Structure palytoxin

Figure 1. Palytoxin carboxylic acid. (Structure kindly provided by Professor Yoshito Kishi.)...

Palytoxin isolated from zoanthids Palythoa spp. is known to be extremely lethal (0.5 fig/kgy mouse, i.p.) and to have the most complicated natural product structure (Figure 4) ever elucidated (13,14). The toxin was later revealed to be a potent tumor promoter (15). Yet, health risks due to the toxin have remained unclear, as the zoathids are the most unlikely organisms to be regarded as foodstuff. Recently, however, data are being compiled to indicate the wide distribution of this toxin among marine biota. 

Many environmental toxins interact with specific cellular receptors, including enzymes, ion channels and ion pumps, and thus provide natural tools for the study of cellular signalling pathways. Palytoxin, a compound isolated from the coelen-terate of genus Palythoa, is one such useful and intriguing compound. The structure of palytoxin was first determined in 1981 independently by Hirata (7) and Moore (2). As one of the most potent marine toxins known, palytoxin has been studied in a variety of systems ranging from erythrocytes to neurons. As a tumor promoter of the non 12-O-tetradecanoylphorbol-13-acetate (TPA) type, palytoxin can also be studied in the context of a growth control system. 

Palytoxin (PTX) is one of the most potent marine toxins known and the lethal dose (LD q) of the toxin in mice is 0.5 Mg/kg when injected i.v. The molecular structure of the toxin has been determined fully (1,2). PTX causes contractions in smooth muscle (i) and has a positive inotropic action in cardiac muscle (4-6). PTX also induces membrane depolarization in intestinal smooth (i), skeletal (4), and heart muscles (5-7), myelinated fibers (8), spinal cord (9), and squid axons (10). PTX has been demonstrated to cause NE release from adrenergic neurons (11,12). Biochemical studies have indicated that PTX causes a release of K from erythrocytes, which is followed by hemolysis (13-15). The PTX-induced release of K from erythrocytes is depress by ouabain and that the binding of ouabain to the membrane fragments is inhibited by PTX (15). 

Figure 1. Structure of palytoxin, isolated from P, tuberculosa (3), immunogen (bovine albumin). The structures of the palytoxins from different Palythoa species vary in the hemiketal ring at position C55 (2, 3).

Palytoxin is a complex marine natural product containing 71 stereochemical elements (Fig. 5). The structure of PTX was elucidated by Moore. PTX is isolated from a zoanthid (order Zoanthidea) a type of soft coral commonly found in coral reefs all around the world. These animals come in a variety of different colonizing formations and in numerous colors. They can be found as individual polyps, attached by a fleshy stolon or a mat that can be created from pieces of sediment, sand and rock (soft coral). PTX is considered to be one of the most toxic nonpeptide substances known, second only to Maitotoxin. Typical symptoms of palytoxin poisoning are angina-like chest pains, asthma-like breathing difficulties, tachycardia, unstable blood pressure, hemolysis (destruction of red blood... 

The most deadly nonproteinaceous toxin known, palytoxin, is also the most complex structure ever established without the aid of X-ray crystallography.535 536 It is produced by marine zoanthids of the genus Paly-thoa and has the molecular formula Q29H223N3O54. 

Palytoxin was isolated in 1971 in Hawaii from Limu mate o Hane ( deadly seaweed of Hana ) which had been used to poison spear points. It is one of the most toxic compounds known requiring only about 0.15 microgram per kilogram for death by injection. The complicated structure was determined a few years later. 

Hydrocarbon frameworks rarely consist of single rings or chains, but are often branched. Rings, chains, and branches are all combined in structures like that of the marine toxin palytoxin that we met at the beginning of the chapter, polystyrene, a polymer made of six-membered rings dangling from linear carbon chains, or of p-carotene, the compound that makes carrots orange,... 

So far, we have talked a lot about compounds by name. Many of the names we ve used (palytoxin, muscone, brevetoxin...) are simple names given to complicated molecules without regard for the actual structure or function of the molecule—these three names, for example, are all derived from the name of the organism from which the compound was first extracted. They are known as trivial names, not because they are unimportant, but because they are used in everyday scientific conversation. 

From time to time throughout the book we have spread before your eyes some wonderful structures. Some have been very large and complicated (such as palytoxin, p. 19) and some small but difficult to believe (such as tetra-f-butyl tetrahedrane, p. 373). They all have one thing in common. Their structures were determined by spectroscopic methods and everyone believes them to be true. Among the most important organic molecules today is Taxol, an anticancer compound from yew trees. Though it is a modern compound, in that chemists became interested in it only in the 1990s, its structure was actually determined in 1971. 

