Design and synthesis of an artificial ladder-shaped polyether that interacts with glycophorin A

Torikai, Kohei; Yari, Hiroshi; Mori, Megumi; Ujihara, Satoru; Matsumori, Nobuaki; Murata, Michio; Oishi, Tohru

doi:10.1016/j.bmcl.2006.09.004

Cited by 22 publications

(10 citation statements)

References 37 publications

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“…Model of the anchoring of maitotoxin into the cell membrane (according to Murata and co-workers). [11,24] Reviews 7186 www.angewandte.org through weak interactions involving primarily N À H···O and C a À H···O hydrogen bonds; [28] Figure 7 shows the hypothetical model for brevetoxin B (6). Thus, when the polyether arrangement of the biotoxin complements the protein structural motif of the target protein, usually an a helix, the match results in binding through a network of hydrogen bonds, which leads to the biological action of the toxin.…”

Section: Biological Properties and Mechanism Of Actionmentioning

confidence: 99%

The Continuing Saga of the Marine Polyether Biotoxins

2008

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The unprecedented structure of the marine natural product brevetoxin B was elucidated by the research group of Nakanishi and Clardy in 1981. The ladderlike molecular architecture of this fused polyether molecule, its potent toxicity, and fascinating voltage-sensitive sodium channel based mechanism of action immediately captured the imagination of synthetic chemists. Synthetic endeavors resulted in numerous new methods and strategies for the construction of cyclic ethers, and culminated in several impressive total syntheses of this molecule and some of its equally challenging siblings. Of the marine polyethers, maitotoxin is not only the most complex and most toxic of the class, but is also the largest nonpolymeric natural product known to date. This Review begins with a brief history of the isolation of these biotoxins and highlights their biological properties and mechanism of action. Chemical syntheses are then described, with particular emphasis on new methods developed and applied to the total syntheses. The Review ends with a discussion of the, as yet unfinished, story of maitotoxin, and projects into the future of this area of research.

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Section: Biological Properties and Mechanism Of Actionmentioning

confidence: 99%

The Continuing Saga of the Marine Polyether Biotoxins

2008

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“…Diverse biological activities of LSPs suggest that they bind to specific molecular targets upon exerting their toxicity, although sharing similar structural features. These observations may imply a notion that there is a general and weakly interacting motif of proteins for LSP [90][91][92] and, when a given LSP exactly matches the binding portion of a target protein, probably due to an arrangement of polyether oxygen atoms, its powerful activity is manifested. Thus, this general motif should provide a clue to understand their potent biological activity.…”

Section: Activity-relevant Conformation and Bimolecular Interactions mentioning

confidence: 99%

“…9). It is hypothesized that one of these is C-H-O hydrogen bonding 92 as seen in the dimerization of GpA. 97 Another possibility lies in the electric dipole interaction between polar functionalities of peptides and ether bonds of LSP.…”

Section: Activity-relevant Conformation and Bimolecular Interactions mentioning

confidence: 99%

Structural Features of Dinoflagellate Toxins Underlying Biological Activity as Viewed by NMR

Murata

Matsumori

Konoki

et al. 2008

Bulletin of the Chemical Society of Japan

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Marine dinoflagellates are a rich source of structurally and biologically intriguing secondary metabolites. Among those, maitotoxin may be one of the best known examples, which is the largest natural product known to date and possesses the most potent toxicity known amongst non-proteinaceous compounds. Structural studies of maitotoxin are reviewed with a particular focus on the configuration and mode of action of this unique toxin. In addition, there are many marine natural products which bind to biomembranes to exert their biological activities. To gain a better understanding of their mode of action, conformation, and bimolecular interaction occurring in biomembranes are particularly important. Recent results from NMR studies of membrane systems in the authors' group are reviewed briefly.

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“…While the reactions of both 49a and 49b proceeded in equally high yield as with the mixture, their selectivities were surprising. Thus, whereas thioketal 49b (major) led to a mixture of methylated products 52b : 52a (∼1.5:1 dr), diastereoisomer 49a (minor) gave exclusively the desired methylated diastereoisomer 52a . These results suggest that the methylation reaction of the corresponding sulfones (i.e., 50a and 50b ) proceeds through a more complex mechanism than assumed (i.e., through nucleophilic attack by a methyl anion on a common oxonium intermediate).…”

Section: Resultsmentioning

confidence: 81%

Synthesis of the QRSTU Domain of Maitotoxin and Its 85-epi- and 86-epi-Diastereoisomers

et al. 2010

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A devised synthetic strategy toward the QRSTU ring system 4 of the marine-derived biotoxin maitotoxin (1) delivered, in addition to 4, its diastereoisomers 85-epi-QRSTU and 86-epi-QRSTU ring systems 5 and 6. The convergent route to these maitotoxin fragments involved coupling of UT and Q building blocks 9 (obtained from 2-deoxy-D-ribose) and 10 (obtained from D-ribose) followed by ring-closing metathesis to afford enol ether 8, whose elaboration to the targeted QRSTU ring system 4 required its conversion to hydroxy ketone 7. The latter compound (7) was transformed to the final product through a hydroxy dithioketal cyclization, followed by oxidationmethylation of the resulting O,S-mixed ketal to install the last of the five methyl groups contained within the target molecule (4). 13 C NMR spectroscopic analysis of synthesized fragments 4, 5 and 6, and comparisons with maitotoxin, provided strong support for the originally assigned structure of the QRSTU domain of the natural product.

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Design and synthesis of an artificial ladder-shaped polyether that interacts with glycophorin A

Cited by 22 publications

References 37 publications

The Continuing Saga of the Marine Polyether Biotoxins

The Continuing Saga of the Marine Polyether Biotoxins

Structural Features of Dinoflagellate Toxins Underlying Biological Activity as Viewed by NMR

Synthesis of the QRSTU Domain of Maitotoxin and Its 85-epi- and 86-epi-Diastereoisomers

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