Second Generation of cycloSal‐Pronucleotides with Esterase‐Cleavable Sites: The ”Lock‐In”‐Concept

Abstract

A conceptual extension of the cycloSal‐pronucleotide approach is presented. The characteristic feature of the new cycloSal‐derivatives of the anti‐HIV active nucleoside analogue d4T 1 is the incorporation of an enzymatically cleavable carboxylic ester moiety with the intention to trap the triesters inside cells (”lock‐in”‐concept). CycloSal‐triesters bearing different ester groups in the 3‐or 5‐position of the cycloSal‐moiety are described. Surprisingly, only acetyl‐and levulinyl esters are cleaved readily in CEM cell extracts while alkyl esters were found to be stable. Nevertheless, in in‐vitro anti‐HIV assays most of the compounds achieve the thymidine–kinase bypass, thus proving that they act at least as nucleotide delivery systems.

^†In honor and celebration of the 70th birthday of Professor Leroy B. Townsend.

Keywords:

• Pronucleotides
• Nucleoside analogue
• Anti‐HIV
• CycloSal‐triesters

Acknowledgments

Financial support by the Deutsche Forschungsgemeinschaft, Germany, the Fonds der Chemischen Industrie, Germany and the René Descartes Prize 2001 of the European Commission is gratefully acknowledged.

Notes

^†In honor and celebration of the 70th birthday of Professor Leroy B. Townsend.