19-epi-Okadaic Acid, a Novel Protein Phosphatase Inhibitor with Enhanced Selectivity

Abstract

A new protein phosphatase inhibitor, 19-epi-okadaic acid, was isolated from the marine dinoflagellate Prorocentrum belizeanum. Its structure and conformation in solution has been determined, and important differences were found when compared with the lead compound okadaic acid. The new metabolite showed nanomolar activities, and its selectivity for PP2A versus PP1 surpasses that shown by okadaic acid 10-fold, making it one of the most selective inhibitors of this class.

Identification of 19-epi-okadaic Acid, a New Diarrhetic Shellfish Poisoning Toxin, by Liquid Chromatography with Mass Spectrometry Detection

“…The isolation and structural determination of a new DSP toxin derivative called 19-epi-okadaic acid, (2) (19-epi-OA) from cultures of the dinoflagellate Prorocentrum belizeanum [14,15], prompted us to undertake an analytical study of this metabolite. A full characterization of this new molecule in our laboratory based on the use of NMR, MS and computational techniques, allowed us to use it as a standard.…”

“…Next a mediumpressure reversed-phase Lobar LiChroprep RP-18 column was eluted with acetonitrile-water (1:1) and methanol-water (3:2). Toxin-containing fractions were pooled and subjected to a HPLC final purification on an XTerra column using an isocratic elution with methanol-water (7:3) to obtain the previously reported toxins OA (1), 7'-hydroxymethyl-2'-methylene-octa-4',7'-dienyl okadaate and DTX-5c [16] as well as 19-epi-OA (2) [15], which has not been characterized by LC-MS previously.…”

Anticancer agents derived from marine algae

“…In vitro Cruz et al, 2007; Okadaic acid The in vivo toxicity is highly toxic against leukaemia cells by inhibiting the enzymes of protein phosphatase 1 and 2A…”

“…Okadaic acid is of average toxicity; however, it is highly toxic against leukaemia through inhibition of protein phosphatase (Takai et al , 1987;Walker and Watson, 1992). 19-epi-Okadaic acid isolated from P. belizeanum is a new protein phosphatase inhibitor (Cruz et al , 2007;. Dinochromes A and B are carotenoids isolated from the freshwater species Peridinium bipes .…”

Corozalic Acid: A Key Okadaic Acid Biosynthetic Precursor with Phosphatase Inhibition Activity

“…[7] Although the majority of naturally occurring analogues of 1 possess only slight structural modifications on its main carbon backbone, the recent isolation of new inhibitors belonging to the "okadaic acid class" has opened new possibilities for the development of useful modulators of the catalytic activity of protein phosphatases. [8] In the present study, we describe the isolation, structural elucidation and biological activity of corozalic acid (2), a new serine/threonine phosphatase inhibitor structurally related to okadaic acid, obtained from cultures of Prorocentrum belizeanum. In addition, we present a plausible biosynthetic pathway where both compounds originate from a common linear precursor.…”