Analysis of structural features responsible for the sweetness of the sesquiterpene,hernandulcin

Summary The relationship between sweetness and structure was studied for several analogues of the intensely sweet sesquiterpene, hernandulcin. These derivatives were prepared synthetically, and were subjected to spectroscopic and conformational analysis. With the exception of the parent substance, none of the derivatives tested proved to be sweet. Evidence gathered in this study suggests that hernandulcin binds to its putative receptor through a three-point interaction, involving the C-1 carbonyl and C-1 hydroxyl groups, and the double bond between C-4 and C-5. In the course of a preliminary safety assessment, the 3-desmethyl derivative of hernandulcin was found to be mutagenic towardSalmonella typhimurium strain TM677.Acknowledgments. We thank Drs A. J. Hopfinger and R. Pearlstein for helpful suggestions concerning the use of CHEMLAB software, and Mr E. F. Robbins of the Research Resources Center, University of Illinois at Chicago for helpful assistance with the MS determinations. During the course of this investigation, one of us (C.M.C.) was affiliated with the Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois, and the gratefully acknowledges the support and encouragement of the late Professor Martin P. Schulman. J. M. P. is the recipient of a Research Career Development Award from the National Cancer Institute (1984–1989).Paper 14 in the series Potential Sweetening Agents of Plant Origin. For paper 13, see Nanayakkara, N. P. D., Hussain, R. A., Pezzuto, J. M., Soejarto, D. D. and Kinghorn, A. D., J. med. Chem., in press.