The objective of this proposal is to develop the first practical, efficient, and enantioselective laboratory synthetic route(s) to the tetracycline antibiotics. The goal is to devise a route of twelve or fewer synthetic steps, perhaps as few as eight steps, beginning with benzoic acid as a starting material. A constraint that the synthetic route be versatile is also imposed, allowing for the introduction of substantive structural variability at a late stage, particularly within the C and D rings of the tetracycline structure, where prior research has shown that there is great opportunity for antibiotic development. Synthesis of a wide range of new tetracyclines for evaluation as improved antibiotics and, potentially antitumor agents is proposed. A particular focus is the development of effective antibiotics against tetracycline-resistant microorganisms. Adaptation and/or modification of these synthetic routes to target new tetracycline structures with antitumor activity, such as SF-2575 (TAN-1518 X) will also be attempted.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI048825-03
Application #
6626402
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Tseng, Christopher K
Project Start
2001-01-01
Project End
2005-12-31
Budget Start
2003-01-01
Budget End
2003-12-31
Support Year
3
Fiscal Year
2003
Total Cost
$244,500
Indirect Cost
Name
Harvard University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Kummer, David A; Li, Derun; Dion, Amelie et al. (2011) A practical, convergent route to the key precursor to the tetracycline antibiotics. Chem Sci 2:1710-1718
Wright, Peter M; Myers, Andrew G (2011) Methodological Advances Permit the Stereocontrolled Construction of Diverse Fully Synthetic Tetracyclines Containing an All-Carbon Quaternary Center at Position C5a. Tetrahedron 67:9853-9869
Sun, Cuixiang; Wang, Qiu; Brubaker, Jason D et al. (2008) A robust platform for the synthesis of new tetracycline antibiotics. J Am Chem Soc 130:17913-27
Brubaker, Jason D; Myers, Andrew G (2007) A practical, enantioselective synthetic route to a key precursor to the tetracycline antibiotics. Org Lett 9:3523-5
Charest, Mark G; Lerner, Christian D; Brubaker, Jason D et al. (2005) A convergent enantioselective route to structurally diverse 6-deoxytetracycline antibiotics. Science 308:395-8