Second-Generation cycloSal-d4TMP Pronucleotides Bearing Esterase-Cleavable Sites — The “Trapping” Concept

✍ Scribed by Chris Meier; Christian Ducho; Henning Jessen; Dalibor Vukadinović-Tenter; Jan Balzarini

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 179 KB
• Volume: 2006
• Category: Article
• ISSN: 1434-193X
• DOI: 10.1002/ejoc.200500490

✦ Synopsis

Abstract

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)