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A straightforward synthesis of the two new furanoid sugar amino acids f-SAA 106 and f-SAA 107 in high yields in a few steps from glucose was developed. The described new synthetic pathway allows an easy access to f-SAA 106 and f-SAA 107, making them useful building blocks and structural templates for drug design and combinatorial syntheses. Their synthesis starts from readily available diacetone glucose, and is faster, easier to scale up and cheaper, than the syntheses of other SAAs so far known. f-SAA 106s and f-SAA 107s structural properties have been studied. Linear and cyclic mixed oligomers of f-SAA 106 and f-SAA 107 were synthesized and solution structures extensively investigated by circular dichroism (CD) and 2D-NMR spectroscopy. The linear oligomer Fmoc[f-SAA106beta-hGly]3OH 113 exhibited 12/10/12 helical secondary structure in MeCN as proven by NMR, and subsequent molecular dynamics calculations. It is very remarkable that 113 forms a stable secondary structure, since stable secondary structures were only reported for beta-peptides consisting almost exclusively of a- or b-substituted beta-amino acids. The unsubstituted beta-homoglycin is obviously much more flexible than substituted b-amino acids. f-SAA 106 therefore very strongly induces turn elements in short oligomeric sequences. Furthermore the insights gained on the structure inducing properties of the f-SAAs 106 and 107, were applied to biologically active systems. A first library of 12 somatostatin analogues was designed under consideration of structure activity relationships. After biological testing (antiproliferation and selective induction of apoptosis on tumor cells) the identified lead structures were further optimized, in a second, larger library. From those libraries several promising drug candidates against both cancer and inflammatory diseases could be extracted. 10 analogues have IC50 values in the low µM-range. 142, 143, 148 and 158 possess antiproliferative and apoptotic activity against several different multidrug-resistant and/or drug-sensitive carcinoma cell lines. Some of these compounds are more active than TT232 135, the only other compound known to show apoptotic and antiproliferative activity against multi drugresistant carcinoma cell lines. Preliminary studies suggest that our compounds selectively exert thTThe nonproteinogenic properties of f-SAAs 106 and 107 should make the compounds physiologically more stable than the purely peptidic TT232 (135), the only other compound known to comparably induce either apoptosis on multidrug resistant tumor cells or to prohibit inflammation by substance P release inhibition. Die vorliegende Arbeit beschreibt die Entwicklung neuer, strukturinduzierender Zuckeraminosäuren (SAA), die für die Festphasensynthese und kombinatorische Chemie geeignet sind. Die strukturinduzierenden Eigenschaften dieser SAAs, wurden zunächst durch Synthese und NMR-Strukturuntersuchungen von linearen und cyclischen, gemischten Oligomeren (Foldameren) nachgewiesen. So liegt z.B. das gemischte Oligomer von β-Alanin und der neuen furanoiden β-SAA als 12/10/12-Helix in CH3CN vor. Die so gewonnenen Erkenntnisse wurden auf biologische Systeme angewendet: Die SAAs wurden als strukturinduzierende Elemente in Somatostatinanaloge eingebaut. Diese zeigten starke Anti-Tumor-Aktivität. |
