If scientists are to successfully address the largest biomedical challenges facing society, our ability to both identify and create functional small molecules with unique properties must improve dramatically. Natural products have long provided great starting points for such investigations given that their structures have evolved over millennia to achieve specific biochemical functions and their synthesis improves our skills. Yet, numerous classes of such structures remain untapped. The most significant of these are oligomeric natural products, compound families created in Nature from a simple building block through deliberately uncontrolled reaction pathways that chemists have never been able to temper in the laboratory. This proposal seeks to provide the innovative synthetic solutions needed to alter this paradigm and finally access these classes of molecules in a controlled manner, thus enabling exploration of their full biochemical potential. Our initial proving ground lies with the resveratrol family of natural products, an abundant class of compounds whose properties in initial screens appear perfect for a rich discovery program given their structural uniqueness and anti-tumor, anti-viral, anti-fungal, anti-oxidant, and anti-aging behavior (many by unknown or unique modes of action). Viewing these targets through the lens of a unique synthetic strategy, we show how the diverse carbogenic complexity of the entire class (along with several non-natural structures) can be assembled from a single, common building block well removed from Nature's starting material through a series of creative complexity-building sequences initiated by the simplest of reagents. These largely unexplored compounds will then be screened thoroughly and deeply in concert with collaborators to elucidate their roles in key biochemical events, especially as relates to human biology.

Public Health Relevance

The proposal seeks to determine whether phenols in red wine, such as resveratrol and molecules derived from resveratrol, are responsible for the French paradox. Synthesized compounds will be evaluated for anticancer, antiviral, antiaging, and neuroprotective properties.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM084994-05
Application #
8440354
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2009-04-01
Project End
2014-08-28
Budget Start
2013-03-01
Budget End
2014-08-28
Support Year
5
Fiscal Year
2013
Total Cost
$304,546
Indirect Cost
$115,387
Name
Columbia University (N.Y.)
Department
Chemistry
Type
Other Domestic Higher Education
DUNS #
049179401
City
New York
State
NY
Country
United States
Zip Code
10027
Wright, Nathan E; Snyder, Scott A (2014) 9-Membered carbocycle formation: development of distinct Friedel-Crafts cyclizations and application to a scalable total synthesis of (±)-caraphenol A. Angew Chem Int Ed Engl 53:3409-13
Jepsen, Tue H; Thomas, Stephen B; Lin, Yunqing et al. (2014) Harnessing quinone methides: total synthesis of (±)-vaticanol?A. Angew Chem Int Ed Engl 53:6747-51
Wright, Nathan E; ElSohly, Adel M; Snyder, Scott A (2014) Syntheses of cyclotriveratrylene analogues and their long elusive triketone congeners. Org Lett 16:3644-7
Snyder, Scott A; ElSohly, Adel M; Kontes, Ferenc (2011) Synthetic approaches to oligomeric natural products. Nat Prod Rep 28:897-924
Snyder, Scott A; Wright, Nathan E; Pflueger, Jason J et al. (2011) Total syntheses of heimiol A, hopeahainol D, and constrained analogues. Angew Chem Int Ed Engl 50:8629-33
Snyder, Scott A; Gollner, Andreas; Chiriac, Maria I (2011) Regioselective reactions for programmable resveratrol oligomer synthesis. Nature 474:461-6
Snyder, Scott A; Brill, Zachary G (2011) Structural revision and total synthesis of caraphenol B and C. Org Lett 13:5524-7
Welsch, Matthew E; Snyder, Scott A; Stockwell, Brent R (2010) Privileged scaffolds for library design and drug discovery. Curr Opin Chem Biol 14:347-61
Snyder, Scott A; Sherwood, Trevor C; Ross, Audrey G (2010) Total syntheses of dalesconol A and B. Angew Chem Int Ed Engl 49:5146-50