Methyl okadaate

Diarrheic shellfish 0.2 ppm okadaic acid plus 35-methyl okadaic acid... 

In addition to the proven production of 35S-methyl okadaic acid (Dinophysistoxin -1) by D. fortii (52), with resulting diarrhetic shellfish poisoning (DSP) in Japan, there is strong circumstantial evidence that D. acuminata and possibly other Dinophysis species have produced DSP in Dutch and Spanish waters (53) These species are very widespread and comnK)n in both tropical and temperate waters, but they are not often abundant. They are very difficult to culture and so it is difficult to determine if populations in other areas are toxigenic. 

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. 

The selective oxidation of cellulose to dialdehyde by sodium periodate is well known. It has been postulated by Criegee (74) and by Waters (73) that this reaction proceeds by a free radical mechanism. Toda (76) and Morimoto, Okada, Okada, and Nakagawa (77) have concluded that sodium periodate oxidation should initiate graft polymerization. They succeeded in grafting methyl methacrylate and acrylonitrile onto cellulose substrates, such as rayon and paper. A similar procedure is recommended in a patent of Chemische Werke Huels (78) to graft vinyl monomers onto cotton, polyethylene oxide, copolymers of vinyl chloride-vinyl acetate, and others. 

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). 

Okada, Y. et al. hDOTlL links histone methylation to leukemo-genesis. Cell 2005 121 167-178. 

Okada. Y. Minami. T., Yamamoto, T., and Ichikawa, J., A novel type of chiral diphosphine ligand, rra 75-2.3-/ zT(diphenylphosphino)-l-methyl-l-cyclopropanecai boxylic acid and asymmetric allylic alkylation by the use of its palladium complex, Chem. Lett., 547, 1992. 

Okada, K., Samizo, F., Oda, M., Photochemical Reactions of (9 Anthryl)methyl Methyl Fumarate and Maleate Application to Asymmetric [4 + 2] Photocycloaddition Reaction,... 

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. 

H. Okada, V. Stella, J. Haslam, mid N. Yata, Photolytic degradation of a-[(dibutylamino)methyl]-6,8-di-chloro-2-(30, 4 -dichlorophenyl)-4-quinoline methanol An experimental antimalarial, J. Pharm. Sci. 64, 1665-1667 (1975). 

Okada calculated the approximate AH,C values for various methyl-substituted 1,3-dioxolanes, taking 1,3-dioxolane (AH C = —17.6 kJ mol-1) as the parent monomer 49). The calculated values are given in Table 2.8. Only in one case Okada could compare these values with the experimentally determined ones (indicated below in brackets) ... 

Okada et al.43) have claimed the successful synthesis of random THF-DXL copolymers using methyl fluorosulfonate initiator. With this type of initiator the ionic growth mechanism is accompanied by a covalent one, allowing the partial addition of one monomer to the growing species produced from the other. 

From stmcture-function studies it is also known that esterification of the a-carboxyl group of the D-wo-Glu residue generates nontoxic compounds (34,53), probably as a result of the lack of inhibition of the protein phosphatases. In this context it is interesting to note that the methyl ester of okadaic acid is inactive as well (86). 

From structure-function studies it is known that esterification of the a-carboxyl group of D-iJo-Glu of microcystin generates untoxic compounds, probably as a result of the lack of inhibition of the protein phosphatases (34,53) and that the methyl ester of okadaic acid is inactive as well (86). Correspondingly, this carboxylic function seems to play an essential role. In order to account for the almost identical potency of microcystins and okadaic acid, we have proposed a location of the carboxyl function of the two diverse compounds at the same position and a wrapping of the okadaic polyether chain around part of the microcystin ring and alignment of its hydrophobic tail with the Adda residue side-chain (108). 

Recent observations suggest that at least okadaic acid may have some unknown activities outside the inhibition of phosphatase. This is based on the observation that methyl okadate does show a similar toxic effect in cell cultures than okadaic acid, but methyl okadate is 500 times less potent than okadaic acid to inhibit phosphatases (unpublished results) (Figure 6.2). 

FIGURE 6.2 Inhibition of phosphatase caused by okadaic acid and methyl okadate. 

Numerous sources of okadaic acid exist and some companies offer OA methyl ester. DTX-1 is only available from Wako Chemicals (www.e-reagent.com). The only sonrce of certified reference material and certified calibration solutions is the National Research Conncil (Canada) Certified Reference Materials Programme (CRMP). More information is available online at http //www.imb. nrc.ca/crmp/natural/index e.php. Or email crm.imb nrc-cnrc.gc.ca. 

The crystal structure of OA is characterized by a circular conformation that allows the interaction between its carboxylic group and the hydroxyl at carbon C-24. This spatial conformation exposes the methyl groups of OA at carbons C-10 and C-13 at the surface of the molecule, allowing an interaction with the protein phosphatase pi2-pi3 loop. The whole discussion reported above is based on the currently accepted structure of okadaic acid, although the definitive structural conformation has been recently questioned, requiring possible re-evaluation of the sites of interaction of OA with the phosphatase molecules. 

Yamaki, J. Tanaka, T Ihena, M. Sato, K. Egashira, M. Watanabe, I. Okada, S., Thermal stahUity of methyl difluoroacetate as a novel electrolyte solvent for lithium batteries electrolytes, Electrochemistry 2003, 71,1154. 

Sato, K. Zhao, L. Okada, S. Yamaki, J., LiPF(/methyl difluoroacetate electrolyte with vin-ylene carbonate additive for Li-ion batteries, J. Power Sources 2011,196, 5617-5622. 

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