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Synthesis and Biological Evaluation of QRSTUVWXYZA′ Domains of Maitotoxin
[Image: see text] The synthesis of QRSTUVWXYZA′ domains 7, 8, and 9 of the highly potent marine neurotoxin maitotoxin (1), the largest secondary metabolite isolated to date, is described. The devised synthetic strategy entailed a cascade Takai–Utimoto ester olefination/ring closing metathesis to con...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2014
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4244842/ https://www.ncbi.nlm.nih.gov/pubmed/25374117 http://dx.doi.org/10.1021/ja509829e |
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author | Nicolaou, K. C. Heretsch, Philipp Nakamura, Tsuyoshi Rudo, Anna Murata, Michio Konoki, Keiichi |
author_facet | Nicolaou, K. C. Heretsch, Philipp Nakamura, Tsuyoshi Rudo, Anna Murata, Michio Konoki, Keiichi |
author_sort | Nicolaou, K. C. |
collection | PubMed |
description | [Image: see text] The synthesis of QRSTUVWXYZA′ domains 7, 8, and 9 of the highly potent marine neurotoxin maitotoxin (1), the largest secondary metabolite isolated to date, is described. The devised synthetic strategy entailed a cascade Takai–Utimoto ester olefination/ring closing metathesis to construct ring Y, a hydroxydithioketal cyclization/methylation sequence to cast ring X, a Horner–Wadsworth–Emmons coupling of WXYZA′ ketophosphonate 11 with QRSTU aldehyde 12 to form enone 10, and a reductive hydroxyketone ring closure to forge ring V. 2D NMR spectroscopic analysis and comparison of (13)C chemical shifts with those of the corresponding carbons of maitotoxin revealed close similarities supporting the originally assigned structure of this region of the natural product. Biological evaluations of various synthesized domains of maitotoxin in this and previous studies from these laboratories led to fragment structure–activity relationships regarding their ability to inhibit maitotoxin-elicited Ca(2+) influx in rat C6 glioma cells. |
format | Online Article Text |
id | pubmed-4244842 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-42448422015-11-06 Synthesis and Biological Evaluation of QRSTUVWXYZA′ Domains of Maitotoxin Nicolaou, K. C. Heretsch, Philipp Nakamura, Tsuyoshi Rudo, Anna Murata, Michio Konoki, Keiichi J Am Chem Soc [Image: see text] The synthesis of QRSTUVWXYZA′ domains 7, 8, and 9 of the highly potent marine neurotoxin maitotoxin (1), the largest secondary metabolite isolated to date, is described. The devised synthetic strategy entailed a cascade Takai–Utimoto ester olefination/ring closing metathesis to construct ring Y, a hydroxydithioketal cyclization/methylation sequence to cast ring X, a Horner–Wadsworth–Emmons coupling of WXYZA′ ketophosphonate 11 with QRSTU aldehyde 12 to form enone 10, and a reductive hydroxyketone ring closure to forge ring V. 2D NMR spectroscopic analysis and comparison of (13)C chemical shifts with those of the corresponding carbons of maitotoxin revealed close similarities supporting the originally assigned structure of this region of the natural product. Biological evaluations of various synthesized domains of maitotoxin in this and previous studies from these laboratories led to fragment structure–activity relationships regarding their ability to inhibit maitotoxin-elicited Ca(2+) influx in rat C6 glioma cells. American Chemical Society 2014-11-06 2014-11-19 /pmc/articles/PMC4244842/ /pubmed/25374117 http://dx.doi.org/10.1021/ja509829e Text en Copyright © 2014 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
spellingShingle | Nicolaou, K. C. Heretsch, Philipp Nakamura, Tsuyoshi Rudo, Anna Murata, Michio Konoki, Keiichi Synthesis and Biological Evaluation of QRSTUVWXYZA′ Domains of Maitotoxin |
title | Synthesis
and Biological Evaluation of QRSTUVWXYZA′ Domains of
Maitotoxin |
title_full | Synthesis
and Biological Evaluation of QRSTUVWXYZA′ Domains of
Maitotoxin |
title_fullStr | Synthesis
and Biological Evaluation of QRSTUVWXYZA′ Domains of
Maitotoxin |
title_full_unstemmed | Synthesis
and Biological Evaluation of QRSTUVWXYZA′ Domains of
Maitotoxin |
title_short | Synthesis
and Biological Evaluation of QRSTUVWXYZA′ Domains of
Maitotoxin |
title_sort | synthesis
and biological evaluation of qrstuvwxyza′ domains of
maitotoxin |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4244842/ https://www.ncbi.nlm.nih.gov/pubmed/25374117 http://dx.doi.org/10.1021/ja509829e |
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