Park, Chihyo (2006-12). Combinatorial design and synthesis of peptidomimics and small molecules for protein-protein interactions. Doctoral Dissertation. Thesis uri icon

abstract

  • The solid phase combinatorial method is an excellent tool for the modulation of protein-protein interactions through focused library generations. Nucleophilic aromatic substitution reactions with an iodinated template on solid phase has opened a door for easy and pure libraries of 13-22 membered medium and macrocyclic peptidomimetics. These peptide mimics showed promising activities for tyrosine kinase receptors. Iodine functionality can then be used to modify the products, on the resin, via Sonogashira and Suzuki couplings and presumably through other organometallic catalysis. The coupled products can have conformational biases that differ from the iodinated macrocycles. These coupling reactions also provide a means to introduce additional pharmacophores and to adjust the solubilities of the products. The fluorinated template also gave libraries of cyclic peptidomimetics on solid phase in good yields and purities. These libraries have improved water solubility over the iodinated libraries. The 3-fluorinated template yielded better results than the 5- fluorinated template. Some compounds showed biological activities in cell survival assays providing strong support of our approach to mimic external ????-turn sequences in target proteins. Intrasite dimerization with 1,5-hexadiyne gave a homodimer as a byproduct. Solidphase synthesis of bivalent turn mimics with fluorescent tags has been demonstrated. The key feature of this synthetic route is that homo- and hetero-dimers can be formed chemoselectively from unprotected monomeric precursors. The dimerization reaction is very mild and versatile, as only potassium carbonate is required to affect the coupling. Solution phase library synthesis of small molecule mimics is presented. Some monomers of full sequence mimics have been prepared to afford dimer generations. Theses monomers were combined with linker handles to afford diverse length of dimers. Final combination of monomers to make bivalent compounds is in progress.
  • The solid phase combinatorial method is an excellent tool for the modulation of
    protein-protein interactions through focused library generations. Nucleophilic aromatic
    substitution reactions with an iodinated template on solid phase has opened a door for
    easy and pure libraries of 13-22 membered medium and macrocyclic peptidomimetics.
    These peptide mimics showed promising activities for tyrosine kinase receptors.
    Iodine functionality can then be used to modify the products, on the resin, via
    Sonogashira and Suzuki couplings and presumably through other organometallic
    catalysis. The coupled products can have conformational biases that differ from the
    iodinated macrocycles. These coupling reactions also provide a means to introduce
    additional pharmacophores and to adjust the solubilities of the products.
    The fluorinated template also gave libraries of cyclic peptidomimetics on solid phase
    in good yields and purities. These libraries have improved water solubility over the
    iodinated libraries. The 3-fluorinated template yielded better results than the 5-
    fluorinated template. Some compounds showed biological activities in cell survival
    assays providing strong support of our approach to mimic external ????-turn sequences in
    target proteins.
    Intrasite dimerization with 1,5-hexadiyne gave a homodimer as a byproduct. Solidphase
    synthesis of bivalent turn mimics with fluorescent tags has been demonstrated.
    The key feature of this synthetic route is that homo- and hetero-dimers can be formed
    chemoselectively from unprotected monomeric precursors. The dimerization reaction is
    very mild and versatile, as only potassium carbonate is required to affect the coupling.
    Solution phase library synthesis of small molecule mimics is presented. Some
    monomers of full sequence mimics have been prepared to afford dimer generations. Theses monomers were combined with linker handles to afford diverse length of dimers.
    Final combination of monomers to make bivalent compounds is in progress.

publication date

  • December 2006