Structure okadaic acid

Protein phoshatases Okadaic acid (Structure 16.6) Dinoflagellate, Prorocentrum Anticancer17... 

At the time Murata s study was reported, the solution structure of acyclic portions of the okadaic acid structure were not known despite extensive NOE measurements coupled with distance geometry calculations. Using Jhh coupling constants measured from E. COSY data and "Jch (" = 2, 3), determined predominantly from HETLOC spectra for the contiguous protonated carbon portions of the molecule and phase-sensitive HMBC data for segments containing quaternary carbons, Murata and co-workerswere able to successfully establish the solution structure of okadaic acid. 

Figure 5.59 Molecular structures of the diarrhetic shellfish poisons (a) pectenotoxin-6 (PTX6) (b) okadaic acid (OA) (c) dinophysistoxin-1 (DTXl) (d) yessotoxin (YTX). Reprinted from J. Chromatogr., A, 943, Matrix effect and correction by standard addition in quantitative liquid chromatographic-mass spectrometric analysis of diarrhetic shellfish poisoning toxins , Ito, S. and Tsukada, K., 39-46, Copyright (2002), with permission from Elsevier Science.

Some natural products, or their degradation products, represent a hazard for mammals not because of general toxicity but for subtle, adverse properties, such as carcinogenicity and tumor promotion. They are best known fi om marine dinoflagellates (okadaic acid and structural analogues), filamentous fungi (trichothecenes and ochratoxins), and plants (pyrrolizidine alkaloids). 

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... 

Even more remarkable polyether structures are found in some toxins produced by marine dinoflag-ellates, which are in turn taken up by shellfish and pass on their toxicity to the shellfish. Okadaic acid (Figure 3.76) and related poly ether structures from Dinophysis species are responsible for... 

Tetrahydropyrans bearing halides at C4 can be accessed by a modified Taddei-Ricci reaction. The reaction involves condensation of allyltrimethylsilane, aldehydes and a cyclic acetal 371 in the presence of a Lewis acid to afford all ry -tetrahydropyrans 372 as a single diastereomer. The reaction proceeds via anion mediated ring closure of oxonium ion intermediate 373 (Scheme 89). This methodology was successfully applied to the synthesis of a model compound bearing all the structural motifs present in the eastern subunit of okadaic acid <1997TL2895>. 

Figure 12.1. Structures of known okadaic acid analogues (Hu et al. 1992, 1995b). MW = molecular weight.

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. 

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)]. 

The consumption of shellfish (scallops and mussels) harvested during late spring to early summer fiom the northeastern region of Japan quite often results in what is commonly known as diarrhetic shellfish poisoning. An initial chemical investigation of the toxic mussels resulted in the identification (86) of okadaic acid [108], dinophysistoxin 1 (DTXj) [109] and two toxins of unknown structures. In a later study (87), chemical structures of three new polyether toxins, dinophysistoxin- 3 (DTX3)[110], pectenotoxin-1 [111 ] and pectenotoxin-2 [112] were reported. 

Several phosphatase inhibitors are available and have been useful in many aspects of smooth muscle research. Okadaic acid was the first inhibitor to be widely used and inhibition of phosphatase activity by this compound was demonstrated using smooth muscle (Hartshorne et al., 1989). Calyculin A was also used in several earlier studies. Since 1990 other compounds have been described as phosphatase inhibitors. These are remarkable in that despite considerable differences in structure, they are relatively specific as phosphatase inhibitors. These inhibitors include tau-tomycin, as antifungal antibiotic produced by Strep-tomyces (MacKintosh and Klumpp, 1990 Hori et al.,... 

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). 

---