Brevetoxin B

Brevetoxin-B (BTX-B), produced by the red tide organism, Gymnodium breve Davis, is the first member of marine polycyclic ethers to be structurally elucidated and one of the most potent neurotoxins. The structural feature is a trans-fused polycyclic ether ring system with 23 stereocenters. Its unique, complex structure and potent biological activity have attracted the attention of synthetic organic chemists. Total synthesis of BTX-B has been accomplished via the coupling of the ABCDEFG and IJK-ring segments, each ether ring of which was stereoselectively and efficiently constructed on the basis of SmI2-induced intramolecular cyclization, 6-endo-cyclization of hydroxy epoxide, ring-closing olefin metathesis, and SmI2-induced intramolecular Reformatsky-type reaction. Several kinds of double reactions at the left and right sides were efficiently used through the synthesis.

Brevetoxin B (BTX-B), produced by dinoflagellates of the species Karenia, is a highly reactive molecule, due in part to an α,β-unsaturated aldehyde group at the terminal side chain, leading to the production of metabolites in shellfish by reduction, oxidation, and conjugation. We have investigated in mice the blood elimination of three common bioactive brevetoxin metabolites found in shellfish, which have been semisynthesized from BTX-B in radioactive forms. BTX-B was reduced at C42 to yield [(3)H] dihydro-BTX-B. [(3)H] S-desoxy-BTX-B2 (cysteine brevetoxin B) was semisynthesized from BTX-B by the conjugation of cysteine at the C50 olefinic group then [(3)H] radiolabeled by C42 aldehyde reduction. [(14)C] N-Palmitoyl-S-desoxy-BTX-B2 was prepared using S-desoxy-BTX-B2 as the starting material with addition of the [(14)C] radiolabeled fatty acid via cysteine-amide linkage. The elimination of intravenously administered [(3)H] S-desoxy-BTX-B2, [(14)C] N-palmitoyl-S-desoxy-BTX-B2, or [(3)H] dihydro-BTX-B was measured in blood collected from C57BL/6 mice over a 48 h period. Each brevetoxin metabolite tested exhibited biexponential elimination kinetics and fit a two-compartment model of elimination that was applied to generate toxicokinetic parameters. The rate of transfer between the central compartment (i.e., blood) and the peripheral compartment (e.g., tissue) for each brevetoxin differed substantially, with dihydro-BTX-B exchanging rapidly with the peripheral compartment, S-desoxy-BTX-B2 eliminating rapidly from the central compartment, and N-palmitoyl-S-desoxy-BTX-B2 eliminating slowly from the central compartment. Toxicokinetic parameters were analyzed in the context of the unique structure of each brevetoxin metabolite resulting from a reduction, amino acid conjugation, or fatty acid addition to BTX-B.

Brevetoxin-B (BTX-B), a Gymnodinium breve toxin, isolated from the dinoflagellate, produced contraction of guinea pig ileum and rabbit aorta. Atropine (10(-6) M) and phentolamine (10(-6) M) abolished the BTX-B (10(-7) or 10(-6)-induced contraction of the ileum or aorta, respectively. Tetrodotoxin and saxitoxin (both 5 x 10(-7) M) also abolished the responses to BTX-B in the both tissues. Results suggest that BTX-B produces smooth muscle contractions through the tetrodotoxin- and saxitoxin-sensitive release of transmitters from autonomic nerves.