Mechanisms of action and structure-activity relationships of cytotoxic flavokawain derivatives
[Display omitted] 22 Flavokawain derivatives (FKd) were obtained by one step syntheses in order to conduct a SAR study to understand the structural requirements for optimum and selective cytotoxicity. FKd and natural flavokawains A and B found into kava, a South Pacific traditional beverage, were ev...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2017-03, Vol.25 (6), p.1817-1829 |
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| creator | Thieury, Charlotte Lebouvier, Nicolas Le Guével, Rémy Barguil, Yann Herbette, Gaëtan Antheaume, Cyril Hnawia, Edouard Asakawa, Yoshinori Nour, Mohammed Guillaudeux, Thierry |
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22 Flavokawain derivatives (FKd) were obtained by one step syntheses in order to conduct a SAR study to understand the structural requirements for optimum and selective cytotoxicity. FKd and natural flavokawains A and B found into kava, a South Pacific traditional beverage, were evaluated against nine cancer and one healthy cell lines. The targeted cell cycle phases as well as the effects on the induction of apoptosis and cell cycle protein levels were investigated. Therapeutic improvements (more activity and selectivity) were achieved with FKd compared to natural flavokawains and notably with the 2′,3,4′,6′-tetramethoxychalcone (FKd 19). FKd induced a G1/S arrest on p53 wild-type cells and an M arrest on p53 mutant-type, via the up-regulation of p21 and cyclin B1 proteins, followed by apoptosis. Moreover, FKd exhibited a 24h-effect on Akt/mTor normal cells versus a 48h-effect on Akt/mTor up-regulated cells. The SAR study resulted in the conclusion that trimethoxy A-ring allowed the best compromise between cytotoxicity and selectivity, as well as the substitution of the meta position on the B-ring and the use of halogens substituents. |
| doi_str_mv | 10.1016/j.bmc.2017.01.049 |
| format | Article |
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22 Flavokawain derivatives (FKd) were obtained by one step syntheses in order to conduct a SAR study to understand the structural requirements for optimum and selective cytotoxicity. FKd and natural flavokawains A and B found into kava, a South Pacific traditional beverage, were evaluated against nine cancer and one healthy cell lines. The targeted cell cycle phases as well as the effects on the induction of apoptosis and cell cycle protein levels were investigated. Therapeutic improvements (more activity and selectivity) were achieved with FKd compared to natural flavokawains and notably with the 2′,3,4′,6′-tetramethoxychalcone (FKd 19). FKd induced a G1/S arrest on p53 wild-type cells and an M arrest on p53 mutant-type, via the up-regulation of p21 and cyclin B1 proteins, followed by apoptosis. Moreover, FKd exhibited a 24h-effect on Akt/mTor normal cells versus a 48h-effect on Akt/mTor up-regulated cells. The SAR study resulted in the conclusion that trimethoxy A-ring allowed the best compromise between cytotoxicity and selectivity, as well as the substitution of the meta position on the B-ring and the use of halogens substituents.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2017.01.049</identifier><identifier>PMID: 28214231</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Akt/mTor ; Apoptosis ; Cancer ; Carbon-13 Magnetic Resonance Spectroscopy ; Cell Line ; Cell Line, Tumor ; Chalcone - analogs & derivatives ; Chalcone - chemistry ; Chalcone - pharmacology ; Chemical Sciences ; Cytotoxic ; Drug Screening Assays, Antitumor ; Flavokawain ; Flavonoids - chemistry ; Flavonoids - pharmacology ; Humans ; Life Sciences ; Medicinal Chemistry ; P53 ; Pharmaceutical sciences ; Pharmacology ; Proton Magnetic Resonance Spectroscopy ; Spectrometry, Mass, Electrospray Ionization ; Structure activity relationships ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry, 2017-03, Vol.25 (6), p.1817-1829</ispartof><rights>2017 Elsevier Ltd</rights><rights>Copyright © 2017 Elsevier Ltd. All rights reserved.