Azaspiracid Substituent at C1 Is Relevant to in Vitro Toxicity

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ID: 271544
2008
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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.
Reference Key
botana2008chemicalazaspiracid Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Natalia Vilariño,K. C. Nicolaou,Michael O. Frederick,Eva Cagide,Carmen Alfonso,Eva Alonso,Mercedes Rodriguez Vieytes,Luis M. Botana;Natalia Vilariño;K. C. Nicolaou;Michael O. Frederick;Eva Cagide;Carmen Alfonso;Eva Alonso;Mercedes Rodriguez Vieytes;Luis M. Botana;
Journal Chemical research in toxicology
Year 2008
DOI
10.1021/tx800165c
URL
https://sciprofiles.com/publication/view/a0b17d9a0d7d8e8a3fe682f971c8e53f
Keywords
Cytotoxicity structure-activity relationship cytoskeleton caspase azaspiracid National Center for Biotechnology Information NCBI NLM MEDLINE animals humans pubmed abstract nih national institutes of health national library of medicine research support non-u.s. gov't u.s. gov't non-p.h.s. N.I.H. Extramural Cells Cultured Rats dose-response relationship drug kinetics enzyme activation / drug effects cell survival / drug effects molecular conformation structure-activity relationship stereoisomerism pmid:18707138 pmc2559976 doi:10.1021/tx800165c natalia vilariño k c nicolaou luis m botana caspase inhibitors caspases / metabolism cytoskeleton / chemistry cytoskeleton / drug effects furans / chemical synthesis furans / chemistry* furans / toxicity marine toxins / chemical synthesis marine toxins / chemistry* marine toxins / toxicity* pyrans / chemical synthesis pyrans / chemistry* pyrans / toxicity spiro compounds / chemical synthesis spiro compounds / chemistry* spiro compounds / toxicity*

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