Hepatotoxic cyclic peptides

The C20 amino acid (2.V,3.S, 8.S, 9.S, 4/ , 6 )-3-amino-9-methoxy-2,6,8-tri-methyl-10-phenyldeca-4,6-dienoic acid (Adda 19) is a molecule of interest to biologists and organic chemists as a component of the hepatotoxic cyclic peptides called microcystins. Kim and Toogood used Ireland-Claisen rearrangement in their successful synthesis of Adda8 (Scheme 1.3h). The ester 20 underwent highly diastereoselective Ireland-Claisen rearrangement to provide the acid 21. Conversion of this acid to the phosphonium bromide 22 was achieved in nine... 

Moroder, L. and Rudolph-Bohner, S. (1998) Microcystins and nodularins, hepatotoxic cyclic peptides of cyanobacterial origin, in Studies in Natural Product Chemistry (ed. Atta-Ur-Rahman), vol. 20, pp. 887-920. 

One of the invariant amino acids is a unique P-amino acid called Adda (2S,3S,8S,9S)-3 amino-9 methoxy-2,6,8-trimethyl-10-phei5fldeca-4,6-dienoic acid is the most unusual structure in this group of cyanobacterial cyclic peptide toxins). A two-letter suffix (XY) is ascribed to each individual toxin to denote the two variant amino acids (Carmichael 1988). X is commonly leucine, arginine, or tyrosine. Y is arginine, alanine, or methionine. Variants of all the invarianf amino acids have now been reported, e.g., desmethyl amino acids and/or replacement of the 9-methoxy group of Adda by an acetyl moiety. Currently there are in excess of 60 variants of microcystin that have been characterized (Rinehart 1994 Sivonen and Jones 1999). Of these 60 compounds, microcystin-LR would appear to be the microcystin most commonly found in cyanobacteria. It is also common for more than one microcystin to be found in a particular strain of cyanobacterium (Namikoshi 1992 Lawton 1995). The microcystin variants may also differ in toxicity (Carmichael 1993). The literature indicates that hepatotoxic blooms ofM aeruginosa containing microcystins occur commonly worldwide. 

Penicillium islandicum is a chlorine-containing peptide whose structure was determined later. This organism also produced cyclochlorotine (92), which is an infectant of yellowed rice [133], The fungus Metarhizium anisopliae produces the chlorohydrin cyclic peptide (93) [134], Cyclochlorotine, a hepatotoxic mycotoxin, was also isolated from Penicillium islandicum. 

Studies in several laboratories have shown that strongly hepatotoxic cyclic heptapeptides of a common type occur in different strains of Microcystis [59]. Microcystis aeruginosa, the species most frequently investigated contains the peptide formulated in Fig. 25. The two letter suffix LA designates the two L-amino acids in positions 2 and 4 (X, Y = Leu, Ala) which have been found variable in all of the toxins examined to date. X can also be arginine (R) or methionine (M). The 10-carbon chain jS-amino acid is unique for this type of hepatotoxic compound. Another not quite common structural element is the unsaturated side chain of dehydroalanine (No. 7), the formation of which can readily be imagined by elimination of H2O from serine or H2S from cysteine. 

Cyanobacteria known to produce hepatotoxins include species of Microcystis (32-36), Anabaena (37-40), Nostoc (41,42), Oscillatoria (43,44) and the brackish water Nodularia spumigena (45,46). These cyanobacteria produce a wide range of toxins including neurotoxic alkaloids, lipopolysaccharides, phenolic compounds and most importantly, the cyclic hepatotoxic peptides microcystins and nodularins. Since both microcystins and nodularins were recently discovered even in shellfish (47) and tropical fish species (48), and a nodularin variant was isolated in Papua New Guinea also from the tropical marine sponge Theonella swinhoei (49), marine prokaryotes are apparently producing identical toxins as the cyanobacteria. However, since this nodularin variant was isolated from a marine sponge it may well be produced by a microbial symbiont. 

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