orchids

Main menu:

Postgraduate Training:

Cancer Medicinal Chemistry:
4 year programme funded by CRUK

Read more...

Links:

  • Chemistry
  • EaStCHEM
  • Edinburgh

    • Natural Products

    Hulme group natural product targets span a number of different classes of metabolite, but an overriding theme is that they interact with their biological targets through several, or many, chiral groups.

    Iminosugars

    iminosugar targets

    Iminosugars are a class of natural products where a nitrogen replaces the sugar ring oxygen. Pyrrolidine iminosugars in their protonated form make excellent transition state analogues for glycosidase enzymes. Early Hulme group natural product targets were a small group of iminosugars including the immunomodulators, DAB-1 (Perkin Trans. 1, 2000), CYB-3 (Perkin Trans. 1, 2002), and nectrisine (Tetrahedron Lett., 2003) and we used a direct and efficient approach based around a stereocontrolled aldol reaction between a chiral glycolate enolate equivalent and an amino-acid derived alpha-amino aldehyde. Using this same methodology we then completed the synthesis of the SAPK pathway activator, anisomycin (Org. Lett., 2002) – which led us into the field of Chemical Biology.

    Polyketides

    polyketide targets

    Polyketides are produced through the sequential Claisen-like condensation reactions of malonyl-CoA (or derivatives thereof). They provide attractive targets for synthesis due to their complex stereochemical relationships and high biological activity. Two compounds of recent interest to the Hulme group are octalactin A (Tetrahedron Lett., 1997) and (Org. Lett., 2007), and decarestrictine D.

    Mixed NRPS-PKS

    NRPS-PKS

    Non-ribosomal Peptide Synthases (NRPSs) use mechanisms which are similar to the polyketide synthases (PKSs) to condense amino acid building blocks in a sequential manner. A limited number of natural products result from a fusion of these two pathways. We have recently targetted the synthesis of the mixed PKS-NRPS natural products zwittermicin A (antifungal) and disorazole C1 (antitubulin). [The NRPS-derived sections of each of these molecules has been highlighted in blue.] As part of these studies we have developed a high-yielding route to the non-proteinaceous amino acid albizziine which is incorporated in zwittermicin A (Synlett, 2008).