotomy line to make a line of holes with approximately 5 mm distance between the neighboring holes. An osteotome is used to cut the bone and connect the holes along the osteotomy line at the medial side of the tibia. The lateral tibial cortex is drilled through the medial tibial fissure with each drilling maneuver along the coronal plane, to create a line of holes on the lateral side of the tibia. The osteotome is put into the fissure at the medial side of the tibia to connect the holes on the lateral side of the tibia to create an osteotomy plane. The distal posterior tibial cortex is cut along the osteotomy plane. A K-wire is drilled perpendicular to the coronal plane through the middle of the osteotomy plane. A fibula osteotomy is performed at its middle point with a wire saw. Valgus stress is applied to correct the varus deformity of the tibia till the 2 reference wires parallel to each other. Two additional K-wires are placed across the osteotomy plane for temporary fixation of the fracture. A tibial condyle plate is placed at the medial side of the tibia. Four self-locking screws are placed in respectively at the proximal and distal segments of the tibia for fracture fixation. The K wires for temporary fixation and correction reference are removed. A suction drainage tube is placed to the osteotomy site. The wounds are closed.

Dataset Information

An Expedient Synthesis of Flexible Nucleosides through Enzymatic Glycosylation of Proximal and Distal Fleximer Bases.

Publications

An Expedient Synthesis of Flexible Nucleosides through Enzymatic Glycosylation of Proximal and Distal Fleximer Bases.

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