Novel chimeric scaffolds to extend the exploration of receptor space: hybrid beta-D-glucose-benzoheterodiazepine structures for broad screening. Effect of amide alkylation on the course of cyclization reactions.
New molecular platforms which are hybrids of two scaffolds-namely, beta-d-glucose and benzodiazepine, each able to bind several proteins-were designed, synthesized and functionalized to serve as probes for broad biological screening. Herein, we describe the syntheses and chemical properties of these novel chimeric scaffolds. Attempted cyclization of the functionalized analogues (-)-96 and (-)-97 afforded the corresponding dimers (-)-98 and (-)-99, respectively, under a variety of reaction conditions, even at concentrations of only 0.001 N. Consideration of factors affecting the conformation of amide bonds and their effects on cyclization reactions led us to alkylate the amide bond. As expected, the cyclization of the N-methyl derivative (-)-110 afforded exclusively the unimolecular cyclization product (+)-111. These compounds are only now undergoing broad screening and represent therefore at present a "prospecting library."
Abrous
Leïla
L
University of Pennsylvania, Department of Chemistry, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, USA.
Jokiel
Patrick A
PA
Friedrich
Sarah R
SR
Hynes
John
J
Smith
Amos B
AB
Hirschmann
Ralph
R
D000478:Alkylation; D000577:Amides / Q000737:chemistry*; D001569:Benzodiazepines / Q000737:chemistry*; D004951:Esterification; D005947:Glucose / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D013055:Spectrophotometry, Infrared
D000577:Amides; D001569:Benzodiazepines; D005947:Glucose