Second generation of cycloSal-pronucleotides with esterase-cleavable sites: the "lock-in"-concept.
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.
Meier
Chris
C
Institute of Organic Chemistry, University of Hamburg, Hamburg, Germany. chris.meier@chemie.uni-hamburg.de
Ruppel
Manuel F H
MF
Vukadinović
Dalibor
D
Balzarini
Jan
J
D004950:Esterases / Q000378:metabolism*; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D009711:Nucleotides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*
D009711:Nucleotides; D004950:Esterases