Angell, Yu Li (2007-08). Triazole based peptidomimetics for mimicking protein-protein hot spots. Doctoral Dissertation. Thesis uri icon

abstract

  • Copper-mediated alkyne-azide cycloadditions yield 1,4-disubstituted triazoles with high chemoselectivity that can be used in many ways. For instance, when alkyne or azido peptide units combine via this pathway the reaction is relatively insensitive to the amino acid side-chains. This serves as an excellent way to produce peptidomimetics, particularly because there is some stereoelectronic similarity between 1,2,3-triazoles and amide bonds. Linear peptidomimetic substrates 60 were used to form the cyclic derivatives 61 via copper catalyzed azide alkyne cycloadditions. This reaction is fast, simple to perform and compatible with many solvents and functional groups. A library of eight cyclic peptidomimetics was prepared in solution and the low yield was mostly due to formation of dimers. Computational, NMR, and CD analyses of compounds 61a-c indicate that their most favorable conformational states include type I and type II ?-turn conformations. Monovalent triazole mimics were prepared via cycloaddition reactions in solution. These triazole compounds contain two amino acid chain functionalities at 1- and 4- positions. One is derived from a natural amino acid and the other is a functional group that resembles the side chains of an amino acid. The 1,3-dipolar cycloaddition reactions allow quick and efficient generation of the desired peptidomimetics in good yields. Two monovalent mimics were coupled to the linker scaffold sequentially in solution by simply manipulating the solvent systems. This method allows us to prepare large libraries of bivalent compounds quickly and efficiently. The two monomers were combined with each other cleanly, to achieve one-compound-per-well in sufficient purity for biological testing. Oxidative coupling to give 5,5'-bistriazoles is discussed. The bistriazole products predominate in the copper accelerated "click reaction" of alkynes and azides when carbonate bases are used as additives (ca 1 - 2 M). The reaction seems to be more efficient for propargylic ethers and less hindered substrates. Use of optically active azides could afford separable atropisomeric products, providing a convenient access into optically pure derivatives.
  • Copper-mediated alkyne-azide cycloadditions yield 1,4-disubstituted triazoles
    with high chemoselectivity that can be used in many ways. For instance, when alkyne or
    azido peptide units combine via this pathway the reaction is relatively insensitive to the
    amino acid side-chains. This serves as an excellent way to produce peptidomimetics,
    particularly because there is some stereoelectronic similarity between 1,2,3-triazoles and
    amide bonds.
    Linear peptidomimetic substrates 60 were used to form the cyclic derivatives 61
    via copper catalyzed azide alkyne cycloadditions. This reaction is fast, simple to perform
    and compatible with many solvents and functional groups. A library of eight cyclic
    peptidomimetics was prepared in solution and the low yield was mostly due to formation
    of dimers. Computational, NMR, and CD analyses of compounds 61a-c indicate that
    their most favorable conformational states include type I and type II ?-turn
    conformations.
    Monovalent triazole mimics were prepared via cycloaddition reactions in solution.
    These triazole compounds contain two amino acid chain functionalities at 1- and 4-
    positions. One is derived from a natural amino acid and the other is a functional group
    that resembles the side chains of an amino acid. The 1,3-dipolar cycloaddition reactions
    allow quick and efficient generation of the desired peptidomimetics in good yields.
    Two monovalent mimics were coupled to the linker scaffold sequentially in
    solution by simply manipulating the solvent systems. This method allows us to prepare
    large libraries of bivalent compounds quickly and efficiently. The two monomers were combined with each other cleanly, to achieve one-compound-per-well in sufficient purity
    for biological testing.
    Oxidative coupling to give 5,5'-bistriazoles is discussed. The bistriazole products
    predominate in the copper accelerated "click reaction" of alkynes and azides when
    carbonate bases are used as additives (ca 1 - 2 M). The reaction seems to be more
    efficient for propargylic ethers and less hindered substrates. Use of optically active
    azides could afford separable atropisomeric products, providing a convenient access into
    optically pure derivatives.

publication date

  • August 2007