Okadaic acid from sponges

Protein phosphatases inhibitors. Okadaic acid from marine dinoflagellates that accumulates in a black sponge (Halichondria okadal) and mussels, is a polyether fatty acid derivative. It causes a contracture of smooth and cardiac muscle, is a tumour promoter and selectively inhibits protein phosphatase-1 and phosphatase-2A. It is a causative agent in diarrhoretic shellfish poisoning. 

This chapter describes typical sponge metabolites according to the biosynthetic classification, with references to their important roles in drug discovery as well as in marine ecosystems. To avoid duplication, those compounds described in Comprehensive Natural Products Chemistry are not described in detail here. We do not deal with freshwater sponges, from which only lipids and steroids were reported, except for okadaic acid from the Baikalian sponge Lubomirskia baicalensis ... 

Tachibana, K., et al., Okadaic acid, a cytotoxic polyether from two marine sponges of the genus Halichondria, JACS, 103, 2469, 1981. 

Additional pharmacological studies on the cytotoxic compound acanthifolicin (95), the 9,10-episulfide derivative of okadaic acid obtained from sponge Pandaros acanthifolium [103], showed it to be an inhibitor of phosphatases 1 and 2a (PP1-1 and PP-2a) with similar potencies to okadaic acid [104]. 

Britton, R., Roberge, M., Brown, C., van Soest, R., and Andersen, R. J. 2003. New okadaic acid analogues from file marine sponge Merriamum oxeato and their effect on mitosis. J Nat Prod 66, 838-843. 

Tachibana, K., Scheuer, P.J., Tsukitani, Y, Kikuchi, H., Van Engen, D, Clardy, I, Gopichand, Y, and Schmitz, EJ. 1981. Okadaic acid, a cytotoxic polyether from two marine sponges of the genus Halichondria. J Am Chem Soc 103, 2469-2471. 

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). 

Shibata, S. et al., Contractile effects of okadaic acid, a novel ionophore-like substance from black sponge, on isolated smooth muscles under the condition of Ca deficiency, J. Pharmacol. Exp. Then, 223, 135, 1982. 

Calyctiins, Strongly antitumor active metabolites from the Japanese marine sponge Discodermia calyx. Phosphatases 1 and 2A have been identified as the molecular sites of action. IC50O.5-2 nM(PPl) 0.1 -1 nM (PP2A). With regard to PPl C. A is about 30-200 times more effective than okadaic acid. Acidic, alkaline, and protein-tyrosine phosphatases are not affected. C. is cell permeable and can be used to study... 

Okadaic acid (1), a marine polyether toxin, was first isolated as a potent antitumor agent from two sponges Halichondria okadai and H. melanodocia, and... 

Tachibana K, Scheuer PJ, Tsukitani Y, Kikuchi H, Vanengen D, Clardy J, Gopichand Y, Schmitz EJ (1981) Okadaic Acid, a Cytotoxic Polyether from Two Marine Sponges of the Genus Halichondria. J Am Chem Soc 103 2469... 

Okadaic acid (OA), being a polyether, presents ionophoretic properties (facilitation of ion transport across membranes) as does CTX. It has been found that OA causes contraction in smooth muscles even in the absence of Ca (Ozaki and Karaki 1987 Shibata 1985). Ozaki and Karaki (1987) studied the mechanism of action of OA compared to calyculin A (another polyether isolated from a marine sponge). The results of this work suggest that OA has two separate effects activation of calcium channels as well as activating contractile elements to induce smooth muscle contraction. Recently, OA, in addition to other compounds from marine sources, has been found to be a tumor promoter that is, an agent that promotes tumor formation on already initiated cells (Fujiki 1988). It has been found that the OA class of tumor promoters bind to their own receptors which are present in particulate as well as cytosol fractions. The mechanism of action of these compounds has been partially elucidated. 

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