Synthesis of Nucleoside-like Molecules from a Pyrolysis Product of Cellulose and Their Computational Prediction as Potential SARS-CoV-2 RNA-Dependent RNA Polymerase Inhibitors.

Andrea Defant,Ines Mancini,Nicole Innocenti,Federico Dosi

doi:10.3390/ijms23010518

Andrea Defant, Ines Mancini + Show 2 more

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https://doi.org/10.3390/ijms23010518

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Abstract

(1R,5S)-1-Hydroxy-3,6-dioxa-bicyclo[3.2.1]octan-2-one, available by an efficient catalytic pyrolysis of cellulose, has been applied as a chiral building block in the synthesis of seven new nucleoside analogues, with structural modifications on the nucleobase moiety and on the carboxyl- derived unit. The inverted configuration by Mitsunobu reaction used in their synthesis was verified by 2D-NOESY correlations, supported by the optimized structure employing the DFT methods. An in silico screening of these compounds as inhibitors of SARS-CoV-2 RNA-dependent RNA polymerase has been carried out in comparison with both remdesivir, a mono-phosphoramidate prodrug recently approved for COVID-19 treatment, and its ribonucleoside metabolite GS-441524. Drug-likeness prediction and data by docking calculation indicated compound 6 [=(3S,5S)-methyl 5-(hydroxymethyl)-3-(6-(4-methylpiperazin-1-yl)-9H-purin-9-yl)tetrahydrofuran-3-carboxylate] as the best candidate. Furthermore, molecular dynamics simulation showed a stable interaction of structure 6 in RNA-dependent RNA polymerase (RdRp) complex and a lower average atomic fluctuation than GS-441524, suggesting a well accommodation in the RdRp binding pocket.

Highlights

Cellulose is the most biosynthesized organic substance on earth and is an abundant component of plants
The bio-oil produced by catalytic pyrolysis of cellulose contains anhydromonosaccharides and among them the hydroxylactone LAC (1) (=(1R,5S)-1-hydroxy-3,6-dioxabicyclo[3.2.1]octan-2-one) [1] in Figure 1 turned out to be a compound with added value as chiral building block to be used in asymmetric synthesis
A series of new enantiomerically pure nucleoside analogues were synthesized from the chiral building block LAC obtained as one added value product from cellulose pyrolysis in the context of biorefinery

Summary

Introduction

Cellulose is the most biosynthesized organic substance on earth and is an abundant component of plants. According to the biorefinery concept, it represents a key biomass to produce fuels and chemicals. In line with the sustainability of bioresources, the conversion of the carbohydrate content in lignocellulosic waste represents an interesting valorization. Biomass-derived compounds are often rich in functionalization and stereocenters, so that to be crucial chiral pools for the synthesis of non-racemic molecules. The bio-oil produced by catalytic pyrolysis of cellulose contains anhydromonosaccharides and among them the hydroxylactone LAC (1) (=(1R,5S)-1-hydroxy-3,6-dioxabicyclo[3.2.1]octan-2-one) [1] in Figure 1 turned out to be a compound with added value as chiral building block to be used in asymmetric synthesis. An improved production on the gram scale by pyrolysis in the presence of cheap and eco-friendly catalyst [2] has favored the use of LAC to obtain enantiomerically pure bioactive molecules

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