The work in this proposal involves the development of new furan and pyrrole-based cycloaddition reactions that result in the formation of complex ring systems from simple and readily available components. The cycloaddition mode depends upon the synthetic route and the substitution pattern for the furan/pyrrole core. The [8+2]-cycloaddition mode occurs when alkynes couple with dienylfurans. This reaction assembles the core ring system (furan-bridged ten-membered ring) of the marine-derived experimental anti-cancer agent eleutherobin. The full synthetic potential of this reaction will be developed, including delineation of the scope, limit, and stereochemistry of the [8+2]-cycloaddition followed by a study of the reactivity profile for densely functionalized [8+2]-cycloadducts. These chemical processes will be employed in the design of new anti-cancer agents that structurally resemble eleutherobin. The ability of these compounds to promote microtubule polymerization will be tested, and active candidates will be further tested as anti-cancer agents. The coupling of chromium carbene complexes with ortho-alkynylbenzoyl derivatives leads to activated furan/pyrrole rings, which undergo efficient cycloaddition with a variety of alkenes and alkynes. A variant of this process will be developed where highly unsaturated chromium carbene complexes afford phenanthroid ring systems in a formal [5+5]-cycloaddition reaction. These reactions are the cornerstone for versatile and efficient synthetic approaches to tanshinones, useful for the treatment of hypertension, and to apomorphine, a dopamine receptor useful for the treatment of Parkinson's disease. Work in this proposal provides structurally complex and medicinally important compounds from simple and readily available components. The reaction process can conveniently provide compounds (or more importantly structural analogs) that have shown potent anti-cancer activity, anti-hypertension activity, and activity against neurologic disorders such as Parkinson's disease. These are all very common ailments that negatively impact the quality of life a large portion of the U.S. population.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Enhancement Award (SC1)
Project #
5SC1GM083693-04
Application #
8102728
Study Section
Special Emphasis Panel (ZGM1-MBRS-X (CH))
Program Officer
Lees, Robert G
Project Start
2008-07-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2011
Total Cost
$209,979
Indirect Cost
Name
New Mexico State University Las Cruces
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
173851965
City
Las Cruces
State
NM
Country
United States
Zip Code
88003
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