A Building Block Approach Toward Nanoscale Scaffolds

We are developing a systematic method for the design and synthesis of rigid macromolecular scaffolds capable of displaying chemical functionality in three dimensional space. These scaffolds will enable the study of structure-function relationships in designed receptors, and to examine factors governing biological catalysis. The scaffolds might also be used as tools for the construction of nanoscale devices. The monomers used to synthesize the oligomeric scaffolds are orthogonally protected bis-amino acids. These heterocyclic monomers are coupled through diketopiperazines to neighboring monomers. The formation of two peptide bonds between adjacent monomers eliminates the rotational flexibility in the scaffold backbone, and results in unique spirocyclic fused ring structures that we have christened bis-peptides.We discuss the synthesis of the four stereoisomers of a bis-amino acid monomer derived from 4-hydroxyproline, as well as the development of procedures for fabricating bis-peptides from these monomers. Combinations of all four pro4 monomers were incorporated into oligomers of different lengths. The solution conformation of six oligomers was determined by analysis of their 2D-NMR spectra and using computational modeling. Based upon the conformational preferences of the monomers, two pentamer scaffold oligomers were designed to form distinguishable shapes: a molecular rod, and a curved shape. We confirmed the design hypothesis by labeling the ends of these scaffolds with dansyl and naphthyl fluorophores; this allowed us to determine the approximate end to end distances by measuring the efficiency of fluorescence resonance energy transfer. This result suggests that we can rationally design the physical properties of bis-peptides based upon the stereochemistry of their constituent monomers.We also discuss progress toward the synthesis of chiral molecular cavities from bis-peptides and from assemblies of bis-peptides. The resulting macrocyclic cavities may ultimately serve as receptors for designed sensors of small chiral organic molecules