(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.
| Marshall, James A; Piettre, Arnaud; Paige, Mikell A et al. (2003) Total synthesis and structure confirmation of the annonaceous acetogenins 30(S)-hydroxybullatacin, uvarigrandin a, and 5(R)-uvarigrandin a (narumicin I?). J Org Chem 68:1780-5 |
| Marshall, James A; Piettre, Arnaud; Paige, Mikell A et al. (2003) A modular synthesis of annonaceous acetogenins. J Org Chem 68:1771-9 |
| Marshall, J A; Jiang, H (1999) Total synthesis of the cytotoxic threo, trans, threo, trans, threo annonaceous acetogenin asimin and its C-10 epimer: unambiguous confirmation of absolute stereochemistry. J Nat Prod 62:1123-7 |
