Second generation of cycloSal-pronucleotides with esterase-cleavable sites: the "lock-in"-concept |
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Authors: | Meier Chris Ruppel Manuel F H Vukadinović Dalibor Balzarini Jan |
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Affiliation: | Institute of Organic Chemistry, University of Hamburg, Hamburg, Germany. chris.meier@chemie.uni-hamburg.de |
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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. |
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