Development of functional alpha-helix mimetics

We describe the design and synthesis of three small-molecule scaffolds that mimic the structural features and functional properties of alpha-helical peptides.;A series of new arylamide foldamers were designed to take advantage of a network of intramolecular hydrogen bonds to mimic the structural features of natural alpha-helical antimicrobial peptides. Their amphipathic character provides these compounds with potent antibacterial activity comparable to that of natural antibacterial peptides such as magainin and melittin. Additionally, the new compounds show selectivity for bacterial cells versus human red blood cells suggesting that they have low toxicity against mammalian cells.;The versatile oligoarylamide scaffold was used to design a series of foldamers that mimic the structural features of cell-penetrating peptides (CPP). The new CPP mimetics with three and four basic guanidine groups possess the ability to enter HeLa cells transporting a covalently-attached fluorescein group into the cell. Preliminary studies have shown that clathrin-dependent endocytosis is the most likely internalization mechanism. Upon entering the cell, the compound with three positive charges remains in the endosomes outside the nucleus while the one with four positive charges can be seen in the cytoplasm as well.;Finally, a new alpha-helix mimetic based on a pyridylpyridone scaffold was designed to mimic the surface functionality of an alpha-helical LXXLL motif. Results from fluorescence polarization studies indicate that most compounds bind with Ki values in the low micromolar range. The most potent inhibitors have comparable affinity to that of the control SRC-1 NR II; a peptide that mirrors the second LXXLL motif of the natural SRC-1 coactivator. Extensive structure-activity relationship studies have shown that further functionalization of the bottom pyridone ring is likely to decrease the binding affinity. However, functionalization of the top pyridine ring appears to be a possible strategy to introduce additional functionalization without abolishing activity. Preliminary cell-based data indicate that the compounds are able to enter breast cancer cells and diminish ERalpha-mediated expression.