Solution-phase parallel synthesis of a pharmacophore library of HUN-7293 analogues: a general chemical mutagenesis approach to defining structure-function properties of naturally occurring cyclic (depsi)peptides.
HUN-7293 (1), a naturally occurring cyclic heptadepsipeptide, is a potent inhibitor of cell adhesion molecule expression (VCAM-1, ICAM-1, E-selectin), the overexpression of which is characteristic of chronic inflammatory diseases. Representative of a general approach to defining structure-function relationships of such cyclic (depsi)peptides, the parallel synthesis and evaluation of a complete library of key HUN-7293 analogues are detailed enlisting solution-phase techniques and simple acid-base liquid-liquid extractions for isolation and purification of intermediates and final products. Significant to the design of the studies and unique to solution-phase techniques, the library was assembled superimposing a divergent synthetic strategy onto a convergent total synthesis. An alanine scan and N-methyl deletion of each residue of the cyclic heptadepsipeptide identified key sites responsible for or contributing to the biological properties. The simultaneous preparation of a complete set of individual residue analogues further simplifying the structure allowed an assessment of each structural feature of 1, providing a detailed account of the structure-function relationships in a single study. Within this pharmacophore library prepared by systematic chemical mutagenesis of the natural product structure, simplified analogues possessing comparable potency and, in some instances, improved selectivity were identified. One potent member of this library proved to be an additional natural product in its own right, which we have come to refer to as HUN-7293B (8), being isolated from the microbial strain F/94-499709.
Chen
Yan
Y
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Bilban
Melitta
M
Foster
Carolyn A
CA
Boger
Dale L
DL
D002460:Cell Line; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D008968:Molecular Conformation; D016296:Mutagenesis; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
C097977:HUN 7293; D010456:Peptides, Cyclic; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1