This proposal describes a research program directed towards resolving a stereochemical controversy over the structure of the marine neurotoxin maitotoxin through chemical synthesis, the total synthesis of a truncated version of maitotoxin lacking the side chains, the total synthesis of maitotoxin, and the development of antibodies of suitable maitotoxin-like structures for analytical and biological studies. The escalating challenges of this chemical synthesis program will be met by a convergent strategy involving methods developed in this and other laboratories. Featured in the synthetic plans are olefin metathesis- based carbon-carbon bond forming reactions, novel asymmetric processes and ring closures. Synthetic truncated maitotoxin-like molecules will be tested for biological activity and developed antibodies will become available for the detection and measurement of maitotoxin and further biological studies. The proposed program is also expected to yield significant new synthetic strategies and technologies for broader applications in the drug discovery and development process, particularly for the synthesis of small enantiomerically pure building blocks suitable for pharmaceutical research. Overall the significance of the proposed work lies in improving and assuring environmental health, detecting and measuring marine neurotoxins and cleaning the oceans, as well as to prevent human poisoning through seafood consumption. The project is also expected to significantly advance our knowledge in chemical synthesis, chemical biology, and medicine

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES013314-07
Application #
8067814
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Tyson, Frederick L
Project Start
2005-07-01
Project End
2012-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
7
Fiscal Year
2011
Total Cost
$442,279
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Ferreiro, Sara F; Vilariño, Natalia; Carrera, Cristina et al. (2014) In vivo arrhythmogenicity of the marine biotoxin azaspiracid-2 in rats. Arch Toxicol 88:425-34
Ferreiro, Sara F; Vilariño, Natalia; Louzao, M Carmen et al. (2014) In vitro chronic effects on hERG channel caused by the marine biotoxin azaspiracid-2. Toxicon 91:69-75
Rodríguez, Laura P; Vilariño, Natalia; Louzao, M Carmen et al. (2014) Microsphere-based immunoassay for the detection of azaspiracids. Anal Biochem 447:58-63
Nicolaou, K C; Baker, Thomas M; Nakamura, Tsuyoshi (2011) Synthesis of the WXYZA' domain of maitotoxin. J Am Chem Soc 133:220-6
Nicolaou, K C; Simmons, Nicholas L; Ying, Yongcheng et al. (2011) Enantioselective dichlorination of allylic alcohols. J Am Chem Soc 133:8134-7
Nicolaou, K C; Seo, Jae Hong; Nakamura, Tsuyoshi et al. (2011) Synthesis of the C'D'E'F' domain of maitotoxin. J Am Chem Soc 133:214-9
Nicolaou, K C; Aversa, Robert J (2011) Maitotoxin: An Inspiration for Synthesis. Isr J Chem 51:359-377
Vale, Carmen; Nicolaou, Kyriacos C; Frederick, Michael O et al. (2010) Cell volume decrease as a link between azaspiracid-induced cytotoxicity and c-Jun-N-terminal kinase activation in cultured neurons. Toxicol Sci 113:158-68
Nicolaou, K C; Gelin, Christine F; Seo, Jae Hong et al. (2010) Synthesis of the QRSTU domain of maitotoxin and its 85-epi- and 86-epi-diastereoisomers. J Am Chem Soc 132:9900-7
Nicolaou, K C; Aversa, Robert J; Jin, Jian et al. (2010) Synthesis of the ABCDEFG ring system of maitotoxin. J Am Chem Soc 132:6855-61

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