Azaspiracid substituent at C1 is relevant to in vitro toxicity.

Abstract

The azaspiracids are a group of marine toxins recently described that currently includes 20 analogues. Not much is known about their mechanism of action, although effects on some cellular functions have been found in vitro. We used the reported effects on cell viability, actin cytoskeleton, and caspase activation to study the structure-activity relationship of AZA-1 and AZA-2 and the role of the carboxylic acid moiety in toxicity. AZA-1, AZA-2, and the synthetic AZA-2-methyl ester (AZA-2-ME), where the C1 carboxylic acid moiety of AZA-2 was esterified to the corresponding methyl ester moiety, induced a reduction of cell viability in neuroblastoma and hepatocyte cell lines with similar potency and kinetics. Interestingly, the mast cell line HMC-1 was resistant to AZA-induced cytotoxicity. Actin cytoskeleton alterations and caspase activation appeared after treatment with AZA-1, AZA-2, AZA-2-ME, and biotin-AZA-2 (AZA-2 labeled with biotin at C1) in neuroblastoma cells with similar qualitative, quantitative, and kinetics characteristics. Irreversibility of AZA effects on the actin cytoskeleton and cell morphology after short incubations with the toxin were common to AZA-1, AZA-2, and AZA-2-ME; however, 10-fold higher concentrations of biotin-AZA-2 were needed for irreversible effects. AZA-2-ME was rapidly metabolized in the cell to AZA-2, while transformation of biotin-AZA-2 into AZA-2 was less efficient, which explains the different potency in short exposure times. The moiety present at C1 is related to AZA toxicity in vitro. However, the presence of a methyl moiety at C8 is irrelevant to AZA toxicity since AZA-1 and AZA-2 were equipotent regardless of the readout effect.

• Authors: Natalia Vilariño, K C Nicolaou, Michael O Frederick, Eva Cagide, Carmen Alfonso, Eva Alonso, Mercedes R Vieytes, Luis M Botana
• Journal: Chemical research in toxicology (Chem Res Toxicol) Vol. 21 Issue 9 Pg. 1823-31 (Sep 2008) ISSN: 1520-5010 [Electronic] United States
• PMID: 18707138 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Caspase Inhibitors
• Furans
• Marine Toxins
• Pyrans
• Spiro Compounds
• azaspiracid
• azaspiracid-2
• Caspases

Topics

• Animals
• Caspase Inhibitors
• Caspases (metabolism)
• Cell Survival (drug effects)
• Cells, Cultured
• Cytoskeleton (chemistry, drug effects)
• Dose-Response Relationship, Drug
• Enzyme Activation (drug effects)
• Furans (chemical synthesis, chemistry, toxicity)
• Humans
• Kinetics
• Marine Toxins (chemical synthesis, chemistry, toxicity)
• Molecular Conformation
• Pyrans (chemical synthesis, chemistry, toxicity)
• Rats
• Spiro Compounds (chemical synthesis, chemistry, toxicity)
• Stereoisomerism
• Structure-Activity Relationship