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Novel Chimeric Scaffolds to Extend the Exploration of Receptor Space: Hybrid β- d -Glucose−Benzoheterodiazepine Structures for Broad Screening. Effect of Amide Alkylation on the Course of Cyclization Reactions

2003; American Chemical Society; Volume: 69; Issue: 2 Linguagem: Inglês

10.1021/jo0352068

1520-6904

Leïla Abrous, Patrick A. Jokiel, Sarah R. Friedrich, John Hynes, Amos B. Smith, Ralph Hirschmann,

Asymmetric Synthesis and Catalysis

New molecular platforms which are hybrids of two scaffoldsnamely, β-d-glucose and benzodiazepine, each able to bind several proteinswere 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."