Contribution to the synthesis and the study of analogues of phosphorylated biomolecules such as nucleotides

Les dérivés phosphorylés de nucléosides naturels ou d'analogues (appelés nucléotides) sont des composés primordiaux largement utilisés comme outils biologiques. Certains d'entre eux présentent également un fort potentiel thérapeutique en particulier comme agents antiviraux ou antitumoraux. La préparation des dérivés polyphosphorylés de nucléosides demeure cependant un challenge du fait de rendements de synthèse parfois faibles et des multiples étapes de purification longues et fastidieuses. Ce manuscrit relève donc de la problématique globale de synthèse de ces composés. Le premier chapitre est consacré à l’étude non exhaustive des méthodes de synthèse décrites dans la littérature pour ces dérivés, en rappelant les avantages et inconvénients de ces approches. Le deuxième chapitre rapporte la voie de synthèse en milieux aqueux de nucléotides, et de quelques analogues, que nous avons développée. Des résultats préliminaires de mécanosynthèse basée sur cette même approche sont également présentés. Enfin, le troisième chapitre porte sur deux voies de synthèse supportée de nucléotides. L’une implique la cytidine et son ancrage sur polyéthylène glycol afin de fournir les dérivés 5’-di- et triphosphate correspondants. L’autre porte sur le développement d’un support tétrapode inédit en vue de son utilisation pour la synthèse de dérivés de l'adénosine.Phosphorylated derivatives of endogenous nucleosides or analogues (called nucleotides) are crucial compounds widely used as biological tools. Some of them also have a high therapeutic potential, in particular as antiviral or antitumor agents. However, the synthesis of polyphosphorylated derivatives of nucleosides remains a challenge due to low yields as well as long and tedious multiple purification steps. Thus, this manuscript is dealing with the overall problem of synthesis of these compounds. The first chapter is devoted to the non-exhaustive study of the synthetic methods described in the literature for such compounds, recalling the advantages and disadvantages of these approaches. In the second chapter, we report our contribution to an original synthetic pathway in aqueous media of some nucleotides and analogues. Some preliminary results of mecanosynthesis based on the same approach are also presented. Finally, the third chapter refers to supported synthesis of nucleotides with two different approaches. One involves cytidine and its anchoring on polyethylene glycol in order to provide the corresponding 5'-di- and triphosphate derivatives. The other concerns the development of a novel tetrapod support that may be valuable for the synthesis of adenosine derivatives

One-pot synthesis of nucleotides in water-medium

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One-pot synthesis of nucleotides in water-medium

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New insights for the preparation of cytidine containing nucleotides using a soluble ether-linked polyethylene glycol support

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GREEN APPROACHES FOR THE SYNTHESIS OF NUCLEOTIDES, THEIR CONJUGATES AND ANALOGUES

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Straightforward Ball‐Milling Access to Dinucleoside 5’,5’‐Polyphosphates Through Phosphorimidazolide Intermediates

International audienceA solvent-assisted mechanochemical approach to access symmetrical and mixed dinucleoside 5,5'-polyphosphates is reported. Under ball-milling conditions, nucleoside 5'-monophosphates are quantitatively activated using N,N'-carbonyldiimidazole into their phosphorimidazolide derivatives. The addition of a nucleoside 5'-mono, di or triphosphate directly leads to the formation of the corresponding dinucleotides. Benefits of the reported one-pot method include the use of unprotected nucleotides in their sodium or acid form, activation by the eco-friendly N,N'-carbonyldiimidazole, non-dry conditions, short reaction time, high conversion rates and easy setup and purification. This work offers new perspectives for the synthesis of nucleotide conjugates and analogues, combining the phosphorimidazolide approach and milling conditions

Green approaches for the synthesis of nucleotides, their conjugates and analogues

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Green approaches for the synthesis of nucleotides, their conjugates and analogues

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Expedient Mechanosynthesis of Dinucleotides

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