| Abstract | Molecular engineering of large macrocyclic compounds offers new avenues to disrupt protein-protein interfaces and potentially halt pathways that lead to neurodegenerative diseases such as Alzheimer's. The hallmark of Alzheimer's disease involves the aggregation of so-called amyloid peptides that exhibit characteristic B-sheet structures. Thus, designing macrocycles that structurally/topologically mimic B-sheets should enhance the affinity of these macrocycles towards the amyloid aggregates and lead to rational design of more advanced scaffolds with therapeutic potential. These scaffolds could potentially present opportunities to interfere with protein-protein interactions, thus preventing amyloid plaque formation.
This work will describe the synthesis of structurally- and functionally-diverse macrocyclic scaffolds to understand the factors that contribute to B-sheet formation. Here, 26-atom macrocycles prepared in three-steps will be described. Using a triazine core, a protected hydrazine group and an acetal on an amino acid tether, a monomer can be prepared in two steps. Acetals ranging from 2-4 carbons can be used to yield rings of 22-28 atoms. Treatment with acid leads to dimerization in very high yields. Varying the amino acid choice can lead to synthesis of different homodimers and heterodimers. Previous work proves acetal length dictates morphology; three-carbon acetals give folded conformations and five-carbon acetals yield crinkled B-sheets. Four-carbon acetals yield the flattened B-sheets described here. NMR spectroscopy provides confirmation of synthesis and 2D-NMR techniques offer opportunities to probe solution structure more efficiently. Intramolecular hydrogen bonding within the template exhibited by 1D-NMR may corroborate the belief that that these macrocycles adopt a B-sheet like structure. |
