ABSTRACT
Dinucleoside 5',5'-polyphosphates (DNPs) are endogenous substances that play important intra- and extracellular roles in various biological processes, such as cell proliferation, regulation of enzymes, neurotransmission, platelet disaggregation and modulation of vascular tone. Various methodologies have been developed over the past fifty years to access these compounds, involving enzymatic processes or chemical procedures based either on P(III) or P(V) chemistry. Both solution-phase and solid-support strategies have been developed and are reported here. Recently, green chemistry approaches have emerged, offering attracting alternatives. This review outlines the main synthetic pathways for the preparation of dinucleoside 5',5'-polyphosphates, focusing on pharmacologically relevant compounds, and highlighting recent advances.
Subject(s)
Dinucleoside Phosphates/chemical synthesis , Purinergic P2Y Receptor Agonists/chemical synthesis , Deoxycytosine Nucleotides/agonists , Deoxycytosine Nucleotides/chemistry , Deoxycytosine Nucleotides/pharmacology , Dinucleoside Phosphates/chemistry , Dinucleoside Phosphates/isolation & purification , Dry Eye Syndromes/drug therapy , Green Chemistry Technology , Humans , Ophthalmic Solutions , Phosphorylation , Polyphosphates/chemical synthesis , Polyphosphates/chemistry , Purinergic P2Y Receptor Agonists/chemistry , Purinergic P2Y Receptor Agonists/isolation & purification , Receptors, Purinergic/metabolism , Uracil Nucleotides/chemistry , Uridine/agonists , Uridine/analogs & derivatives , Uridine/chemistry , Uridine/pharmacologyABSTRACT
A solvent-assisted mechanochemical approach to access symmetrical and mixed dinucleoside 5,5'-polyphosphates is reported. Under ball-milling conditions, nucleoside 5'-monophosphates were quantitatively activated using 1,1'-carbonyldiimidazole, forming their phosphorimidazolide derivatives. The addition of a nucleoside 5'-mono-, di- or triphosphate directly led 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 1,1'-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.
