Structure-Taste Correlations in Sweet Dihydrochalcone, Sweet Dihydroisocoumarin, and Bitter Flavone Compounds

• Published in: Journal of medicinal chemistry 1995-10, Vol.38 (21), p.4325-4331
• Main Authors: Shin, Whanchul, Kim, Seung Jun, Shin, Jung Mi, Kim, Sung-Hou
• Format: Article
• Language: English
• Subjects: Chalcone - analogs & derivatives; Chalcone - chemistry; Chalcones; Chemical Phenomena; Chemistry; Chemistry, Physical; Condensed benzenic and aromatic compounds; Condensed matter: structure, mechanical and thermal properties; Coumarins - chemistry; Crystallization; Crystallography, X-Ray; Exact sciences and technology; Flavones; Flavonoids - chemistry; Heterocyclic compounds; Isocoumarins; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Molecular Structure; Organic chemistry; Organic compounds; Physics; Preparations and properties; Structure of solids and liquids; crystallography; Structure of specific crystalline solids; Structure-Activity Relationship; Sweetening Agents - chemistry; Taste; Thermodynamics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00021a022

The dihydrochalcone derivatives of the bitter flavonoids naringin and neohesperedin are intensely sweet. Phyllodulcin is as sweet as the dihydrochalcones with similar taste properties although its structure apparently resembles that of bitter flavanone or flavone. Multifaceted approaches, including X-ray crystal structure analysis, energy calculation, and structure comparison, have been employed to clarify the structure-taste correlations in these classes of compounds. In the crystal, naringin dihydrochalcone assumes a 'J'-shaped conformation with a fully-extended dihydrochalcone moiety while neohesperidin dihydrochalcone assumes the same overall conformation but with a partially-extended moiety. A 2D conformational energy map of dihydrochalcone obtained using molecular mechanics revealed nine local minima. The pseudoequatorial and pseudoaxial forms of phyllodulcin have the same AM1 energies with a low energy barrier between them. The partially-extended form of dihydrochalcone and the pseudoequatorial form of phyllodulcin which are the maximally superposable conformers are proposed to be the active conformers. The major difference between the structures of flavone and phyllodulcin is not in the overall planarity but in the relative orientation of the pyrone and phenyl ring systems.