Synthesis microcystin

Hepatotoxins include microcystins, which are cyclic heptapeptides (Fig. 5.1a) and cylindrospermopsin, a sulfated guanidinium alkaloid (Fig. 5. lb). Microcystins bind to certain protein phosphatases responsible for regulating the distribution of cytoskeletal proteins (Zurawell et al. 2005 Leflaive and Ten-Hage 2007). Hepatocytes exposed to microcystins eventually undergo cellular deformation, resulting in intra-hepatic bleeding and, ultimately, death (Carmichael 2001 Batista et al. 2003). In contrast, cylindrospermopsin appears to have a different mode of activity, possibly involving inhibition of protein or nucleotide synthesis (Codd et al. 1999 Froscio et al. 2003 Reisner et al. 2004). Nevertheless, microcystins are the most common cyanotoxins isolated from cyanobacterial blooms (Sivonen and Jones 1999). 

Cells of C. reinhardtii were exposed to cell-free filtrates from A. flos-aquae, pure microcystin-LR or anatoxin-a, or combinations of the toxins. Both the position of the cells and the chlorophyll-a concentration of the cultures were observed for 12 days. Exposure to crude extracts as well as to combinations of the toxins significantly decreased chlorophyll levels in the cultures. Furthermore, these compounds were all capable of paralyzing the algae and thus promoted the settlement of C. reinhardtii cells. One intriguing aspect of this dynamic interaction is the separate finding that C. reinhardtii may actually induce toxin synthesis in A. flos-aquae (Kearns and Hunter 2000), essentially signaling its own demise. 

Rantala A, Fewer DP, Hisbergues M, Rouhiainen L, Vaitomaa J, Bomer T, Sivonen K (2004) Phylogenetic evidence for the early evolution of microcystin synthesis. Proc Natl Acad Sci... 

Shreder KR, Liu Y, Nomanhboy T et al (2004) Design and synthesis of AX7574 a microcystin-derived, fluorescent probe for serine/threonine phosphatases. Bioconjug Chem 15 790-798... 

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... 

Fig. 6. Synthesis of N-Boc-Adda-OH, according to D Aniello et al. (91), as suitably protected intermediate for the preparation of nodularin or microcystin.

Fig. 7. Synthesis of the microcystin fragment Ac-D-7-Glu-Mdha-D-Ala-Leu-NH2 by solid phase peptide synthesis (100).

We have shown that treatment of Se-(4-methoxybenzyl)-selenocysteine or related peptides with DBU in dimethylformamide produces in quantitative manner the related dehydroalanine-compounds as shown in Fig. 8 (101). As this method can be applied to the Fmoc/tBu strategy of solid phase peptide synthesis (102), if Fmoc removal is carried out with due precautions, it should represent a very efficient synthetic approach to microcystins. 

Motuporin and other members of serine/threonine phosphatase inhibitors such as calyculins, microcystins, nodularins have attracted considerable synthetic interest in the last years. Schreiber s group reported the first total synthesis of motuporin in 1995 [154], whereas very recently three alternative approaches appeared in the literature [155]. 

The structure of the final complex, predicted by computer modelling, is presented in Fig. 10. This complex contains one molecule of Microcystin-LR, one molecule of AMPSA and six molecules of UAEE. The same molar ratio predicted by the modeling program was then used for the synthesis of the polymer. Two of the four monomers selected for the annealing process were unable to establish direct binding with the toxin, probably due to steric factors and internal competition (the monomers favored interaction with one another rather than with Microcystin-LR). 

B. Computationally Designed Imprinted Polymer for Microcystin-LR Synthesis and Testing... 

Ala), where X and Z represent two variable L-amino acids, and Adda stands for 3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4,6-dienoic acid. The main differences in variants are based on different variable amino acids in positions 2 and 4 of heptapeptide. Most commonly occurring MC contain leucine (L) and arginine (R) or tyrosine (Y), and their names are abbreviated as MC-LR, MC-RR, and MC-YR, respectively. Microcystins with different stmcture of Adda (in position 5), such as stereoisomers or 9-(9-desmethyl-Adda, were also identified. Production of MC by cyanobacteria depends on different factors such as intensity and wavelength of light, temperature, pH, concentration of nutrients such as phosphoms and nitrogen. Their synthesis is an energy (ATP)-dependent process that can be also affected by the presence of some trace metals. Reported occurrences of most common MC in different environmental samples, where different MC are produced by different cyanobacteria are shown in Table 1. ... 

Toogood et al. used the rearrangement of the chiral (Z)-allylic ester 160 as a key step during their synthesis of microcystines and related toxins (Scheme 5.2.51). The rearrangement product 161 was used as starting material for the synthesis of two unusual amino acids obtained in these cyclopeptides [92]. All these peptides... 

Lera and coworkers successfully employed this thallium(i) hydroxide-aecelerated Suzuki reaction in the stereocontrolled polyene syntheses of retinol (vitamin A) and derivatives and polyenic alarm pheromones of cephalaspidean molluscs navenone A and haminol Despite some initial examples where thallium(i) ethoxide failed as an alternative for thallium(i) hydroxide there are an appreciable number of cases where thallium(i) ethoxide furnished great results. The first successful use of thallium(i) ethoxide was reported by Chamberlin and coworkers in the total synthesis of microcystin LA, a serine-threonine phosphatase inhibitor (Scheme 20.17). A few years after the synthesis of mieroeystin L, Roush and coworkers extended the use of thallium(i) ethoxide in Suzuki couplings for a range of boronic acids and halides. Simultaneously, Danishefslq and Chemler ... 

Beatty, M.F., Jennings-White, C., and Avery, MA. (1992) Stereo-controlled synthesis of (2S,3S,8S,9S,4E,6 )-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4,6-dienoic add (Adda), the amino add characteristic of microcystins and nodularin. J. Chem. Soc. Perkin Trans. 1,1637-1641. 

Humphrey, J.M., Aggen, J.B., and Chamberlin. A.R. (1996) Total synthesis of the serine-threonine phosphatase inhibitor microcystin-LA./. Am. Chem. Soc., 118,11759-11770. 

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