Cyclosal-pronucleotides--development of first and second generation chemical trojan horses for antiviral chemotherapy

Pronucleotides represent a promising alternative to improve the biological activity of nucleoside analogs against different viral diseases. Moreover, pronucleotides are valuable tools for studies concerning the nucleoside/nucleotide metabolism. The basic idea is to achieve nucleotide delivery into cells, bypassing limitations with intracellular formation of nucleotides from their nucleoside precursors. The cycloSal-concept is one of several pronucleotide systems reported so far but is the only approach in which a pronucleotide is cleaved successfully by a simple but selective chemical hydrolysis. Beside others, for the nucleoside analog d4T the application of the cycloSal-approach improved antiviral potency. In the first part, the basic concept, the chemistry, different structural modifications and their effects on the antiviral potency of the cycloSal-d4TMP triesters have been discussed in this review. In the second part, first results of a conceptional extension of the original cycloSal-approach will be summarized. Once the pronucleotides have passed the membrane, the aim is to trap the cycloSal-phosphate triesters inside the cells. Therefore, enzyme-cleavable groups have been attached via a linker to the cycloSal-moiety.