Natural products that have been isolated from the marine environment show promise as pharmacological agents. However, because of the supply problems associated with their isolation, a thorough evaluation of their properties requires their chemical synthesis. This proposal describes the chemical synthesis of three biologically important marine natural products. The first of these is gambierol, a marine ladder toxin associated with ciguatera poisoning. The second is armatol A, a polycyclic ether that has demonstrated interesting cytotoxicity in preliminary testing. The third is halichondrin B, a potent anticancer agent that has been recommended for preclinical trials in spite of its short supply. Gambierol, armatol A, and halichondrin B have in common a fused polycyclic ether skeleton. This proposal outlines the chemical synthesis of these agents centered around carbon-glycosides. As carbon-glycosides have been demonstrated to be important, not only in synthetic chemistry, but also in medicinal chemistry, we believe that this strategy might have broad implications. In addition, by coupling our carbon-glycoside forming chemistry with efficient annulation protocols, we believe that we will be able to efficiently generate polycyclic ethers including the natural products listed above. Furthermore, these efforts will undoubtedly lead to the generation of a number of interesting and biologically important analogs whose properties will be evaluated.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM056677-07
Application #
6579719
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
1998-01-01
Project End
2006-12-31
Budget Start
2003-01-01
Budget End
2003-12-31
Support Year
7
Fiscal Year
2003
Total Cost
$224,625
Indirect Cost
Name
University of Utah
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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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