Possible Biosynthetic Products and Metabolites of Kainic Acid from the Red Alga Digenea simplex and Their Biological Activity

Four kainic acid (KA, 1)-related compounds, 4-hydroxykainic acid (2), allo-4-hydroxykainic acid (3), N-dimethylallyl-l-glutamic acid (4), and N-dimethylallyl-threo-3-hydroxyglutamic acid (5), were isolated from the red alga Digenea simplex. The structures of these compounds were elucidated using spectroscopic methods. Compounds 2 and 3 are possible oxidative metabolites of KA and allo-KA (6), respectively. Compound 4 was recently reported as the biosynthetic precursor of KA, but the absolute configuration of 4 has not been previously determined. Herein, we determined the absolute configuration of 4 as 2(S) using advanced Marfey's method. Compound 5 is similar to N-geranyl-3(R)-hydroxy-l-glutamic acid (8), which was previously identified in a domoic acid (DA)-containing red alga. Compounds 5 and 8 are predicted to be biosynthetic byproducts of the radical-mediated cyclization reaction to form the pyrrolidine rings of KA and DA, respectively. Furthermore, the toxicities of 1-5 in mice were examined by intracerebroventricular injection. The toxicity of 2 was less than that of KA; however, the mice injected with 2 showed symptoms similar to those induced by KA, while 3-5 did not induce typical symptoms of KA in mice.