Acid Promoted Cinnamyl Ion Mobility within Peptide Derived Macrocycles

• Published in: Journal of the American Chemical Society Vol. 130; no. 42; pp. 13864 - 13866
• Main Authors: Zhao, Hongda, Negash, Lidet, Wei, Qi, LaCour, Thomas G, Estill, Sandi Jo, Capota, Emanuela, Pieper, Andrew A, Harran, Patrick G
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 22.10.2008; Amer Chemical Soc
• Subjects: Acids - chemistry; Animals; Cell Proliferation - drug effects; Chemistry; Chemistry, Multidisciplinary; Cinnamates - chemistry; Cyclization; Dentate Gyrus - cytology; Dentate Gyrus - drug effects; Ions - chemistry; Macrocyclic Compounds - chemical synthesis; Macrocyclic Compounds - chemistry; Macrocyclic Compounds - pharmacology; Mice; Molecular Conformation; Peptides - chemistry; Physical Sciences; Polymers - chemistry; Science & Technology; Stereoisomerism; REARRANGEMENT; DIVERSITY
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja803299h

We are developing methods that restrict the conformational mobility of peptides and related heteropolymers while simultaneously altering their properties. Our experiments occur as processes wherein a conserved, lipophilic reagent is activated in stages to form composite products with unprotected polyamides in parallel. For each starting oligomer, the goal is to create not one, but rather a collection of products. The intent is for those materials to retain molecular recognition elements of the biopolymer, yet display that functionality as part of stable, cyclic structures having defined shapes and enhanced membrane solubility/permeability. Here we describe reagent 2 and its two-step integration into peptides to afford macrocyclic ethers (e.g., 4 when starting with W-W-Y). When those materials are treated with protic acid in anhydrous solvent, the cinnamyl unit migrates from the oxygen of tyrosine to distribute throughout the structure, forming new products via carbon/carbon bonding. These changes occur concomitantly with acid-promoted rearrangements/cyclizations of the dienyne appendage to generate mixtures containing unique macrocycles such as 15. Similar amalgamations of 2 with more diverse peptides is a means to begin accessing complex peptidomimetics systematically. From a library of screening fractions generated in this way, we have identified a small molecule that selectively promotes hippocampal neurogenesis in the adult mouse brain.