A general synthetic strategy is presented for the synthesis of several anthracyclinones based on the reactions of chromium carbene complexes with acetylenes. The synthetic targets include the aglycones of daunorubicin and adriamycin which are important chemotherapeutic agents for the treatment of a broad range of human cancers. The strategy is flexible to allow for the synthesis of both the 11-oxy and the 11-deoxy anthracyclinones and we propose to develop from it the first convergent synthesis for these two major classes of anthracyclinones. The 11-deoxy anthracyclinones have been of more recent interest due to the finding that some memberrs of this class have comparable activity to that of adriamycin but with a reduced level of cardiotoxicity. It is proposed to synthesize the aglycones of six members of this class which include aklavinone (the aglycone of aclacinomycin) and 7-con-o-methylnogarol, a semi-synthetic derivative of nogalamycin, which will shortly go into human clinical trials. Preliminary results indicate that this strategy is flexible enough to provide for the regioselective synthesis of several unnatural mono fluoro derivatives of aklavinone.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA032974-03
Application #
3170863
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1983-05-01
Project End
1986-04-30
Budget Start
1985-05-01
Budget End
1986-04-30
Support Year
3
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Chicago
Department
Type
Schools of Arts and Sciences
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637