ANTITUMOR AGENTS: BOUVARDIN AND LUZOPEPTINS
Principal Investigator: Dale Boger
Affiliation: The Scripps Research Institute
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
- Total synthesis and evaluation of [Psi[CH2NH]Tpg4]vancomycin aglycon: reengineering vancomycin for dual D-Ala-D-Ala and D-Ala-D-Lac bindingBrendan 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....
- The mechanism of action of ramoplanin and enduracidinXiao 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...
- Alanine scan of [L-Dap(2)]ramoplanin A2 aglycon: assessment of the importance of each residueJoonwoo 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...
- Total synthesis, stereochemical reassignment, and absolute configuration of chlorofusinSang 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
- Total synthesis of chlorofusin, its seven chromophore diastereomers, and key partial structuresRyan 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....
- Synthesis and evaluation of vancomycin aglycon analogues that bear modifications in the N-terminal D-leucyl amino acidChristine M Crane
Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA
J Med Chem 52:1471-6. 2009....
- The isolation, total synthesis and structure elucidation of chlorofusin, a natural product inhibitor of the p53-mDM2 protein-protein interactionRyan 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....