Abstract

The major objective of this research is to make significant contributions to organic chemistry and medicine through studies directed towards the synthesis of natural products with antitumor activity or tumor-promoting activity, including halichondrins, C-indolactam V, cytoblastin, taxol/cephalomannine, mycalamides/onnamide, and daunomycin analogs. We believe that the power of organic chemistry, especially organic synthesis, is most effectively extended by challenging complex systems, and much of the progress of medicine certainly depends upon extension of the power of chemistry. More specifically, research efforts will be made first to develop general, flexible, and efficient syntheses of certain natural products and then to apply these to the synthesis of their analogs and derivatives, whose study will provide clues for developing better antitumor drugs or for understanding the tumor-promoting process. Among the five programs proposed, the halichondrin project is most advanced in our quest for an antitumor drug, and research plans are presented to identify a drug candidate for further clinical development.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA022215-24
Application #
6341829
Study Section
Special Emphasis Panel (NSS)
Program Officer
Lees, Robert G
Project Start
1978-03-17
Project End
2003-12-31
Budget Start
2001-01-01
Budget End
2001-12-31
Support Year
24
Fiscal Year
2001
Total Cost
$461,573
Indirect Cost

  Institution

Name
Harvard University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
071723621
City
Cambridge
State
MA
Country
United States
Zip Code
02138

  Publications

Kishi, Yoshito (2011) Chemistry of mycolactones, the causative toxins of Buruli ulcer. Proc Natl Acad Sci U S A 108:6703-8
Spangenberg, Thomas; Kishi, Yoshito (2010) Highly sensitive, operationally simple, cost/time effective detection of the mycolactones from the human pathogen Mycobacterium ulcerans. Chem Commun (Camb) 46:1410-2
Spangenberg, Thomas; Aubry, Sylvain; Kishi, Yoshito (2010) Synthesis and structure assignment of the minor metabolite arising from the frog pathogen Mycobacterium liflandii. Tetrahedron Lett 51:1782-1785
Jackson, Katrina L; Li, Wenju; Chen, Chi-Li et al. (2010) Scalable and efficient synthesis of the mycolactone core. Tetrahedron 66:2263-2272
Dong, Cheng-Guo; Henderson, James A; Kaburagi, Yosuke et al. (2009) New syntheses of E7389 C14-C35 and halichondrin C14-C38 building blocks: reductive cyclization and oxy-Michael cyclization approaches. J Am Chem Soc 131:15642-6
Kim, Han-Je; Jackson, Katrina L; Kishi, Yoshito et al. (2009) Heterogeneity in the stereochemistry of mycolactones isolated from M. marinum: toxins produced by fresh vs. saltwater fish pathogens. Chem Commun (Camb) :7402-4
Chen, Chi-Li; Namba, Kosuke; Kishi, Yoshito (2009) Attempts to improve the overall stereoselectivity of the Ireland-Claisen rearrangement. Org Lett 11:409-12
Liu, Songbai; Kim, Joseph T; Dong, Cheng-Guo et al. (2009) Catalytic enantioselective Cr-mediated propargylation: application to halichondrin synthesis. Org Lett 11:4520-3
Kim, Dae-Shik; Dong, Cheng-Guo; Kim, Joseph T et al. (2009) New syntheses of E7389 C14-C35 and halichondrin C14-C38 building blocks: double-inversion approach. J Am Chem Soc 131:15636-41
Guo, Haibing; Dong, Cheng-Guo; Kim, Dae-Shik et al. (2009) Toolbox approach to the search for effective ligands for catalytic asymmetric Cr-mediated coupling reactions. J Am Chem Soc 131:15387-93

Showing the most recent 10 out of 33 publications