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Second‐Generation cyclo Sal‐d4TMP Pronucleotides Bearing Esterase‐Cleavable Sites — The “Trapping” Concept
Author(s) -
Meier Chris,
Ducho Christian,
Jessen Henning,
VukadinovićTenter Dalibor,
Balzarini Jan
Publication year - 2006
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.200500490
Subject(s) - chemistry , moiety , cleavage (geology) , hydrolysis , stereochemistry , alkyl , esterase , enzyme , organic chemistry , geotechnical engineering , fracture (geology) , engineering
An extension of the cyclo Sal‐pronucleotide approach is presented. Attachment of an enzyme‐cleavable ester/acylal group to the cyclo Sal‐d4TMP triesters should allow these compounds to be trapped intracellularly after cleavage. The ester/acylal groups were introduced in the 3‐ or 5‐position of the cyclo Sal ring system, and surprising differences were observed in hydrolysis studies in CEM cell extracts with respect to the ester/acylal moiety. While acetyl and levulinyl esters were readily cleaved, alkyl esters of cyclo Sal‐d4TMP acids proved to be resistant to enzymatic cleavage. In contrast, AM‐, POM‐ and POC‐acylals were rapidly cleaved in the extracts, leading to cyclo Sal‐d4TMP acids. The antiviral activity of the compounds against HIV is also presented. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)