Synthesis and biological evaluation of triazole analogues of antillatoxin
Antillatoxin 1, a cyclic lipopeptide, is known as an activator of voltage-gated sodium channels and exhibits potent neurotoxicity toward Neuro 2a mouse neuroblastoma cells. To investigate the biological effects of the side-chain structures at C5 and C5′ in detail, we planned SAR studies of C5- and C...
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| Veröffentlicht in: | Tetrahedron 2011-09, Vol.67 (35), p.6659-6672 |
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| container_title | Tetrahedron |
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| creator | Goto, Ryosuke Okura, Ken Sakazaki, Hayato Sugawara, Tatsuya Matsuoka, Shigeru Inoue, Masayuki |
| description | Antillatoxin
1, a cyclic lipopeptide, is known as an activator of voltage-gated sodium channels and exhibits potent neurotoxicity toward Neuro 2a mouse neuroblastoma cells. To investigate the biological effects of the side-chain structures at C5 and C5′ in detail, we planned SAR studies of C5- and C5′-modified antillatoxin analogues. To diversify the structures at the last step of the synthesis, two key intermediates
4 and
6 possessing terminal alkynes at the C5- and C5′-positions were designed and synthesized using two distinct strategies. Sixteen side-chain derivatives were then prepared from
4 and
6 by coupling with a wide variety of azides via click chemistry, and subjected to the cytotoxicity assay. Although almost all of the C5-substituted analogues exhibited no cytotoxicity, the C5′-substituted analogues showed modest cytotoxicity. These results showed that C5′ is more tolerant than C5 to structural modifications. The present SAR study will provide valuable information for designing new antillatoxin-based molecular probes for neuroscience research.
[Display omitted] |
| doi_str_mv | 10.1016/j.tet.2011.05.012 |
| format | Article |
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1, a cyclic lipopeptide, is known as an activator of voltage-gated sodium channels and exhibits potent neurotoxicity toward Neuro 2a mouse neuroblastoma cells. To investigate the biological effects of the side-chain structures at C5 and C5′ in detail, we planned SAR studies of C5- and C5′-modified antillatoxin analogues. To diversify the structures at the last step of the synthesis, two key intermediates
4 and
6 possessing terminal alkynes at the C5- and C5′-positions were designed and synthesized using two distinct strategies. Sixteen side-chain derivatives were then prepared from
4 and
6 by coupling with a wide variety of azides via click chemistry, and subjected to the cytotoxicity assay. Although almost all of the C5-substituted analogues exhibited no cytotoxicity, the C5′-substituted analogues showed modest cytotoxicity. These results showed that C5′ is more tolerant than C5 to structural modifications. The present SAR study will provide valuable information for designing new antillatoxin-based molecular probes for neuroscience research.
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1, a cyclic lipopeptide, is known as an activator of voltage-gated sodium channels and exhibits potent neurotoxicity toward Neuro 2a mouse neuroblastoma cells. To investigate the biological effects of the side-chain structures at C5 and C5′ in detail, we planned SAR studies of C5- and C5′-modified antillatoxin analogues. To diversify the structures at the last step of the synthesis, two key intermediates
4 and
6 possessing terminal alkynes at the C5- and C5′-positions were designed and synthesized using two distinct strategies. Sixteen side-chain derivatives were then prepared from
4 and
6 by coupling with a wide variety of azides via click chemistry, and subjected to the cytotoxicity assay. Although almost all of the C5-substituted analogues exhibited no cytotoxicity, the C5′-substituted analogues showed modest cytotoxicity. These results showed that C5′ is more tolerant than C5 to structural modifications. The present SAR study will provide valuable information for designing new antillatoxin-based molecular probes for neuroscience research.
