Design, synthesis, and evaluation of conformationally-constrained Grb2 SH2 ligands and a concise total synthesis of lycopladine A

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Title: Design, synthesis, and evaluation of conformationally-constrained Grb2 SH2 ligands and a concise total synthesis of lycopladine A
Author: Delorbe, Johnathan E.
Abstract: Conformationally constrained ligands and their flexible analogues were prepared as inhibitors of the Grb2 SH2 domain in order to study the structural and energetic effects of ligand preorganization in protein -ligand interactions . The compounds were prepared by using trans -cyclopropane -containing amino acid mimics , macrocyclization , or [alpha ,alpha] -disubstituted amino acid residues . All trans -cyclopropane containing peptides were more potent than their corresponding succinate containing analogues due to an enthalpic advantage . Surprisingly , the binding of constrained peptides to the domain was entropically disfavored relative to their flexible controls . Effects of proton transfer and desolvation as being the source of the unprecedented entropic penalty for the constrained ligands relative to their respective controls were precluded , and X -ray crystallographic studies revealed that the binding conformations for the respective cyclopropane and succinate containing ligands were similar . This led us to believe that differential changes in protein dynamics may occur upon binding of the constrained and flexible ligands , which could contribute to the observed binding energetics . Two 23 -membered macrocyclic ligands were slightly more potent than their corresponding linear controls . The amino acids used to link the N - and C -termini of the linear peptides to form the macrocycles were found to affect the energetics of binding . In one case , the 23 -membered macrocycle was more potent than its control due to an entropic advantage , whereas the other 23 -membered macrocycle was more potent than its control because it benefited from an enthalpic advantage . [alpha ,alpha] -Disubstituted and [alpha] -monosubstituted residues that varied in hydrophobic character were incorporated into Grb2 SH2 domain binding tripeptides , and binding became more favorable as nonpolar surface area increased only for the set of tripeptides possessing cyclic [alpha ,alpha] -disubstituted residues . The increase in affinity was due to an increasing enthalplic term , whereas the entropy of binding became less favorable . A total synthesis of ) -lycopladine A was achieved in five steps from known compounds . The tricyclic core of the natural product was prepared utilizing a novel two -step sequence comprising a conjugate addition of a metalated picoline derivative followed by an intramolecular enolate arylation . It was demonstrated that the natural product existed in a solvent dependent equilibrium with its isomeric lactol .
URI: http : / /hdl .handle .net /2152 /ETD -UT -2010 -05 -795
Date: 2010-10-05

Citation

Design, synthesis, and evaluation of conformationally-constrained Grb2 SH2 ligands and a concise total synthesis of lycopladine A. Doctoral dissertation, University of Texas at Austin. Available electronically from http : / /hdl .handle .net /2152 /ETD -UT -2010 -05 -795 .

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