Document Detail

Acid promoted cinnamyl ion mobility within peptide derived macrocycles.
MedLine Citation:
PMID:  18811162     Owner:  NLM     Status:  MEDLINE    
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.
Hongda Zhao; Lidet Negash; Qi Wei; Thomas G LaCour; Sandi Jo Estill; Emanuela Capota; Andrew A Pieper; Patrick G Harran
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-09-24
Journal Detail:
Title:  Journal of the American Chemical Society     Volume:  130     ISSN:  1520-5126     ISO Abbreviation:  J. Am. Chem. Soc.     Publication Date:  2008 Oct 
Date Detail:
Created Date:  2008-10-15     Completed Date:  2008-12-22     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7503056     Medline TA:  J Am Chem Soc     Country:  United States    
Other Details:
Languages:  eng     Pagination:  13864-6     Citation Subset:  IM    
Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, USA.
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MeSH Terms
Acids / chemistry*
Cell Proliferation / drug effects
Cinnamates / chemistry*
Dentate Gyrus / cytology,  drug effects
Ions / chemistry
Macrocyclic Compounds / chemical synthesis*,  chemistry,  pharmacology
Molecular Conformation
Peptides / chemistry*
Polymers / chemistry
Reg. No./Substance:
0/Acids; 0/Cinnamates; 0/Ions; 0/Macrocyclic Compounds; 0/Peptides; 0/Polymers

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