Neurotrophic factors and the treatment of neurodegenerative diseases: Studies on the total synthesis of kirkinine, a uniquely potent neurotrophic agent

ORGN 712

Paul A. Wender, wenderp@stanford.edu1, F. Christopher Bi2, Nicole Buschmann2, Francis Gosselin2, Cindy Kan2, Jung-Min Kee2, and Hirofumi Ohmura2. (1) Department of Chemistry, Department of Molecular Pharmacology, Stanford University, Stanford, CA 94305, (2) Department of Chemistry, Stanford University, Stanford, CA 94305
Kirkinine is an impressively complex daphnane diterpene isolated from the roots of the tropical plant Synaptolepis kirkii on the basis of its exceptionally potent neurotrophic activity. It exhibits activity comparable to NGF, the endogenous nerve growth factor, a protein essential for the development and maintenance of neuronal cells and an agent of possible use in the treatment of neurodegenerative diseases. Unfortunately, NGF does not penetrate the blood-brain barrier and can only be used through invasive surgery. In contrast, small-molecule neurotrophic agents, of which kirkinine is currently the most potent, can pass through the blood-brain barrier and induce NGF-like activity, offering a potential treatment for currently untreatable diseases like Alzheimer's, ALS and other neurodegenerative diseases. Providing a starting point for the investigation of this exciting lead, we have now successfully achieved the synthesis of the complete tricyclic core of kirkinine, based on an oxidopyrylium [5+2] cycloaddition and a palladium-mediated cyclization.

 

Total Synthesis, Materials, Molecular Recognition, Process R&D, and Physical Organic Chemistry
8:00 PM-10:00 PM, Wednesday, 13 September 2006 Moscone Center -- Hall D, Poster

Sci-Mix
8:00 PM-10:00 PM, Monday, 11 September 2006 Moscone Center -- Hall D, Sci-Mix

Division of Organic Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006