At 2 hours after p.o. administration with 140 pg kg of gambierol, electron microscopy showed that the cardiac mnscle fibers in the myocardium separated each other by edema and congestion (Figs. 1.4a and 1.4b), althonghthe cell structure had no changes. Similar systemic congestions have been reported by palytoxin and cignatoxins (Ito, Ohkusu, and Yasnmoto 1996 Terao et al. 1991). 

Figure 5.1. Proposed structure of palytoxin from a Tahitian Palythoa sp. (1A). The two paiytoxins from Hawaiian P toxica are the related C-55 hemiketais (partiai structures 1B and 1C). Reproduced with permission from Moore and Bartolini 1981, American Chemical Society.

Palytoxin from the Tahitian Palythoa has a molecular form of Cj29H22iN30j4 (Mj. 2659). On the other hand, palytoxin from P. toxica has a molecular form of C,29H223N3054 (M. 2611), with two possible structures (Fig. 5.1) that differ from the former in the C-55 hemiketal ring. Palytoxin from the Hawaiian P. tuberculosa is a mixture of the three palytoxins from the Tahitian Palythoa and P. toxica (Mooie and Bartolini 1981). The two components in palytoxin from the Okinawan P. tuberculosa (Mj. 2681 Macfarlane et al. 1980) may be the related C-54 ketal and hemiketal (Moore and Bartolini 1981). The palytoxin from P. caribaoreum has a molecnlar mass of 2680, while the palytoxin-like substance isolated from Lophozozymus pictor crab, which showed a very similar positive ion MS profile, was estimated to possess a molecular mass of 2681.0 Da (Lau et al. 1995). 

Figure 5.2. Complete structure of the major palytoxin from P. tuberculosa (1) and of minor palytoxins (2) homo-palytoxin, (3) bishomopalytoxin, (4) neopalytoxin, and (5) deoxypalytoxin. Reproduced with permission from Uemura etal. 1985, Elsevier.

Figure 5.3. Planar structure of reference Pacific palytoxin (P-PTX) showing the UV chromophores. Asterisk denotes carbon eight. Reproduced with permission from Lenoir et al. 2004, Blackwell Publishing.

Exposure of palytoxin to both visible and UV light results in structural changes in both the 263 and 233 chromophores and can reduce its toxicity at least twentyfold in only 5 minutes in UV and 30 minutes invisible light (Hewetsonet al. 1990). 

Many studies aimed at structural elucidation of palytoxin have included data derived from NMR determinations on various degradation products from periodate oxidation or ozonolysis (Moore and Bartolini 1981 Cha et al. 1982 Moore et al. 1982a). The complete chemical shift assigmnent of H and NMR signals of the whole P. tuberculosa palytoxin molecule was reported by Kan et al. (2001 Table 5.1). A detailed description of NMR spectra is beyond the purpose of this chapter. However, it is interesting to note that deuterated methanol (CDjOD or CDjOH) gave much sharper... 

O. siamensis was first characterized as a toxin producer by Nakajima et al. (1981). Some years later, Yasumoto et al. (1987) and Holmes et al. (1988) reported the lethafity and haemolytic activity of the O. siamensis toxins. Usami et al. (1995) were the first to elucidate the structure of the major ostreocin produced by O. siamensis (strain SOA 1 from Aka island, Okinawa, Japan) and point out its structural and chemical properties resemblance to palytoxin. This major constituent was named ostreocin-D and accounted for 90% of total toxicity of extracts. None of the other (more than 10) minor ostreocins present in the O. siamensis extracts were identical to palytoxin, as initially indicated by ESl-MS (Ukena et al. 2001, 2002). New Zealand O. siamensis isolates have also been reported to produce toxins exhibiting strong haemolytic activity and mouse lethality (Rhodes et al. 2000, 2002). Recently, Penna et al. (2005) have reported the presence of toxins with strong delayed haemolytic activity in Ostreopsis cf siamensis from the NW Mediterranean Sea. This haemolytic activity was inhibited by the palytoxin antagonist ouabain, indicating the palytoxin-like nature of these toxins. 

Figure 5.5. Structures of palytoxin (1) and ostreocin-D (2). Reproduced with permission from Ukena et al. 2002, John Wiley Sons Limited.

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