Jamaicamides

Fig. 10.6. Structure of jamaicamide A (2) showing a key NOE defining the geometry of a tri-substituted olefin.

Edwards DJ, Marquez BL, Nogle LM, McPhail K, Goeger DE, Roberts MA, Gerwick WH (2004) Structure and Biosynthesis of the Jamaicamides, New Mixed Polyketide-Peptide Neurotoxins from the Marine Cyanobacterium Lyngbya majuscula. Chem Biol 11 817... 

Jamaicamides A, B, and G exhibited cytotoxidty to both the H-460 human lung carcinoma and neuro-2a mouse neuroblastoma cell lines. The LG50S were approximately 15 p,M for all three compounds to both cell lines. All three compounds also exhibited sodium charmel-blocking activity at 5 p,M concentration. In the goldfish toxicity assay, a system that has been useful for the detedion of neurotoxic activity in cmde extrads as well as purified compounds, jamaicamide B was the most active (100 % lethality at 5 ppm after 90 min), followed by jamaicamide G (100 % lethality at... 

Dissection of the chemical structure of jamaicamides A-C led to the speculation that these metabolites derive from a mixture of polyketides (nine acetate units), amino acids (t-Ala and p-Ala), and the S-methyl group of methionine. To map out the biosynthetic subunits of these molecules, isotopically labeled precursors were supplied to I. majuscula JHB, and the labeling patterns discerned by NMR spectroscopy (Figure 6.12). From these experiments, insights were gained into the biochemical transformations that produce the jamaicamides, especially the mechanism of formation of the vinyl chloride group [157]. 

Several of these genes vere deduced to program for polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) enzymes as well as novel tailoring enzymes, including those that create the various unusual functional groups in jamaicamide A. 

Fig. 6.13 Gene cluster and predicted biosynthetic assembly of jamaicamide A [157].

Figure 5 The future of natural products. Salinosporamide comes from a new genus of marine actinomycetes, while jamaicamide A and curacin A are produced by cyanobacteria. ECO-02301 was discovered by mining a bacterial genome.

Jamaicamide Lyngbya majuscula JamF JamG JamH JamI JamJ N-terminal... 

While there are many natural products that are either NRPS or PKS derived, there are multidomain megasynthases that contain both NRPS and PKS biosynthetic features. Examples of such biosynthetic motifs are epothilone, jamaicamide, and the endiyne C-1027.33-35 At NRPS-PKS interfaces in these systems, the condensation of malonyl takes place with an amino acid that was activated by an A domain. Alternatively, an amino acid loaded on a T domain condenses with an elongating polyketide. Since the substrates and intermediates in NRPS, PKS, or hybrid NRPS/PKS biosynthesis introduce mass changes on T domains, they are ideal candidates for investigation by MS. 

Another common class of lipopeptide from cyanobacteria includes a starter PKS lipid section, almost always found as an eight-carbon chain (exceptions being jamaicamide, carmabin, and palau amide ), in which oxidation of the Ci -terminus occurs to typically produce a terminal alkyne functionality. Such terminally oxidized PKS motifs can be further dissected into those with an overall linear structure, such as the jamaica-mides, ° apramides, dragonamides, carmabins, " and dragamabin, and those possessing a 3-hydroxy or... 

Two distinctive series of secondary metaholites were isolated from a cultured Jamaican L. majuscula, hectochlorin (79) and the jamaicamides. The structures of the jamaicamides were assembled hy normal spectroscopic methods in addition to being an early test case for a new NMR pulse sequence, the Accordion 1,1-Adequate, which facilitates detection of all two-bond yccH couplings in a molecule. The major metabohte, jamaicamide A (93), was unique in its possession of an acetylenic bromide functionality, only previously observed once before in namre. The jamaicamides show moderate neurotoxicity in a cellular model with low micromolar inhibition of the VGSC. 

Some features of the biosynthesis of mirabimide E (94) were examined through feeding experiments with [l,2- C2]acetate and [methyl- C]methionine, which showed the decanoate and C-4 and C-5 of the pyrrolinone unit to derive from six units of acetate, and the C- and 0-methyl groups to derive from methionine. Considering the models provided by jamaicamide A (93) ° and barbamide (78), it seems likely that the decanoate may derive from hexanoate, which is multiply halogenated by a radical halogenase related to that described from barbamide. This would be extended by two rounds of PKS extension, C-methylation with SAM and simple ketoreduction of the /3-carbonyl formed after the second extension. An NRPS with specificity for L-alanine is likely responsible for amide bond formation and this product is then extended by one more acetate... 

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