Dissertation/Thesis Abstract

Utilizing advanced techniques in NMR spectroscopy to study the conformational aspects of membrane permeability for N-methylated cyclic peptides
by Renzelman, Chad M., M.S., University of California, Santa Cruz, 2012, 56; 1516196
Abstract (Summary)

The conformational hypothesis of membrane permeability hypothesizes that certain macrocyclic scaffolds can exhibit an abnormally high degree of permeability producing a larger logP value than expected due to intramolecular hydrogen bonding which locks the macrocycle into a specific conformation where the hydrophilic functional groups are buried within the molecule causing it to become lipophilic enough to cross the membrane. Exploring this concept in previous work resulted in the synthesis of a 32 membered library of cyclic peptides with the same sequence varying in stereochemistry and N-methylation pattern. From this library two cyclic peptides, compounds 1 and 2 were found to exhibit an abnormally large logP value when assayed using the PAMPA permeability assay. This result lead us to synthesize more of these compounds and subject them to a series of NMR and other analytical experiments to computationally determine these two molecules 3D structure as they exist in chloroform solution, used to mimic the environment of the inside of membrane bilayer. These NMR structures were produced using NOESY derived distance restraints and the molecular modeling program CYANA. These structures provide valuable information about what types of conformational motifs can be used when designing novel therapeutic compounds.

Indexing (document details)
Advisor: Lokey, R. Scott, Scott, William G.
Commitee: Oliver, Scott RJ
School: University of California, Santa Cruz
Department: Chemistry
School Location: United States -- California
Source: MAI 51/02M(E), Masters Abstracts International
Subjects: Biochemistry, Organic chemistry, Pharmacy sciences
Keywords: CYANA conformational analysis, Cyclic peptides, Lipinski Rule of 5, Membrane permeability, NOESY NMR structure determination, PAMPA
Publication Number: 1516196
ISBN: 978-1-267-53382-1
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