The research program outlined in this proposal embodies our commitment to the synthesis of architecturally challenging, pharmacologically significant natural and non-natural products. Our entry into this arena comes not only from a desire to synthesize bioactive agents but also from a fascination with the development of concise organic synthesis strategies and efficient synthetic methodology. These areas of study will not only impact organic chemistry but also the development of new medicines and the understanding of biological processes. Specific to this program are strategies to medicinally interesting polycyclic ether natural andnon- natural products that involve C-glycoside/ketoside synthesis and enol ether-olefin ring-closing metathesis. The first part of this proposal outlines our synthesis of members of the marine ladder toxin family, specifically, gambieric acid and brevenal. These agents are non-toxic polycyclic ethers isolated from dinoflagellates that, in preliminary studies, have demonstrated the somewhat puzzling ability to displace one of the brevetoxins from its target (voltage gated sodium channels) in the absence of neurotoxicity. Interestingly, both of these agents have demonstrated other biological activity that could prove to be important to human health (anti-fungal activity for gambieric acid and the ability to clear mucous from sheep lungs as a model for cystic fibrosis for brevenal). Also outlined is a program targeting the generation of polycyclic ether libraries in an effort to gain a better understanding of their unique biology. This application also contains our proposal to expand the C-glycoside, metathesis chemistry to medicinally relevant non-ladder toxin natural products. Specifically, we are interested in the actin binding pectenotoxin family. That actin binders have been shown to target cells lacking the p53 protein makes the pectenotoxins excellent anticancer leads and our efforts in this area potentially important.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Hagan, Ann A
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University of Utah
Schools of Arts and Sciences
Salt Lake City
United States
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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

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