[Display omitted]</description><subject>Alkynes</subject><subject>Bioactive</subject><subject>Biological activity</subject><subject>Channels</subject><subject>Chemistry</subject><subject>Derivatives</subject><subject>Exact sciences and technology</subject><subject>Heterocyclic compounds</subject><subject>Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings</subject><subject>Natural products</subject><subject>Neurotoxin</subject><subject>Organic chemistry</subject><subject>Peptides</subject><subject>Preparations and properties</subject><subject>Sodium</subject><subject>Strategy</subject><subject>Structure–activity relationship</subject><subject>Synthesis (chemistry)</subject><subject>Terminals</subject><subject>Total synthesis</subject><issn>0040-4020</issn><issn>1464-5416</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><recordid>eNp9kE1LAzEQhoMoWKs_wNteBC-7TjYfW_EkxY-C4EE9h2l2VlO2G03SYv31prR4lBwC4Zk37zyMnXOoOHB9tagSpaoGzitQFfD6gI241LJUkutDNgKQUEqo4ZidxLgAyGQtRmz2shnSB0UXCxzaYu5879-dxb6gNfYrTM4Phe-KFBz--J4yhZlYUdy-4pBc32Py3244ZUcd9pHO9veYvd3fvU4fy6fnh9n09qm0QkMqZa0Vgu7sROR6SiChFThHpVphr2EisaZ2rjrOpcDmup2Tltzmw63ouokSY3a5y_0M_iv3SGbpoqVcYyC_ioY3UupGNzVklO9QG3yMgTrzGdwSw8ZwMFttZmGyNrPVZkCZrC3PXOzjMWYNXcDBuvg3WEuZg1WTuZsdR3nXtaNgonU0WGpdIJtM690_v_wCWhiDAQ</recordid><startdate>20110902</startdate><enddate>20110902</enddate><creator>Goto, Ryosuke</creator><creator>Okura, Ken</creator><creator>Sakazaki, Hayato</creator><creator>Sugawara, Tatsuya</creator><creator>Matsuoka, Shigeru</creator><creator>Inoue, Masayuki</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>IQODW</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7SR</scope><scope>7U5</scope><scope>8BQ</scope><scope>8FD</scope><scope>JG9</scope><scope>L7M</scope></search><sort><creationdate>20110902</creationdate><title>Synthesis and biological evaluation of triazole analogues of antillatoxin</title><author>Goto, Ryosuke ; Okura, Ken ; Sakazaki, Hayato ; Sugawara, Tatsuya ; Matsuoka, Shigeru ; Inoue, Masayuki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c360t-4265a06fc8346453aeac3aba55d3c9084a2edb5f1143a79dbe641c1c11c3ff853</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Alkynes</topic><topic>Bioactive</topic><topic>Biological activity</topic><topic>Channels</topic><topic>Chemistry</topic><topic>Derivatives</topic><topic>Exact sciences and technology</topic><topic>Heterocyclic compounds</topic><topic>Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings</topic><topic>Natural products</topic><topic>Neurotoxin</topic><topic>Organic chemistry</topic><topic>Peptides</topic><topic>Preparations and properties</topic><topic>Sodium</topic><topic>Strategy</topic><topic>Structure–activity relationship</topic><topic>Synthesis (chemistry)</topic><topic>Terminals</topic><topic>Total synthesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Goto, Ryosuke</creatorcontrib><creatorcontrib>Okura, Ken</creatorcontrib><creatorcontrib>Sakazaki, Hayato</creatorcontrib><creatorcontrib>Sugawara, Tatsuya</creatorcontrib><creatorcontrib>Matsuoka, Shigeru</creatorcontrib><creatorcontrib>Inoue, Masayuki</creatorcontrib><collection>Pascal-Francis</collection><collection>CrossRef</collection><collection>Engineered Materials Abstracts</collection><collection>Solid State and Superconductivity Abstracts</collection><collection>METADEX</collection><collection>Technology Research Database</collection><collection>Materials Research Database</collection><collection>Advanced Technologies Database with Aerospace</collection><jtitle>Tetrahedron</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Goto, Ryosuke</au><au>Okura, Ken</au><au>Sakazaki, Hayato</au><au>Sugawara, Tatsuya</au><au>Matsuoka, Shigeru</au><au>Inoue, Masayuki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and biological evaluation of triazole analogues of antillatoxin</atitle><jtitle>Tetrahedron</jtitle><date>2011-09-02</date><risdate>2011</risdate><volume>67</volume><issue>35</issue><spage>6659</spage><epage>6672</epage><pages>6659-6672</pages><issn>0040-4020</issn><eissn>1464-5416</eissn><coden>TETRAB</coden><abstract>Antillatoxin
1, a cyclic lipopeptide, is known as an activator of voltage-gated sodium channels and exhibits potent neurotoxicity toward Neuro 2a mouse neuroblastoma cells. To investigate the biological effects of the side-chain structures at C5 and C5′ in detail, we planned SAR studies of C5- and C5′-modified antillatoxin analogues. To diversify the structures at the last step of the synthesis, two key intermediates
4 and
6 possessing terminal alkynes at the C5- and C5′-positions were designed and synthesized using two distinct strategies. Sixteen side-chain derivatives were then prepared from
4 and
6 by coupling with a wide variety of azides via click chemistry, and subjected to the cytotoxicity assay. Although almost all of the C5-substituted analogues exhibited no cytotoxicity, the C5′-substituted analogues showed modest cytotoxicity. These results showed that C5′ is more tolerant than C5 to structural modifications. The present SAR study will provide valuable information for designing new antillatoxin-based molecular probes for neuroscience research.
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| source | ScienceDirect Journals (5 years ago - present) |
| subjects | Alkynes Bioactive Biological activity Channels Chemistry Derivatives Exact sciences and technology Heterocyclic compounds Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings Natural products Neurotoxin Organic chemistry Peptides Preparations and properties Sodium Strategy Structure–activity relationship Synthesis (chemistry) Terminals Total synthesis |
| title | Synthesis and biological evaluation of triazole analogues of antillatoxin |
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