This proposal describes a research program directed towards the total synthesis of azaspiracids-l, -2, -3, and -6, and fragments thereof, for biological and analytical purposes. Isolated from the mussel Mytilus edulis, these marine neurotoxins are the causative agents of seafood poisoning in humans and tumorogenesis in rats. These extremely scarce biotoxins have been isolated only in minute quantities and it remains for chemical synthesis to render them available for the acutely needed analytical work to detect and quantify them in seafood before releasing it for human consumption. Considerable progress has been made already by this group, uniquely positioning us to accomplish the efficient total synthesis of all four azaspiracids, develop antibodies against them, and investigate their mechanism of action and full spectrum of biological properties. The latter investigations will be carried out in collaboration with biology experts and are expected to result, in particular, in the development (through antibody production) of a bioassay for the determination of the toxins. The significance of the proposed work lies primarily in improving and assuring environmental health, detecting and measuring marine biotoxins, and cleaning the oceans, as well as to prevent seafood poisoning in humans that may include both short (e.g. nausea, vomiting, severe diarrhea and stomach cramps) and long term (e.g. lung, liver, spleen and lymphocyte damage as well as cancer) health hazards. The project is also expected to advance our knowledge in chemical synthesis and impact favorably the drug discovery and development process.
| 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; 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; 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 |
| 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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