Toward an understanding of the design and synthesis of carbohydrate-related mimetics of peptidal beta-turns

This dissertation provides significant further validation for the use of glycoside scaffolds as mimics of peptidal β-turns. In addition we have found for the first time that our β-D-glucosides are stable in gastric acid and resist cleavage by glucosidases.; A major objective of the research was to increase the water solubility of our glycosides typified by (+)-12. The replacement of the C4-benzyl substituent (known not to be required for binding at the NK-1 receptor) by the three isomeric picolyl groups and by methylimidazole group, achieved the desired goal. In addition these new chemical entities showed moderately enhanced affinity compared with (+)-12 at this receptor. Our best ligand to date remains the unsubstituted alcohol (−)-37. Taken together the data suggest that a hydrophilic environment surrounds the C4 position.; The heterocyclic glycosides were also evaluated at the SRIF receptor subtypes. An unexpected affinity enhancement was observed specifically for the 3-picolyl containing glycoside (+)-88 at the human SRIF subtype 4 receptor by a factor of 3 (360 nM). To understand the basis for the improvement in affinity, a number of additional heterocyclic analogs were prepared. We concluded that a hydrogen bond rather than a salt bridge between the receptor and the nitrogen of the 3-picolyl substituent enhanced the affinity. This conclusion is also supported by the discovery that the corresponding neutral pyrazinyl substituent (+)-104 (a known hydrogen bond acceptor) also enhances affinity (IC₅₀ 375 nM). As expected, the 4-fluoro-3-picolyl substituent, (+)-102, known to be a weaker hydrogen bond acceptor, did not show an enhancement in affinity (IC₅₀ 1160 nM). Incorporation of both a 3-picolyl at the C4 position and a methylimidazole at C2 further increased binding (IC₅₀ 60 nM). Based on earlier research by the group this result suggests that (+)-88 and (+)-12 bind in an analogous way.*; The desire to improve the affinity at the SRIF receptors further, led to the design and synthesis of (+)-158. This objective was not accomplished but (+)-158 was found to inhibit the phosphorylation of IκB kinase via reversible binding to the substrate, thereby exemplifying a rare inhibition of a protein-protein interaction by a low molecular weight molecule. Significantly this observation provides yet another example of the promiscuity of the glycoside scaffold suitable platforms for ligand design.*; The term privileged platform is well accepted but no chemical basis for this promiscuity has been identified. We propose that the radial-pseudosymmetry inherent in the glucose scaffold can account for the promiscuity of this platform. In addition we suggest that exposed surfaces of molecules such as turns or helices can represent a ‘privileged element’ that induces promiscuity. Thus sugars are privileged not only exhibit pseudosymmetry but also mimic β-turns.; Other radially-pseudosymmetric scaffolds namely carbacyclic analog (+)- 170 and substituted armomatic scaffolds 191 and 192 have been prepared. A more simplified catechol-based ligand 195 has also been generated to determine the minimum requirements for binding the SRIF receptor with an aromatic scaffold. These compounds have been submitted for biological evaluation. These assays may in addition, shed light on the role of the pyranose oxygen in binding at the NK-1 and SRIF receptors.*; *Please refer to dissertation for diagrams.