A Synthetic Library of Cell-Permeable Molecules

• DOI: 10.1021/ja0023377
• Publication Date: 2002-07-26T04:52:22Z
• Authors: Kazunori Koide; Joshua M. Finkels...; Zachary Ball; Gregory L. Verdine
• Keywords: Biomolecule; Olefin Metathesis; Chemical Biology; Reprogramming

Small molecules that induce or stabilize the association of macromolecules have proven to be useful effectors a wide variety biological processes. To date, all examples such chemical inducers dimerization involved known ligands well-characterized proteins. The generality this approach could broadened by enabling discovery heterodimerizers target having no established ligand, produce novel biologic response in screens predetermined macromolecular target. Toward end, we report construction diversified library synthetic consisting an invariant ligand targets FK506-binding protein (AP1867) attached 320 substituted tetrahydrooxazepines (THOXs). THOX components were generated combination liquid- and solid-phase procedures employing sequential Mitsonobu displacements join two structurally olefin-containing monomers, followed ruthenium-mediated olefin metathesis effect closure seven-membered ring. resin-bound coupled parallel AP1867, products released from resin yield candidate sufficient purity used directly testing. A representative panel 25 tested for their ability pass through membrane human fibrosarcoma cells, found possess activity tissue culture system. These studies pave way further aimed at using small-molecule heterodimerization responses intact cells.