Liu, Jing (2008-12). Heterocyclic small molecule peptidomimetics. Doctoral Dissertation. Thesis uri icon

abstract

  • Polymer-supported synthesis of a close analog (i.e. A) of an early lead, a 14- membered ring peptidomimetic D3, was described. The monovalent molecule was attached to different length linkers, and they were then paired sequentially on a triazine scaffold via our previously published methodology to give a small library of bivalent compounds 1 representing all combinations of linkers of the different lengths in a fast and efficient combinatorial manner. Cellular assays identified 1-ss as a TrkA receptor antagonist towards NGF and it was shown to bind TrkA with ~200 nM affinity and retains high selectivity towards TrkA in binding assays. A set of monovalent diketopiperazine (DKP) mimics 4-7 was synthesized efficiently from corresponding dipeptides via intramolecular SN2 cyclization reactions in solution. These DKP compounds contain two amino acid side-chain functionalities to mimic the sequences that occur at "hot-spots" in loop regions. The monovalent mimics were assembled into a library of biotin-labeled bivalent molecules 9 via the combinatorial strategy described above with some modification. In primary screening, compound 9gg showed preferential binding to TrkC receptors in FACScan assay and blocked the trophic activity of NT-3 in TrkC cells at 10 uM in cell survival assay. The preparation of monovalent 1,3,4-oxadizole-based mimics 12 was achieved from corresponding amino acid building blocks on gram scale in a highly efficient solution phase parallel synthesis manner in good yields. These heterocyclic compounds feature various natural amino acid side-chain functionalities including those occuring most frequently at hot-spots such as those of Tyr, Lys, Glu and Ser. Attempts to assemble them into bivalent molecules were done by coupling the monovalent mimics to the triazine scaffold sequentially in solution and simply manipulating the solvent systems. For some reasons, some reactions did not proceed cleanly. Studies have been carried out and the problems were partially solved. The biological activities of these oxadiazoles are under investigation. So far, six compounds have shown activities in four different bioassays. Two different peptidomimetic types that resemble protein A and protein G binding regions were generated and tested as binding factors in affinity columns for purification of IgG. They are cyclic hexapeptides 19, which were prepared via Fmoc- SPPS and solution phase intramoleculer macrocyclization, and heterocycle-based small molecules 22 and 23 featuring a variety of aromatic functionalities generated via solution phase parallel synthesis. Four compounds showed some affinity towards a Fab fragment of IgG in SAR screening, and they were attached to a dendrimer core on a solid support to give four multivalent mimetics 25.
  • Polymer-supported synthesis of a close analog (i.e. A) of an early lead, a 14-
    membered ring peptidomimetic D3, was described. The monovalent molecule was
    attached to different length linkers, and they were then paired sequentially on a triazine
    scaffold via our previously published methodology to give a small library of bivalent
    compounds 1 representing all combinations of linkers of the different lengths in a fast and
    efficient combinatorial manner. Cellular assays identified 1-ss as a TrkA receptor
    antagonist towards NGF and it was shown to bind TrkA with ~200 nM affinity and
    retains high selectivity towards TrkA in binding assays.
    A set of monovalent diketopiperazine (DKP) mimics 4-7 was synthesized
    efficiently from corresponding dipeptides via intramolecular SN2 cyclization reactions in
    solution. These DKP compounds contain two amino acid side-chain functionalities to
    mimic the sequences that occur at "hot-spots" in loop regions. The monovalent mimics
    were assembled into a library of biotin-labeled bivalent molecules 9 via the combinatorial
    strategy described above with some modification. In primary screening, compound 9gg
    showed preferential binding to TrkC receptors in FACScan assay and blocked the trophic
    activity of NT-3 in TrkC cells at 10 uM in cell survival assay.
    The preparation of monovalent 1,3,4-oxadizole-based mimics 12 was achieved
    from corresponding amino acid building blocks on gram scale in a highly efficient
    solution phase parallel synthesis manner in good yields. These heterocyclic compounds
    feature various natural amino acid side-chain functionalities including those occuring
    most frequently at hot-spots such as those of Tyr, Lys, Glu and Ser. Attempts to
    assemble them into bivalent molecules were done by coupling the monovalent mimics to the triazine scaffold sequentially in solution and simply manipulating the solvent systems.
    For some reasons, some reactions did not proceed cleanly. Studies have been carried out
    and the problems were partially solved. The biological activities of these oxadiazoles are
    under investigation. So far, six compounds have shown activities in four different
    bioassays.
    Two different peptidomimetic types that resemble protein A and protein G
    binding regions were generated and tested as binding factors in affinity columns for
    purification of IgG. They are cyclic hexapeptides 19, which were prepared via Fmoc-
    SPPS and solution phase intramoleculer macrocyclization, and heterocycle-based small
    molecules 22 and 23 featuring a variety of aromatic functionalities generated via solution
    phase parallel synthesis. Four compounds showed some affinity towards a Fab fragment
    of IgG in SAR screening, and they were attached to a dendrimer core on a solid support
    to give four multivalent mimetics 25.

publication date

  • December 2008