Cylindrospermopsin alkaloids

Another interesting application is the synthesis of a model tricyclic core of the cylindrospermopsin alkaloids 66-68 (Fig. 9.6) reported by Murphy s group following a Biginelli reaction as a key step of the process (Scheme 9.26) [77], These alkaloids are marine natural products that exhibit diverse cytotoxic activities [78], and they have been the focus of a different total synthesis. 

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). 

Fig. 5.1 Common cyanobacterial hepatotoxins. (a) Generalized structure of microcystin, a cyclic heptapeptide. Note that X and Z are L-amino acids. For example, microcystin-LR possesses lysine and arginine residues at X and Z, respectively, (b) Cylindrospermopsin, a hepatotoxic alkaloid from Cylindrospermopsis raceborskii...

M. Runnegar, K. Shou-Ming, Z. Ya-Zhen and C. Shelly, Inhibition of reduced glutathione synthesis by cyanobacterial alkaloid cylindrospermopsin in cultured rat hepatocytes, Biochem. Pharmacol., 49 (1995) 219-255. 

Cylindrospermopsin resulted in a hepatotoxic alkaloid that is capable of inhibiting protein synthesis, and it appears to have a progressive effect on several other vital organs snch as the kidney in addition to the liver (Terao 1994 Falconer 1999). Cylindrospermopsin was shown to be a potent inhibitor of protein synthesis. The same stndies described the liver as the main target of this phyco-toxin, with four consecutive phases of the pathological changes in the liver protein synthesis inhibition, membrane proliferation, fat droplet accumulation, and cell death. 

Runnegar, M.T.C, King, S.M., Zhong, Y.Z., and Lu, S.C. 1995. Inhibition of reduced glutathione synthesis by cyanobacterila alkaloid cylindrospermopsin in cultured rat hepatocytes. Biochemistry and Pharmacology 49(2) 219-225. 

Cylindrospermopsin (CYN) is an alkaloid containing a tricyclic guanidine combined with hydroxymethyl uracyl (Figure 27.1C) with a molecular weight of 415 daltons. Intraperitoneal injection of cells containing CYN in mice is followed by diarrhea, anorexia, irregular respiration, and... 

Cylindrospermopsin is an alkaloid cyanotoxin produced by several freshwater cyanobacteria genera, including Cylindrospermopsis, Aphanizomenon, Anabaena, Lyngbya, Umezakia, and Raphidiopsis (Guzman-Guillen et al., 2013). It is foxmd worldwide in surface freshwaters (de la Cruz et al., 2013). 

Cylindrospermopsin is an alkaloid consisting of a tricyclic guanidine coupled with hydrox3unethyluracil (Figure 31.2). It is a zwitterionic, highly water-soluble molecule (Ohtani et al., 1992). There are two known structural variants deoxycylindrospermopsin (Norris et al., 1999), which is relatively less toxic, and 7-epicyl-indrospermopsin (Banker et al., 2001), which is relatively... 

Shaw, G.R., Seawright, A.A., Moore, M.R., et al., 2000. Cylindrospermopsin, a cyanobacterial alkaloid evaluation of its toxicologic activity. Ther. Drug... 

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