ANTITUMOR AGENTS: BOUVARDIN AND LUZOPEPTINS

Summary

Principal Investigator: Dale Boger
Affiliation: The Scripps Research Institute
Country: USA
Abstract: DESCRIPTION (Investigator's Abstract): The completion of efforts on the total synthesis of the naturally occurring antitumor antibiotics related to deoxybouvardin and RA-I-VII are detailed and include efforts to address the total synthesis of bouvardin based on implementation of an intramolecular Ullmann macrocyclization reaction for formation of the functionalized 14-memberedcycloisodityrosine subunit. Extensions of the studies to conduct a totalsynthesis of piperazinomycin and to model studies that will establish theirviability for application in the synthesis of the vancomycin class of glycopeptide antibiotics are described. Additional studies on the synthesis, biological evaluation, and conformational properties of deoxybouvardin analogs are detailed and include efforts to experimentally define the conformational properties of the agents and their relationship to the agent biological properties, and the conduct of structure-activity relationships within the newlyassigned deoxybouvardin pharmacophore. The total syntheses of the naturally occurring antitumor antibiotics sandramycin and luzopeptin A-C, E2, cyclic decadepsipeptides, are detailed and studies to systematically evaluate their biological properties are described. The agents constitute effective DNA binding agents that interact with DNA through bifunctional intercalation and complementary minor groove binding. Studies will be pursued to delineate the structural features of the agents contributing to their DNA binding affinityand specificity.
Funding Period: 1985-07-01 - 1996-05-31
more information: NIH RePORT

Top Publications

  1. ncbi Total synthesis and evaluation of [Psi[CH2NH]Tpg4]vancomycin aglycon: reengineering vancomycin for dual D-Ala-D-Ala and D-Ala-D-Lac binding
    Brendan M Crowley
    Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. USA
    J Am Chem Soc 128:2885-92. 2006
  2. ncbi The mechanism of action of ramoplanin and enduracidin
    Xiao Fang
    Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02128, USA
    Mol Biosyst 2:69-76. 2006
  3. ncbi Alanine scan of [L-Dap(2)]ramoplanin A2 aglycon: assessment of the importance of each residue
    Joonwoo Nam
    Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
    J Am Chem Soc 129:8747-55. 2007
  4. ncbi Total synthesis, stereochemical reassignment, and absolute configuration of chlorofusin
    Sang Yeul Lee
    Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    J Am Chem Soc 129:9860-1. 2007
  5. ncbi Total synthesis of chlorofusin, its seven chromophore diastereomers, and key partial structures
    Ryan C Clark
    Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
    J Am Chem Soc 130:12355-69. 2008
  6. ncbi Synthesis and evaluation of vancomycin aglycon analogues that bear modifications in the N-terminal D-leucyl amino acid
    Christine M Crane
    Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA
    J Med Chem 52:1471-6. 2009
  7. ncbi The isolation, total synthesis and structure elucidation of chlorofusin, a natural product inhibitor of the p53-mDM2 protein-protein interaction
    Ryan C Clark
    Department of Chemistry, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, California 92037, USA
    Nat Prod Rep 26:465-77. 2009

Scientific Experts

  • Xiao Fang
  • Dale L Boger
  • Ryan C Clark
  • Sang Yeul Lee
  • Christine M Crane
  • Joonwoo Nam
  • Brendan M Crowley
  • Mark Searcey
  • Yosup Rew
  • Dongwoo Shin

Detail Information

Publications7

  1. ncbi Total synthesis and evaluation of [Psi[CH2NH]Tpg4]vancomycin aglycon: reengineering vancomycin for dual D-Ala-D-Ala and D-Ala-D-Lac binding
    Brendan M Crowley
    Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. USA
    J Am Chem Soc 128:2885-92. 2006
    ....
  2. ncbi The mechanism of action of ramoplanin and enduracidin
    Xiao Fang
    Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02128, USA
    Mol Biosyst 2:69-76. 2006
    ..These results provide compelling evidence that ramoplanin's and enduracidin's primary cellular target is the transglycosylation step of peptidoglycan biosynthesis...
  3. ncbi Alanine scan of [L-Dap(2)]ramoplanin A2 aglycon: assessment of the importance of each residue
    Joonwoo Nam
    Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
    J Am Chem Soc 129:8747-55. 2007
    ..The antimicrobial activity of the resulting library of analogues provides insight into the importance and potential role of each residue of this complex glycopeptide antibiotic...
  4. ncbi Total synthesis, stereochemical reassignment, and absolute configuration of chlorofusin
    Sang Yeul Lee
    Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    J Am Chem Soc 129:9860-1. 2007
  5. ncbi Total synthesis of chlorofusin, its seven chromophore diastereomers, and key partial structures
    Ryan C Clark
    Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
    J Am Chem Soc 130:12355-69. 2008
    ....
  6. ncbi Synthesis and evaluation of vancomycin aglycon analogues that bear modifications in the N-terminal D-leucyl amino acid
    Christine M Crane
    Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA
    J Med Chem 52:1471-6. 2009
    ....
  7. ncbi The isolation, total synthesis and structure elucidation of chlorofusin, a natural product inhibitor of the p53-mDM2 protein-protein interaction
    Ryan C Clark
    Department of Chemistry, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, California 92037, USA
    Nat Prod Rep 26:465-77. 2009
    ....