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
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| 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 |
| 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 |
| 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 |
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