(Principal Investigator's) Synthetic approaches to representative Annonaceous acetogenins will be developed. These plant-derived materials exhibit a wide range of biological activities. Of special interest is their remarkably high ED50's against solid human tumor cell lines and their selective toxicity to tumor over normal cells. The active compounds inhibit mammalian NADH:ubiquinone reductase at Complex I in the mitochondria thereby causing shutdown of oxidative phosphorylation. Interestingly, they specifically inhibit the ubiquinone:NADH oxidase system in the plasma membranes of cancerous cells. They have also been found to exhibit immunosuppressant activity and to stimulate transport of potassium ions from lymphocytes by a mechanism similar to ionophore antibiotics. The use of the Annonaceous plants and their edible fruits in folk medicine suggest that the acetogenins therein are not highly toxic to humans. The synthetic approach will employ chiral allylic and allenic organometal reagents to introduce stereogenic centers with concurrent formation of carbon-carbon bonds.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM056769-03
Application #
6151191
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
1998-02-01
Project End
2002-01-31
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
3
Fiscal Year
2000
Total Cost
$204,322
Indirect Cost
Name
University of Virginia
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904