Major Research Areas
Molecular Pharmacology & Chemistry
Research in our lab focuses on synthetic organic chemistry and its applications to biological problems. In the area of diversity-oriented synthesis, we are developing new synthetic routes and strategies to access small molecules containing structural motifs commonly found in biologically active natural products. These efforts provide exciting opportunities to develop new synthetic methodologies and insights into chemical reactivity. After efficient, flexible synthetic routes have been developed, combinatorial libraries are synthesized for screening against promising new targets in cancer and infectious diseases through collaborations with other labs in the Tri-Institutional program and NIH Molecular Libraries Initiative. We are also engaged in a complementary program involving rational design of novel antibiotics that target natural product biosynthetic pathways. We use mechanistic and structural information about individual targets of interest to design small molecule inhibitors. Among these are compounds that block siderophore biosynthesis pathways critical for bacterial iron uptake and virulence. We again leverage synergistic multidisciplinary collaborations with biologists in our Tri-Institutional program and elsewhere in these efforts. More information about these projects is available below.

  • Spiroketals
    Spiroketals are privileged substructures found in numerous natural products. Even relatively simple spiroketals exhibit a range of biological activities. In more complex structures, spiroketals often serve as rigid scaffolds to present sidechains along well-defined three-dimensional vectors. Thus, spiroketals are attractive targets for diversity-oriented synthesis.
  • Linear Polyketides
    Many linear polyketides exhibit impressive biological activity. Examples from the anticancer arena include discodermolide, depudecin, and trichostatin. These molecules derive much of their structural diversity through variations in stereochemical configuration using a very limited number of building blocks.
  • Polycyclics
    Polycylic structures are found in nearly every biosynthetic class of natural products. In particular, an amazing range of rigid densely functionalized polycylic compounds are formed from simple polyisoprenoid precursors during terpene biosynthesis.
  • Adenylation Inhibitors
    Non-ribosomal peptide (NRP) natural products have been identified as key players in bacterial iron uptake, biofilm formation, commensalism, and virulence. Thus, small molecule inhibition of NRP biosynthesis provides a powerful means to study the biological roles of these natural products and a potential avenue to develop novel antibiotics.

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