Okadaic acid isolation

Norte, M., Padilla, A., Fernandez, XX, and Souto, M.L. 1994. Structural determination and biosynthetic origin of two ester derivatives of okadaic acid isolated from Prorocentrum lima. Tetrahedron 50(30), 9175-9180. 

Hu, T. et al.. New diol ester (of okadaic acid) isolated from cultures of Prorocentrum lima and Prorocentrum concavum, J. Nat. Prod., 55,1631, 1992. 

Acanthifolidn is the episulfide in 9-10 of okadaic acid. Isolated from the sponge Pandaros acanthifolium, it is not yet known whether this compormd results from a modification of okadaic acid by the sponge, or whether it is a new derivative of an epiphyte or symbiotic dinoflagellate. Its toxidty and biological properties are similar to those of okadaic acid and dinophysistoxins (Schmitz et al, 1981). 

Three classes of polyethers, okadaic acid derivatives, pectenotoxins, and yessotoxin were isolated from bivalves in connection with diarrhetic shellfish poisoning. The etiology of the toxins, toxicological properties, and determination methods are described. 

During the protein isolation step, the presence of protease inhibitors is crucial to preserve the integrity of the antigen under study. Some protease inhibitors, such as phenybnethylsulfonylfluoride (PMSF), have a wide spectrum of activity and are therefore commonly used, whereas other inhibitors, such as okadaic acid are used primarily when the phosphorylated form of protein is of interest. O Table 8-3 contains a list of some commonly used protease inhibitors and their activity spectra. 

Properties of toxins. Dinophysistoxin-1 was isolated as a white amorphous solid m.p. 134 C ] +28 (c 0.046, chloroform) Rf in TLC 0.42 minimum lethal dose to mouse 160 ig/kg (i.p.). El mass spectrum gave a dehydrated ion peak at m/z 800, pointing to a composition C45H5gOi2 Overall features of both PMR and CMR spectra of dinophys is toxin-1 closely resembled those of okadaic acid (I ) except the presence of an additional methyl in dinophysistoxin-1. Comparison of the spectra of okadaic acid and dinophysistoxin-1 and supplemental spin-spin decoupling measurements enabled us to assign dinophysistoxin-1 to 35(5)-methyl okadaic acid (II) (5). A component tentatively named dinophysistoxin-2 was slightly more polar than dinophysistoxin-1 but its characterization was unsuccessful due to the extreme smallness of the sample size. 

Ciguatoxin (CTX) is the major chemical entity associated with ciguatera fish poisoning. CTX, a term given to the low dalton lipid by Scheuer et al. (JL) was isolated from livers of Gymnothorax obtained from an endemic area in the Pacific. A recent study by Tachibana ( 2) in Scheuer s laboratory suggests that CTX consists of numerous cyclic polyether residues similar to okadaic acid (3-5) and monensin ( ). ... 

Additionally, a number of marine toxins with medical and toxicological importance have been isolated from marine flora and fauna. Okadaic acid, Fig. (62) is the main toxin produced by dinoflagellates, which can accumulate in the hepatopancreas of mussels and caused diarrhetic shellfish poisoning in consumers [505,506], However, this toxin is also a tumor promoter and a specific potent inhibitor of protein phosphatases which may provokes mitotic arrest and apoptosis of leukemia cells [507-509], These types of compounds have been reported in shellfish and phytoplankton, and more recently, in Spanish mussels [510], Portuguese bivalves [511], and the diatom Thalassiosira weissflogii [512],... 

Tautomycin. a secondary metabolite from Streptontyces spiroi erti-citlatiis was first isolated by l.sono, who also established its structure.1 The unusual structural feature of this compound is an unsaturated anhydride group, which in aqueous medium is in equilibrium with the free acid. This probably is essential to the compound s biological activity, as is suggested by its structural relationship to such substances as the calyculins or okadaic acid.1... 

Draisci, R., Giannetti, L., Lucentini, L., Marchiafava, C., James, K.J., Bishop, A.G., Healy, B.M., and Kelly, S.S. 1998. Isolation of a new okadaic acid analogue from phytoplankton implicated in diarrhetic shellfish poisoning. J. Chromatogr. A, 798, 137-145. 

The sponge Halichondria okadai contains a polyether metabohte named okadaic acid (16) that was also isolated as a causative agent of diarrhetic shellfish poisoning (DSP) from mussels and other bivalves (14). However, the real producers are dinoflagellates of the genus Dinophysis. It is a potent cancer promoter that was found to be caused by inhibition of protein phosphatases 1 and 2A at nanomolar levels. Pectenotoxins are also involved in DSP and are produced by Dinophysis spp. pectenotoxin 2 (17) inhibits actin polymerization (14). 

Isolation of marine polyethers (Fig. lb) is more recent than from terrestrial sources with structures for okadaic acid 11 and brevetoxin B 12 reported in 1981. Since that time, numerous polyether structures have been isolated from marine sources and several have had their biosynthetic pathways investigated through classical feeding experiments [e.g., okadaic acid (10)]. 

Okadaic acid 11 is a potent and specific inhibitor of protein phosphatases produced by the dinoflagellates Prorocentrum lima, Dinophysisfortii, and Dirwphysis accuminata. It accumulates in bivalves and is one of the main toxins responsible for diarrhetic shellfish poisoning (DSP) (11). It has a highly unusual biosynthesis that has generated a lot of speculation because of the presence of isolated acetate chain methyl carbon atoms (10). Okadaic acid is a potent inhibitor of protein phosphatase A (11). 

Okadaic acid was first isolated Irom the sponges Halichondria okadai and Halichondria melanodocia and was shown to be ultimately produced by dinoflagellates such as Prow-centrum lima. Okadaic acid contributes substantially to the analysis of phosphorylation and... 

An abbreviated synthesis of a substituted 1,7-dioxaspiro[5.5]undec-3-ene system constituting the C3-C14 portion of okadaic acid was developed in the laboratory of C.J. Forsyth. The C3-C8 fragment, a substituted valerolactone, was prepared in three steps. The diastereoselective a-hydroxylation of this lactone was accomplished by using Davis chirai camphorsuiphonyi oxaziridine on the corresponding lithium enolate at -78 °C. The isolated yield was 61% and the ratio of diastereomers was 10 1. 

Diarrheic shellfish poisoning caused by okadaic acid is a gastrointestinal illness without chronic se-quellae. There is no evidence of neurotoxicity and no fatal cases have ever been reported. Diarrhea is the most commonly reported symptom, closely followed by nausea and vomiting with onset 30 min to 12 h from ingestion of contaminated shellfish. Complete clinical recovery is seen even in severe cases within 3 days. DSP has been reported predominantly in Japan and Europe. The toxin has also been isolated from P. lima cultures from the Gulf of California, Mexico. The incidence of DSP in this location as a result of this is unknown. 

Ginsenoside Rgl, one of the major active ingredients isolated from Panax Ginseng, has neuroprotective effects in animal models with memory impairment. Intracerebroventricular (i.c.v.) okadaic acid (OKA), a potent phosphatase inhibitor, induced memory impairment, decrease of phospho-tau and phospho-GSK3p, and formation of p-amyloid deposits in the brain of treated rats. All these changes were reversed by Rgl [272],... 

Prorocentin (197), a C35 polyketide with four pendant methyl groups, possessing an all-trtfwrtriene moiety, an epoxide, a fnran ring, and the 6/6/6-trans-fused/spiro-linked tricyclic ether rings, was isolated from an okadaic acid-producing strain of P. The relative stereostructure was elucidated on the basis of spectral data. 

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