The plan of this investigation is twofold in nature. The overall objective is to develop concise and efficient syntheses of synthetically and technically challenging 2-aminoimidazole based sponge alkaloids known as the oroidin alkaloids. In particular, we plan to synthesize sceptrin (4), dibromoagelaspongin (6), ageliferin (7), palau'amine (9), agelastatin D (12), and axinellamine (14). Collectively, these and other structurally related metabolites possess a myriad of potent biological effects. An important goal within this research endeavor is the development and validation of a unifying chemical approach to this structurally novel class of natural products. The proposed methods and routes are essentially devoid of protecting groups and are guided by biogenetic considerations. The synthetic plan calls for methods development for transforming 2- aminoimidazoles into key intermediates for the synthesis of the naturally occurring compounds. The preparation of these intermediates and the facility of the ensuing molecular rearrangements would tend to support or disclaim the biogenetic hypothesis. Versatile and efficient syntheses of these metabolites would provide access to structurally modified or specifically labeled substrates for biomedical research. In addition, the methods developed in this area will be applied to synthesis of the red-tide toxins, saxitoxin, gonyautoxin I and gonyautoxin IV. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM071985-05
Application #
7253344
Study Section
Special Emphasis Panel (ZRG1-BPC-B (02))
Program Officer
Schwab, John M
Project Start
2004-07-15
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2009-06-30
Support Year
5
Fiscal Year
2007
Total Cost
$280,426
Indirect Cost
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
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Maekawa, Naoya; Abe, Jun-ichi; Shishido, Tetsuro et al. (2006) Inhibiting p90 ribosomal S6 kinase prevents (Na+)-H+ exchanger-mediated cardiac ischemia-reperfusion injury. Circulation 113:2516-23
Ding, Bo; Abe, Jun-Ichi; Wei, Heng et al. (2005) A positive feedback loop of phosphodiesterase 3 (PDE3) and inducible cAMP early repressor (ICER) leads to cardiomyocyte apoptosis. Proc Natl Acad Sci U S A 102:14771-6
Miyake, Fumiko Y; Yakushijin, Kenichi; Horne, David A (2005) Biomimetic synthesis of grossularines-1. Angew Chem Int Ed Engl 44:3280-2