Affiliation: Senior Manager, Chemistry, Life Sciences Solutions, Thermo Fisher Scientific. 2130 Woodward Street, Austin, TX 78744- 1832, USA.
Nucleoside tetraphosphates perform numerous functions in a wide variety of living species from bacteria to complex eukaryotes. In human beings, various nucleoside tetraphosphates have been shown to serve as agonists for a variety of purogenic receptors and kinases, influencing intraocular pressure, platelet activation, vasoconstriction, and extracellular signaling. Also, they are involved in cell division, and bacteria growth and development. Synthetic derivatives can be used in discovery to explore their in vivo function, or in the development of more powerful receptor agonists and kinase inhibitors. They also show promise in such fields as drug delivery and nucleic acid assays. Although nucleoside polyphosphates can refer to phosphates attached at multiple hydroxyl positions on the same ribose moiety of deoxyribo- or ribonucleosides, here we concentrate on the syntheses of nucleosides attached to a tetraphosphate moiety, where the tetraphosphate chain can serve as a single adduct or as a linker between two nucleosides or a nucleoside and another moiety. Syntheses to create these important molecules and their derivatives have included both chemical and enzymatic approaches. Each approach has its own pros and cons. Chemical synthesis allows the creation of products with highly diverse structures enabling structure-activity relationship (SAR) studies. However, these often require multiple protection-deprotection steps, which can be synthetically challenging. Enzymatic synthesis, on the other hand, allows a targeted reaction with no protecting group chemistry involved, but it is limited in its substrate specificity and in its chemo- and regioselective products and can be prohibitively expensive for large- scale production. This comprehensive review covers the evolutionary progress in synthesizing various nucleoside tetraphosphates since the discovery of the first example, adenosine 5'-tetraphosphate, in 1953. It compares the advantages and limitations among the different approaches. The intent of this review is to provide researchers both a primer and a reference for the best method for their own syntheses. We hope it will encourage more in-depth biological studies and broaden the biological applications of these molecules.