The marine environment continues to provide us with a wide variety of biologically and architecturally interesting natural products. Unfortunately, we are unable to isolate sufficient quantities of many of these bioactive compounds for their full evaluation. Outlined herein are our plans to improve the status quo through the synthesis of bioactive marine toxins and the development of new and improve (more efficient synthetic techniques. The synthesis of the bioactive marine natural products that are described in this proposal will not only provide quantities of materials that are not currently available but it is only through these efforts that a true understanding of the properties of these molecules will become available. We are drawn to two targets. One of these, pinnatoxin A, is a potent neurotoxin though to be responsible for seasonal outbreaks of food poisoning from the ingestion of shellfish throughout Asia. The other, gambieric acid A, is among the most potent antimicrobial agents known to man. Both of these, as well as other similar species, are believed to come from dinoflagellates are probably at least partially responsible for red tide catastrophes. Our synthesis of pinnatoxin A will include many novel transformations including free-radical approaches to spiro-fused rings, macrocylic rings and bis-ketal rings as well as free-radical coupling reactions which utilize silicon as a stereo-and regio-controlling feature. We anticipate that these studies will have implications far beyond the synthesis of pinnatoxin A. We intend to answer several important questions during the synthesis of gambieric acid A. First, can an iterative strategy employing enol ether epoxidation and ring closing metathesis be used to generated fused ethers of various ring sizes as are present in the marine """"""""ladder toxins""""""""? Also, is this strategy amenable to its use on a solid support? Once this last goal has been achieved, it is conceivable that libraries of pharmacologically relevant fused cyclic ethers could become available. In addition to their synthesis through our iterative strategy, we are also interested in the biosynthesis of fused cyclic ethers and plan to explore polyepoxide cyclizations towards their synthesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM056677-04
Application #
6342954
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
1998-01-01
Project End
2002-12-31
Budget Start
2001-01-01
Budget End
2001-12-31
Support Year
4
Fiscal Year
2001
Total Cost
$181,800
Indirect Cost
Name
University of Arizona
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Zhang, Yuan; Rainier, Jon D (2016) Synthesis of the ABCDEF and FGHI ring system of yessotoxin and adriatoxin. J Antibiot (Tokyo) 69:259-72
Martínez-Morales, Evelyn; Kopljar, Ivan; Rainier, Jon D et al. (2016) Gambierol and n-alkanols inhibit Shaker Kv channel via distinct binding sites outside the K(+) pore. Toxicon 120:57-60
Kopljar, Ivan; Grottesi, Alessandro; de Block, Tessa et al. (2016) Voltage-sensor conformation shapes the intra-membrane drug binding site that determines gambierol affinity in Kv channels. Neuropharmacology 107:160-167
Kopljar, Ivan; Labro, Alain J; de Block, Tessa et al. (2013) The ladder-shaped polyether toxin gambierol anchors the gating machinery of Kv3.1 channels in the resting state. J Gen Physiol 141:359-69
VanderWaal, Kristyn E; Yamamoto, Ryosuke; Wakabayashi, Ken-ichi et al. (2011) bop5 Mutations reveal new roles for the IC138 phosphoprotein in the regulation of flagellar motility and asymmetric waveforms. Mol Biol Cell 22:2862-74
Zhang, Yuan; Rohanna, John; Zhou, Jie et al. (2011) Total synthesis of brevenal. J Am Chem Soc 133:3208-16
Zhou, Jie; Rainier, Jon D (2009) Olefinic-amide and olefinic-lactam cyclizations. Org Lett 11:3774-6
Rohanna, John C; Rainier, Jon D (2009) Olefinic-lactone cyclizations to macrocycles. Org Lett 11:493-5
Kopljar, Ivan; Labro, Alain J; Cuypers, Eva et al. (2009) A polyether biotoxin binding site on the lipid-exposed face of the pore domain of Kv channels revealed by the marine toxin gambierol. Proc Natl Acad Sci U S A 106:9896-901
Zhang, Yuan; Rainier, Jon D (2009) Two-directional olefinic-ester ring-closing metathesis using reduced Ti alkylidenes. A rapid entry into polycyclic ether skeletons. Org Lett 11:237-9

Showing the most recent 10 out of 17 publications