The design and synthesis of $\beta$-D-glucose derived peptidomimetics and the discovery of a novel etherification protocol

Maria Anne Cichy-Knight, University of Pennsylvania


The design and syntheses of several $\beta$- scD-glucose derived non-peptide peptidomimetics for the peptide hormone somatostatin and the neurotransmitter substance P are described. Based on SAR data, manipulations in the peptidomimetic scaffold were made in attempts to improve affinity for these G-protein coupled receptors. Manipulations include conversion from an O-glycoside to a C-glycoside, incorporation of 4-fluorophenol, 4-fluorobenzyl, 2-methylnaphthyl and/or picolyl moieties, and conversion from the glucose to the glucosamine scaffold. Assay results obtained for these new analogs range from low nanomolar affinity to complete inactivity culminating in hypotheses concerning binding orientations, optimal side chain length, and solubilizing properties.^ During the synthesis of the above peptidomimetics, a novel etherification protocol was discovered. Treatment of a sugar alcohol with the triflate of 5-azidopentanol led to etherification in vacuo without the addition of solvent or base. This mild method was utilized in the synthesis of over 25 carbohydrates and was essential for the preparation of several base sensitive sugars. Studies on the utility of this novel reaction were initiated and the scope of this method is not limited to carbohydrates or simple primary alcohols.^ The design of future peptidomimetics was based on known potent literature compounds in conjunction with the SARs obtained in this dissertation. Properties which we wish to expand on include solubility, oral bioavailability, and specificity in addition to affinity. The $\beta$- scD-glucose scaffold has proven itself as a privileged platform on which potent peptidomimetics have been derived for both somatostatin and substance P and these peptidomimetics have provided valuable information about these receptors not revealed by their endogenous ligands. ^

Subject Area

Chemistry, Organic|Chemistry, Pharmaceutical

Recommended Citation

Cichy-Knight, Maria Anne, "The design and synthesis of $\beta$-D-glucose derived peptidomimetics and the discovery of a novel etherification protocol" (1998). Dissertations available from ProQuest. AAI9829875.