Structure-activity relationships in sweeteners. II. Saccharins, acesulfames, chlorosugars, tryptophans and ureas

The previously introduced conceptual parameters (α, δ, ω and S) to describe the stereochemical requirements for organic compounds to taste sweet, were now applied to another series of sweeteners and to some well-known potent substances. With the help of an adapted STERIMOL computer program, the positions of relevant, hydrophobic side chains were determined in ureas, saccharins, tryptophans, chlorosugars and acesulfame derivatives in relation to their AH-B moieties. The results obtained were compared with previous findings for five other homologous series of sweeteners. There is evidence to suggest that 6-substituted acesulfame derivatives and saccharin employ the same receptor site. δ in 5-substituted acesulfame derivatives coincides with that of sulphamates calculated earlier. δ in 6-chloro-D-tryptophan was found to be at equal distances from H and B, a position which was earlier also observed for the methyl ester group in aspartame. In the dulcin series of the urea derivatives, two AH-B moieties can be distinguished: the HN-CO group gives rise to α, δ and ω's which fit in the earlier calculated nitroaniline receptor site, while for the OC-NH 2 group they are located near those found for isocoumarins. The chlorine atoms in 1′ ' 1 6′-dichlorosucrose are located above and below the plane of the pyranose ring at almost the same positions with respect to the OH groups at positions 3 and 4 (in fact, two equal δ's), which are supposed to form the AH-B moiety. The high relative sweetness values of 1′,6′-dichlorosucrose and 1′,4,6′-trichlorogalactosucrose are most probably due to the fact that both sweeteners can interact with the receptor site in two ways (as such and upside-down). It is remarkable that the average δ positions belonging to sweeteners with similar AH-B moieties are located very close to each other.