Lactonamycin was isolated by Matsumoto and coworkers in 1996 from Streptomyces rishiriensis in a screen for new antibiotics active against drug resistant bacterial strains. Lactonamycin exhibits potent antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). Structurally related polyketides including the tetracenomycins and elloramycin display potent antitumor activity. The goals of this research program are as follows: 1) Development of general synthetic methods to access lactonamycin, elloramycin, saintopin E, and the numerous tetracenomycin structures. In particular the construction of the ABCD-ring systems through a strategy of tandem 1,4-addition-Dieckmann ring closure will provide access to the natural product targets as well as analogs. 2) Construct advanced synthetic intermediates postulated as biosynthetic precursors of lactonamycin as part of elucidating the biosynthetic pathway to lactonamycin. 3) Construct an appropriate form of the carbohydrate L-rhodinose for completion of a chemical synthesis of lactonamycin. 4) Expand and define the scope of the tandem 1,4-addition-Dieckmann ring closure for applications to related type II polyketide natural products. Further expansion of the methodology to the synthesis of condensed polycyclic heterocycles. 5) Expand the [3+2] cycloaddition reaction of quinones with nitrile oxides to gain access to diverse type II polyketide structures such as DNA helicase inhibitor heliquinomycin.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI058045-02
Application #
6910894
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Tseng, Christopher K
Project Start
2004-07-01
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
2
Fiscal Year
2005
Total Cost
$256,167
Indirect Cost
Name
Rice University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
050299031
City
Houston
State
TX
Country
United States
Zip Code
77005
Lodeiro, Silvia; Xiong, Quanbo; Wilson, William K et al. (2009) Protostadienol biosynthesis and metabolism in the pathogenic fungus Aspergillus fumigatus. Org Lett 11:1241-4
Zhang, Xiujun; Alemany, Lawrence B; Fiedler, Hans-Peter et al. (2008) Biosynthetic investigations of lactonamycin and lactonamycin z: cloning of the biosynthetic gene clusters and discovery of an unusual starter unit. Antimicrob Agents Chemother 52:574-85