Cylindrospermopsin is a potent hepatotoxin produced by freshwater cyanobacteria. Blooms of cyanobacteria have recently increased dramatically, likely due to the rise in global temperatures and eutrophication. Release of the toxin into water that is subsequently ingested can lead to liver damage, potentially fatal. Monitoring the levels of cylindrospermopsin (CYN) in freshwater has become a human health issue, and is a subject of recent reports by the US Environmental Protection Agency and USDA. The problem is that accurate quantitative measurements of CYN concentration requires pure, isotopically labeled analytical standards, which can be used in isotope dilution mass-spectrometric assays. Producing this standard from cultures of cyanobacteria using feeding with labeled additives proved to be tedious, unreliable, and lengthy (over 2 years before results are known) process. This project proposes to access the analytical standard by total chemical synthesis, which holds a promise as a reliable source of the much-needed material. Our lab has a strong expertise in producing isotopically labeled complex molecules, including natural products, by total synthesis.

Public Health Relevance

Total synthesis of natural products is a powerful tool for the preparation of valuable complex organic molecules used in many fields of science and industry, and especially in pharmaceuticals development, materials science, and agriculture. In this proposal, our goal is to develop a synthetic route to an important analytical standard, isotopicall labeled freshwater toxin cylindrospermopsin (CYN). CYN has been identified as a particularly dangerous toxin produced by freshwater cyanobacteria exposure to which can lead to serious liver damage. Increased occurrence of CYN in fresh water has been associated with widespread blooms of cyanobacteria in many freshwater environments, perhaps linked to higher global temperatures or other factors. Reliable detection of CYN is increasingly important to maintain fresh water and seafood safety. The proposed synthesis of CYN will pave the way for the production of an analytical standard for accurate, quantitative detection using isotope-dilution mass-spectrometric assays.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Small Research Grants (R03)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Tyson, Frederick L
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University of California Santa Barbara
Schools of Arts and Sciences
Santa Barbara
United States
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Reid, Bradley T; Mailyan, Artur K; Zakarian, Armen (2018) Total Synthesis of (+)-Guadinomic Acid via Hydroxyl-Directed Guanidylation. J Org Chem 83:9492-9496
Mailyan, Artur K; Chen, Joanna L; Li, Weiwei et al. (2018) Short Total Synthesis of [15N5]-Cylindrospermopsins from 15NH4Cl Enables Precise Quantification of Freshwater Cyanobacterial Contamination. J Am Chem Soc 140:6027-6032
Mailyan, Artur K; Young, Kyle; Chen, Joanna L et al. (2016) Stereoselective Synthesis of Cyclic Guanidines by Directed Diamination of Unactivated Alkenes. Org Lett 18:5532-5535
Mailyan, Artur K; Eickhoff, John A; Minakova, Anastasiia S et al. (2016) Cutting-Edge and Time-Honored Strategies for Stereoselective Construction of C-N Bonds in Total Synthesis. Chem Rev 116:4441-557