Synthesis of Natural and Unnatural Inhibitors of ftsZ

Summary

Principal Investigator: Jared T Shaw
Abstract: [unreadable] DESCRIPTION (provided by applicant): The goal of this proposal is to demonstrate that certain antimicrobial natural products derive their biological activity from inhibition of ftsZ, the bacterial analog of mammalian tubulin that is required for bacterial cell division. FtsZ is an exciting new target for developing new methods of combating bacterial infections that are currently resistant to other forms of therapy. To date, very few small molecules have been shown to inhibit ftsZ, and the few that do so are toxic to mammalian cells. Research at the ICCB has revealed several new small molecules that inhibit ftsZ, 1 of which shares a common core structure with a series of known antibiotic natural products. These natural products are derived from plant extracts that are currently used for traditional medicine, so it is likely that there mammalian toxicity is quite low. We will synthesize these natural products so that their biological mode of action can be discerned. In the process, we will develop new and highly efficient chemical reactions that allow rapid and flexible assembly of the core structures, and use these synthetic techniques in a diversity-oriented approach to a variety of structural analogs. If successful, this proposal will demonstrate that plant-derived compounds, as well as synthetic analogs thereof, will inhibit ftsZ and offer some hope of discovering compounds that exploit this unique mode of activity for therapeutic value. [unreadable] [unreadable]
Funding Period: 2005-04-15 - 2007-09-30
more information: NIH RePORT

Top Publications

  1. pmc Synthesis of antimicrobial natural products targeting FtsZ: (+/-)-dichamanetin and (+/-)-2' ''-hydroxy-5' '-benzylisouvarinol-B
    Sameer Urgaonkar
    Broad Institute of Harvard and MIT, Chemical Biology Program, Cambridge, Massachusetts 02141, USA
    Org Lett 7:5609-12. 2005
  2. ncbi Synthesis of kaempferitrin
    Sameer Urgaonkar
    Chemical Biology Program, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA
    J Org Chem 72:4582-5. 2007
  3. pmc N-Benzyl-3-sulfonamidopyrrolidines as novel inhibitors of cell division in E. coli
    Shubhasish Mukherjee
    Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA
    Bioorg Med Chem Lett 17:6651-5. 2007

Detail Information

Publications4

  1. pmc Synthesis of antimicrobial natural products targeting FtsZ: (+/-)-dichamanetin and (+/-)-2' ''-hydroxy-5' '-benzylisouvarinol-B
    Sameer Urgaonkar
    Broad Institute of Harvard and MIT, Chemical Biology Program, Cambridge, Massachusetts 02141, USA
    Org Lett 7:5609-12. 2005
    ..Two natural products have been synthesized using a ZnCl2-mediated benzylic coupling reaction. Both are potent inhibitors of the GTPase activity of FtsZ, a highly conserved protein that is essential for bacterial cytokinesis...
  2. ncbi Synthesis of kaempferitrin
    Sameer Urgaonkar
    Chemical Biology Program, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA
    J Org Chem 72:4582-5. 2007
    ..This synthesis will allow the preparation of derivatives for further explorations into the origins of this compound's biological activity...
  3. pmc N-Benzyl-3-sulfonamidopyrrolidines as novel inhibitors of cell division in E. coli
    Shubhasish Mukherjee
    Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA
    Bioorg Med Chem Lett 17:6651-5. 2007
    ..A library of analogs has been prepared and several alkyne-tagged photoaffinity probes have been synthesized for use in experiments to elucidate the primary target of this compound...