This application is in response to NIH Notice Number NOT-OD-09-058: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. This research program focuses on the development of new synthetic strategies for the total synthesis of biologically active complex alkaloid natural products. Within each total synthesis goal lies the implicit aim of discovering and exploiting new reactions that push the boundaries of chemical synthesis innovation. In this context, new strategies for the total synthesis of several guanidine-containing complex alkaloids will be explored. These classes of targets include the family of anti-HIV/immunomodulating batzelladine alkaloids, the family of anticancer and ion-channel disrupting crambescidin alkaloids, the potent cytotoxin cylindrospermopsin, and the powerful immunosuppressant palau'amine. All of these natural products exhibit significant yet distinct biological responses, yet they are all structurally characterized by at least one guanidine moiety embedded within a complex polycyclic architecture, a synthetic challenge that will be addressed by investigating novel annulation strategies and reactions for nitrogen-heterocycle synthesis. The added aim that constitutes the expansion of research objectives is the development of complementary strategies for the total synthesis of the C19-diterpenoid alkaloids. The C19 family of diterpene alkaloids comprises an expansive number of alkaloids, several members of which have demonstrated potent and selective activity as modulators of ion channel function. As such, these natural products have proven to be extremely useful molecular probes to dissect ion channel biology. Successful synthesis of these target molecules will not only lay the foundation of efficient and practical strategies for complex alkaloid synthesis, but also provide access to complex natural products of biological interest and therapeutic potential in a variety of health areas, including small molecule cytotoxic/anticancer, antiviral, and immunomodulating agents, as well as unique heterocyclic constructs that specifically disrupt ion channel function.

Public Health Relevance

This research program focuses on the development of new synthetic strategies for the total synthesis of biologically active complex guanidine alkaloid natural products. Successful synthesis of these target molecules will not only lay the foundation of efficient and practical strategies for complex molecule synthesis, but also provide access to natural products of biological interest and therapeutic potential in a variety of health areas, including small molecule cytotoxic/anticancer, antiviral, and immunomodulating agents, as well as unique heterocyclic constructs that specifically disrupt ion channel function.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM067659-08S1
Application #
7846631
Study Section
Special Emphasis Panel (ZRG1-BCMB-A (96))
Program Officer
Schwab, John M
Project Start
2009-09-30
Project End
2011-08-31
Budget Start
2009-09-30
Budget End
2011-08-31
Support Year
8
Fiscal Year
2009
Total Cost
$572,363
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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Carra, Ryan J; Epperson, Matthew T; Gin, David Y (2008) Application of an intramolecular dipolar cycloaddition to an asymmetric synthesis of the fully oxygenated tricyclic core of the stemofoline alkaloids. Tetrahedron 64:3629-3641
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