6-Bromotryptophan amino acids

One major recent development in the area of natural products is the discovery and subsequent medicinal application of the toxic peptides from cone snails. These Conus peptides, several of which contain a 6-bromotryptophan amino acid, are finding utility for the treatment of neuropathic pain and other neurological conditions (1074-1078). For example, oo-conopeptide MVIIA (Ziconotide, trade name Prialt) has been approved by the US FDA since 2004 for the treatment of severe pain. It is estimated that the 500-700 species of cone snails (Conus genus) contain... 

The majority of conotoxin structures (115 of 125 structures in the PDB) have been determined by NMR spectroscopy as opposed to X-ray crystallography. They have significant structural diversity as a result of their diverse sequences and disulphide connectivities. Furthermore, conotoxins also have a large number of post-translational modifications, including the presence of hydroxyproline, y-carboxyglutamic acid and bromotryptophan residues, epimerisation, glycosyla-tion and amidation,144,145 that enhance their structural diversity. A recent analysis of NMR data for the unusual amino acids present in conotoxins3 provides a reference source for chemical shifts of post-translationally modified amino acids. 

Radiotracer experiments were used to elucidate the biosynthetic precursors to eudistomin H (7) and I (8) in Floridian collections of Eudistoma olivaceum. Both radiolabeled tryptophan and proline were incorporated by E. olivaceum into eudistomins H and I and tryptamine was incorporated into eudistomin I, to the exclusion of eudistomin H. Bromotryptamine and bromotryptophan are incorporated into eudistomin H (Scheme 30). These results suggest eudistomin biosynthesis proceeds from the amino acids via decarboxylation, halogenation, then condensation with proline. 

A study in which carbon 14-labeled bromotryptophan and trititrm-labeled proline were incorporated into Eudistoma olivaceum showed that these two amino acids (Trp and Pro) are the precursors of eudistomins H and I, tryptophan being transformed into tryptamine (Shen and Baker, 1994a, 1994b). 

The cyclic peptides are ubiqxiitous in the order lithistida, where many structural variations are observed, in particular the existence of bicyclic peptides and also mono- and bicyclic glycopeptides. Several of these complex molecules contain original or atypical a- and P-amino acids, many of them have a a-ketoamide structural element and some have halogen (bromotryptophan) or stilfur atoms (thia-zole). They are all biologically active and most are cytotoxic or have antitumoral or antifungal activity. To provide as complete an overview as possible, the main peptides are presented in Table 19.28. 

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