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c496t-465ef2a8638eb29902a4f6eb615810872f08b2834326af4750b19fe45760af353</citedby><cites>FETCH-LOGICAL-c496t-465ef2a8638eb29902a4f6eb615810872f08b2834326af4750b19fe45760af353</cites><orcidid>0000-0002-3939-409X ; 0000-0003-2280-7545</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmc.2017.01.049$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,778,782,883,3539,27907,27908,45978</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28214231$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://univ-rennes.hal.science/hal-01485126$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Thieury, Charlotte</creatorcontrib><creatorcontrib>Lebouvier, Nicolas</creatorcontrib><creatorcontrib>Le Guével, Rémy</creatorcontrib><creatorcontrib>Barguil, Yann</creatorcontrib><creatorcontrib>Herbette, Gaëtan</creatorcontrib><creatorcontrib>Antheaume, Cyril</creatorcontrib><creatorcontrib>Hnawia, Edouard</creatorcontrib><creatorcontrib>Asakawa, Yoshinori</creatorcontrib><creatorcontrib>Nour, Mohammed</creatorcontrib><creatorcontrib>Guillaudeux, Thierry</creatorcontrib><title>Mechanisms of action and structure-activity relationships of cytotoxic flavokawain derivatives</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>[Display omitted]
22 Flavokawain derivatives (FKd) were obtained by one step syntheses in order to conduct a SAR study to understand the structural requirements for optimum and selective cytotoxicity. FKd and natural flavokawains A and B found into kava, a South Pacific traditional beverage, were evaluated against nine cancer and one healthy cell lines. The targeted cell cycle phases as well as the effects on the induction of apoptosis and cell cycle protein levels were investigated. Therapeutic improvements (more activity and selectivity) were achieved with FKd compared to natural flavokawains and notably with the 2′,3,4′,6′-tetramethoxychalcone (FKd 19). FKd induced a G1/S arrest on p53 wild-type cells and an M arrest on p53 mutant-type, via the up-regulation of p21 and cyclin B1 proteins, followed by apoptosis. Moreover, FKd exhibited a 24h-effect on Akt/mTor normal cells versus a 48h-effect on Akt/mTor up-regulated cells. The SAR study resulted in the conclusion that trimethoxy A-ring allowed the best compromise between cytotoxicity and selectivity, as well as the substitution of the meta position on the B-ring and the use of halogens substituents.</description><subject>Akt/mTor</subject><subject>Apoptosis</subject><subject>Cancer</subject><subject>Carbon-13 Magnetic Resonance Spectroscopy</subject><subject>Cell Line</subject><subject>Cell Line, Tumor</subject><subject>Chalcone - analogs & derivatives</subject><subject>Chalcone - chemistry</subject><subject>Chalcone - pharmacology</subject><subject>Chemical Sciences</subject><subject>Cytotoxic</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Flavokawain</subject><subject>Flavonoids - chemistry</subject><subject>Flavonoids - pharmacology</subject><subject>Humans</subject><subject>Life Sciences</subject><subject>Medicinal Chemistry</subject><subject>P53</subject><subject>Pharmaceutical sciences</subject><subject>Pharmacology</subject><subject>Proton Magnetic Resonance Spectroscopy</subject><subject>Spectrometry, Mass, Electrospray Ionization</subject><subject>Structure activity relationships</subject><subject>Structure-Activity Relationship</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcFu1DAQhi1ERZfCA3BBOcIhweM4Xlucqgoo0qJe2iuW44y1XpJ4sZ3Avj0JW3rkNNLMN99I8xPyBmgFFMSHQ9UOtmIUthWFinL1jGyAC17WtYLnZEOVkCWVSlySlykdKKWMK3hBLplkwFkNG_L9G9q9GX0aUhFcYWz2YSzM2BUpx8nmKWK5NmefT0XE3qzztPfHv7g95ZDDb28L15s5_DC_jB-LDqOfF3DG9IpcONMnfP1Yr8jD50_3N7fl7u7L15vrXWm5ErnkokHHjBS1xJYpRZnhTmAroJFA5ZY5Klsma14zYRzfNrQF5ZA3W0GNq5v6irw_e_em18foBxNPOhivb693eu1R4LIBJmZY2Hdn9hjDzwlT1oNPFvvejBimpEEKpYRQfNXCGbUxpBTRPbmB6jUCfdBLBHqNYDmhlwiWnbeP-qkdsHva-PfzBfh4BnB5yOwx6mQ9jhY7H9Fm3QX_H_0f8S2WqQ</recordid><startdate>20170315</startdate><enddate>20170315</enddate><creator>Thieury, Charlotte</creator><creator>Lebouvier, Nicolas</creator><creator>Le Guével, Rémy</creator><creator>Barguil, Yann</creator><creator>Herbette, Gaëtan</creator><creator>Antheaume, Cyril</creator><creator>Hnawia, Edouard</creator><creator>Asakawa, Yoshinori</creator><creator>Nour, Mohammed</creator><creator>Guillaudeux, Thierry</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>1XC</scope><scope>VOOES</scope><orcidid>https://orcid.org/0000-0002-3939-409X</orcidid><orcidid>https://orcid.org/0000-0003-2280-7545</orcidid></search><sort><creationdate>20170315</creationdate><title>Mechanisms of action and structure-activity relationships of cytotoxic flavokawain derivatives</title><author>Thieury, Charlotte ; Lebouvier, Nicolas ; Le Guével, Rémy ; Barguil, Yann ; Herbette, Gaëtan ; Antheaume, Cyril ; Hnawia, Edouard ; Asakawa, Yoshinori ; Nour, Mohammed ; Guillaudeux, Thierry</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c496t-465ef2a8638eb29902a4f6eb615810872f08b2834326af4750b19fe45760af353</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Akt/mTor</topic><topic>Apoptosis</topic><topic>Cancer</topic><topic>Carbon-13 Magnetic Resonance Spectroscopy</topic><topic>Cell Line</topic><topic>Cell Line, Tumor</topic><topic>Chalcone - analogs & derivatives</topic><topic>Chalcone - chemistry</topic><topic>Chalcone - pharmacology</topic><topic>Chemical Sciences</topic><topic>Cytotoxic</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Flavokawain</topic><topic>Flavonoids - chemistry</topic><topic>Flavonoids - pharmacology</topic><topic>Humans</topic><topic>Life Sciences</topic><topic>Medicinal Chemistry</topic><topic>P53</topic><topic>Pharmaceutical sciences</topic><topic>Pharmacology</topic><topic>Proton Magnetic Resonance Spectroscopy</topic><topic>Spectrometry, Mass, Electrospray Ionization</topic><topic>Structure activity relationships</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Thieury, Charlotte</creatorcontrib><creatorcontrib>Lebouvier, Nicolas</creatorcontrib><creatorcontrib>Le Guével, Rémy</creatorcontrib><creatorcontrib>Barguil, Yann</creatorcontrib><creatorcontrib>Herbette, Gaëtan</creatorcontrib><creatorcontrib>Antheaume, Cyril</creatorcontrib><creatorcontrib>Hnawia, Edouard</creatorcontrib><creatorcontrib>Asakawa, Yoshinori</creatorcontrib><creatorcontrib>Nour, Mohammed</creatorcontrib><creatorcontrib>Guillaudeux, Thierry</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Thieury, Charlotte</au><au>Lebouvier, Nicolas</au><au>Le Guével, Rémy</au><au>Barguil, Yann</au><au>Herbette, Gaëtan</au><au>Antheaume, Cyril</au><au>Hnawia, Edouard</au><au>Asakawa, Yoshinori</au><au>Nour, Mohammed</au><au>Guillaudeux, Thierry</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mechanisms of action and structure-activity relationships of cytotoxic flavokawain derivatives</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2017-03-15</date><risdate>2017</risdate><volume>25</volume><issue>6</issue><spage>1817</spage><epage>1829</epage><pages>1817-1829</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>[Display omitted]
22 Flavokawain derivatives (FKd) were obtained by one step syntheses in order to conduct a SAR study to understand the structural requirements for optimum and selective cytotoxicity. FKd and natural flavokawains A and B found into kava, a South Pacific traditional beverage, were evaluated against nine cancer and one healthy cell lines. The targeted cell cycle phases as well as the effects on the induction of apoptosis and cell cycle protein levels were investigated. Therapeutic improvements (more activity and selectivity) were achieved with FKd compared to natural flavokawains and notably with the 2′,3,4′,6′-tetramethoxychalcone (FKd 19). FKd induced a G1/S arrest on p53 wild-type cells and an M arrest on p53 mutant-type, via the up-regulation of p21 and cyclin B1 proteins, followed by apoptosis. Moreover, FKd exhibited a 24h-effect on Akt/mTor normal cells versus a 48h-effect on Akt/mTor up-regulated cells. The SAR study resulted in the conclusion that trimethoxy A-ring allowed the best compromise between cytotoxicity and selectivity, as well as the substitution of the meta position on the B-ring and the use of halogens substituents.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>28214231</pmid><doi>10.1016/j.bmc.2017.01.049</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-3939-409X</orcidid><orcidid>https://orcid.org/0000-0003-2280-7545</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Akt/mTor Apoptosis Cancer Carbon-13 Magnetic Resonance Spectroscopy Cell Line Cell Line, Tumor Chalcone - analogs & derivatives Chalcone - chemistry Chalcone - pharmacology Chemical Sciences Cytotoxic Drug Screening Assays, Antitumor Flavokawain Flavonoids - chemistry Flavonoids - pharmacology Humans Life Sciences Medicinal Chemistry P53 Pharmaceutical sciences Pharmacology Proton Magnetic Resonance Spectroscopy Spectrometry, Mass, Electrospray Ionization Structure activity relationships Structure-Activity Relationship |
| title | Mechanisms of action and structure-activity relationships of cytotoxic flavokawain derivatives |
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