cycloSal Phosphates as Chemical Trojan Horses for Intracellular Nucleotide and Glycosylmonophosphate Delivery — Chemistry Meets Biology

Pronucleotides represent a promising alternative to improve the biological activity of nucleoside analogs in antiviral and cancer chemotherapy. In addition, pronucleotides are valuable tools for studies regarding the nucleoside/nucleotide metabolism. The aim is to achieve nucleotide delivery into cells and thereby bypass limitations during intracellular formation of nucleotides from their nucleoside precursors. The cyclo Sal approach is one of several conceptually different pronucleotide systems known but is the only approach in which a pronucleotide is cleaved successfully by simple but selective chemical hydrolysis. The basic concept, chemistry, different structural modifications, and their effects on the antiviral potency of the cyclo Sal d4TMP triesters are briefly discussed first. Then, the application of the approach to various biologically active nucleoside analogs against different targets is summarized. In the second part, the results of a conceptual extension of the cyclo Sal approach are presented: once cyclo Sal pronucleotides have passed the membrane, they should be trapped inside the cells after an enzyme‐catalyzed process and then release the nucleotide. Finally, results are summarized that demonstrate that the cyclo Sal approach is not restricted to the delivery of bioactive nucleotides but is also applicable to the intracellular delivery of hexose‐1‐phosphates. Chemical synthesis, biophysical studies, and biological evaluation will be discussed in combination throughout this paper to demonstrate the strength of the cyclo Sal approach. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)