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. pmc Investigation into the functional impact of the vancomycin C-ring aryl chloride
    Joseph R Pinchman
    Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, United States
    Bioorg Med Chem Lett 23:4817-9. 2013
  2. pmc Probing the role of the vancomycin e-ring aryl chloride: selective divergent synthesis and evaluation of alternatively substituted E-ring analogues
    Joseph R Pinchman
    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 Med Chem 56:4116-24. 2013
  3. pmc A Pd(0)-mediated indole (macro)cyclization reaction
    Steven P Breazzano
    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 135:1600-6. 2013
  4. pmc Silver(I)-promoted conversion of thioamides to amidines: divergent synthesis of a key series of vancomycin aglycon residue 4 amidines that clarify binding behavior to model ligands
    Akinori Okano
    Department of Chemistry and Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
    J Am Chem Soc 134:8790-3. 2012
  5. pmc Synthesis and evaluation of selected key methyl ether derivatives of vancomycin aglycon
    Christine M Crane
    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 Med Chem 53:7229-35. 2010
  6. pmc A redesigned vancomycin engineered for dual D-Ala-D-ala And D-Ala-D-Lac binding exhibits potent antimicrobial activity against vancomycin-resistant bacteria
    Jian Xie
    Department of Chemistry, The Skaggs Institute for Chemical Biology, La Jolla, California 92037, United States
    J Am Chem Soc 133:13946-9. 2011
  7. pmc Synthesis and stereochemical determination of complestatin A and B (neuroprotectin A and B)
    Steven P Breazzano
    Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
    J Am Chem Soc 133:18495-502. 2011
  8. pmc Total synthesis of [Ψ[C(═S)NH]Tpg4]vancomycin aglycon, [Ψ[C(═NH)NH]Tpg4]vancomycin aglycon, and related key compounds: reengineering vancomycin for dual D-Ala-D-Ala and D-Ala-D-Lac binding
    Jian Xie
    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 134:1284-97. 2012
  9. pmc Redesign of glycopeptide antibiotics: back to the future
    Robert C James
    Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    ACS Chem Biol 7:797-804. 2012
  10. pmc Total synthesis of complestatin: development of a Pd(0)-mediated indole annulation for macrocyclization
    Hiroyuki Shimamura
    Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
    J Am Chem Soc 132:7776-83. 2010

Scientific Experts

  • Xiao Fang
  • Dale L Boger
  • Jian Xie
  • Akinori Okano
  • Robert C James
  • Steven P Breazzano
  • Joshua G Pierce
  • Christine M Crane
  • Joseph R Pinchman
  • Ryan C Clark
  • Sang Yeul Lee
  • Hiroyuki Shimamura
  • Joie Garfunkle
  • John D Trzupek
  • F Scott Kimball
  • Joonwoo Nam
  • Brendan M Crowley
  • Yam B Poudel
  • Simon Stamm
  • Siegfried S F Leung
  • Julian Tirado-Rives
  • William L Jorgensen
  • Mark Searcey
  • Masaki Tomishima
  • Shinobu Takizawa
  • Yosup Rew
  • Dongwoo Shin

Detail Information

Publications21

  1. pmc Investigation into the functional impact of the vancomycin C-ring aryl chloride
    Joseph R Pinchman
    Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, United States
    Bioorg Med Chem Lett 23:4817-9. 2013
    ....
  2. pmc Probing the role of the vancomycin e-ring aryl chloride: selective divergent synthesis and evaluation of alternatively substituted E-ring analogues
    Joseph R Pinchman
    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 Med Chem 56:4116-24. 2013
    ..The robust borylation reaction also enabled the functionalization of a minimally protected vancomycin aglycon (N-Boc-vancomycin aglycon) and provides a direct method for the preparation of previously inaccessible analogues...
  3. pmc A Pd(0)-mediated indole (macro)cyclization reaction
    Steven P Breazzano
    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 135:1600-6. 2013
    ....
  4. pmc Silver(I)-promoted conversion of thioamides to amidines: divergent synthesis of a key series of vancomycin aglycon residue 4 amidines that clarify binding behavior to model ligands
    Akinori Okano
    Department of Chemistry and Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
    J Am Chem Soc 134:8790-3. 2012
    ....
  5. pmc Synthesis and evaluation of selected key methyl ether derivatives of vancomycin aglycon
    Christine M Crane
    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 Med Chem 53:7229-35. 2010
    ....
  6. pmc A redesigned vancomycin engineered for dual D-Ala-D-ala And D-Ala-D-Lac binding exhibits potent antimicrobial activity against vancomycin-resistant bacteria
    Jian Xie
    Department of Chemistry, The Skaggs Institute for Chemical Biology, La Jolla, California 92037, United States
    J Am Chem Soc 133:13946-9. 2011
    ....
  7. pmc Synthesis and stereochemical determination of complestatin A and B (neuroprotectin A and B)
    Steven P Breazzano
    Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
    J Am Chem Soc 133:18495-502. 2011
    ....
  8. pmc Total synthesis of [Ψ[C(═S)NH]Tpg4]vancomycin aglycon, [Ψ[C(═NH)NH]Tpg4]vancomycin aglycon, and related key compounds: reengineering vancomycin for dual D-Ala-D-Ala and D-Ala-D-Lac binding
    Jian Xie
    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 134:1284-97. 2012
    ..In sharp contrast, 8 and related residue 4 thioamides failed to bind either 2 or 4 to any appreciable extent, do not exhibit antimicrobial activity, and serve to further underscore the remarkable behavior of the residue 4 amidines...
  9. pmc Redesign of glycopeptide antibiotics: back to the future
    Robert C James
    Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    ACS Chem Biol 7:797-804. 2012
    ....
  10. pmc Total synthesis of complestatin: development of a Pd(0)-mediated indole annulation for macrocyclization
    Hiroyuki Shimamura
    Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
    J Am Chem Soc 132:7776-83. 2010
    ..Just as significant, the atroposelectivity represents a complete reversal of the diasteroselectivity observed with analogous macrocyclizations conducted using a Suzuki biaryl coupling...
  11. pmc Total synthesis of chloropeptin II (complestatin) and chloropeptin I
    Joie Garfunkle
    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 131:16036-8. 2009
    ..Intrinsic in the design of the approach and by virtue of the single-step acid-catalyzed conversion of chloropeptin II (1) to chloropeptin I (2), the route also provides a total synthesis of 2...
  12. pmc Functional and biochemical analysis of a key series of ramoplanin analogues
    Xiao Fang
    Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA
    Bioorg Med Chem Lett 19:6189-91. 2009
    ....
  13. 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...
  14. pmc 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...
  15. pmc 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
  16. pmc 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
    ....
  17. pmc 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
    ....
  18. pmc 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
    ....
  19. pmc 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
    ....