Synthesis of ether analogues derived from HUN-7293 and evaluation as inhibitors of VCAM-1 expression.
The cyclic depsipeptide HUN-7293 (1) and its D-lactate analogue 2 are highly potent inhibitors of inducible cell adhesion molecule expression. We report the synthesis of ether analogues varying in stereochemistry and side chain at the former hydroxyl acid position by employing a 'cut and paste chemistry' methodology starting from 1. As an additional fruit of this synthetic effort, a cyclodepsipeptide featuring a tertiary amine instead of a tertiary amide between PrLEU and MALA was obtained. Results on the inhibitory profile of these compounds in assays of VCAM-1 and ICAM-1 protein expression are discussed.
Schreiner
Erwin P
EP
Novartis Institutes for BioMedical Research GDC, Brunner Strasse 59, A-1235 Vienna, Austria. erwin.schreiner@pharma.novartis.com
Kern
Michael
M
Steck
Andrea
A
Foster
Carolyn A
CA
D004987:Ethers / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000187:drug effects; D010456:Peptides, Cyclic / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis / Q000187:drug effects*
D004987:Ethers; C097977:HUN 7293; D010456:Peptides, Cyclic; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1