2-[(3-Methoxyphenylethyl)phenoxy]-Based ABCB1 Inhibitors: Effect of Different Basic Side-Chains on Their Biological Properties
Recently, 2-[(3-methoxyphenylethyl)phenoxy]-moiety has been selected for the design and synthesis of new small ABCB1 inhibitors. In the present paper, this moiety has been linked through a spacer of 2−5 carbon atoms to the nitrogen of three different basic nuclei such as: (i) N-4-arylpiperazine, (ii...
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| Veröffentlicht in: | Journal of medicinal chemistry 2008-12, Vol.51 (23), p.7602-7613 |
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| container_title | Journal of medicinal chemistry |
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| creator | Colabufo, Nicola Antonio Berardi, Francesco Perrone, Roberto Rapposelli, Simona Digiacomo, Maria Vanni, Michael Balsamo, Aldo |
| description | Recently, 2-[(3-methoxyphenylethyl)phenoxy]-moiety has been selected for the design and synthesis of new small ABCB1 inhibitors. In the present paper, this moiety has been linked through a spacer of 2−5 carbon atoms to the nitrogen of three different basic nuclei such as: (i) N-4-arylpiperazine, (ii) N-4-methylpiperazine, and (iii) 6,7-dimethoxytetrahydroisoquinoline. The results demonstrated that all the selected basic nuclei were well tolerated and that, globally, the best inhibitory activity for each series was obtained when the spacer between the 2-[(3-methoxyphenylethyl)phenoxy] moiety and the basic nucleus consisted of a four-carbon chain. Among the synthesized compounds, N-4-methylpiperazine- 10c (IC50 = 0.15 μM) and tetrahydroisoquinoline-derivatives 11c (IC50 = 0.08 μM) with the spacer n = 4 for both series, displayed the best potency to inhibit ABCB1 activity. Moreover, for each compound, the ABCB1 interacting mechanism has been evaluated by three combined biological assays. N-4-methylpiperazine- (10a−d) and tetrahydroisoquinoline- (11a−d) derivatives were Cyclosporin A-like ABCB1 nontransported substrates. |
| doi_str_mv | 10.1021/jm800928j |
| format | Article |
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In the present paper, this moiety has been linked through a spacer of 2−5 carbon atoms to the nitrogen of three different basic nuclei such as: (i) N-4-arylpiperazine, (ii) N-4-methylpiperazine, and (iii) 6,7-dimethoxytetrahydroisoquinoline. The results demonstrated that all the selected basic nuclei were well tolerated and that, globally, the best inhibitory activity for each series was obtained when the spacer between the 2-[(3-methoxyphenylethyl)phenoxy] moiety and the basic nucleus consisted of a four-carbon chain. Among the synthesized compounds, N-4-methylpiperazine- 10c (IC50 = 0.15 μM) and tetrahydroisoquinoline-derivatives 11c (IC50 = 0.08 μM) with the spacer n = 4 for both series, displayed the best potency to inhibit ABCB1 activity. Moreover, for each compound, the ABCB1 interacting mechanism has been evaluated by three combined biological assays. N-4-methylpiperazine- (10a−d) and tetrahydroisoquinoline- (11a−d) derivatives were Cyclosporin A-like ABCB1 nontransported substrates.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm800928j</identifier><identifier>PMID: 19053888</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Columbus, OH: American Chemical Society</publisher><subject>Antineoplastic agents ; ATP Binding Cassette Transporter, Sub-Family B ; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors ; Binding Sites - drug effects ; Biological and medical sciences ; Caco-2 Cells ; Cell Membrane Permeability - drug effects ; Dose-Response Relationship, Drug ; Drug Design ; Fluoresceins - chemistry ; Fluoresceins - metabolism ; General aspects ; Humans ; Medical sciences ; Molecular Structure ; Pharmacology. Drug treatments ; Phenyl Ethers - chemical synthesis ; Phenyl Ethers - chemistry ; Phenyl Ethers - pharmacology ; Receptor, Serotonin, 5-HT1A - drug effects ; Receptors, Dopamine D2 - drug effects ; Stereoisomerism ; Structure-Activity Relationship ; Tumor Cells, Cultured</subject><ispartof>Journal of medicinal chemistry, 2008-12, Vol.51 (23), p.7602-7613</ispartof><rights>Copyright © 2008 American Chemical Society</rights><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a381t-6387dd0dcd1a8aa2c0095987c19f42a2ac51729bb13d220259c666aa0e00c9083</citedby><cites>FETCH-LOGICAL-a381t-6387dd0dcd1a8aa2c0095987c19f42a2ac51729bb13d220259c666aa0e00c9083</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm800928j$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm800928j$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20965732$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19053888$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Colabufo, Nicola Antonio</creatorcontrib><creatorcontrib>Berardi, Francesco</creatorcontrib><creatorcontrib>Perrone, Roberto</creatorcontrib><creatorcontrib>Rapposelli, Simona</creatorcontrib><creatorcontrib>Digiacomo, Maria</creatorcontrib><creatorcontrib>Vanni, Michael</creatorcontrib><creatorcontrib>Balsamo, Aldo</creatorcontrib><title>2-[(3-Methoxyphenylethyl)phenoxy]-Based ABCB1 Inhibitors: Effect of Different Basic Side-Chains on Their Biological Properties</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Recently, 2-[(3-methoxyphenylethyl)phenoxy]-moiety has been selected for the design and synthesis of new small ABCB1 inhibitors. In the present paper, this moiety has been linked through a spacer of 2−5 carbon atoms to the nitrogen of three different basic nuclei such as: (i) N-4-arylpiperazine, (ii) N-4-methylpiperazine, and (iii) 6,7-dimethoxytetrahydroisoquinoline. The results demonstrated that all the selected basic nuclei were well tolerated and that, globally, the best inhibitory activity for each series was obtained when the spacer between the 2-[(3-methoxyphenylethyl)phenoxy] moiety and the basic nucleus consisted of a four-carbon chain. Among the synthesized compounds, N-4-methylpiperazine- 10c (IC50 = 0.15 μM) and tetrahydroisoquinoline-derivatives 11c (IC50 = 0.08 μM) with the spacer n = 4 for both series, displayed the best potency to inhibit ABCB1 activity. Moreover, for each compound, the ABCB1 interacting mechanism has been evaluated by three combined biological assays. N-4-methylpiperazine- (10a−d) and tetrahydroisoquinoline- (11a−d) derivatives were Cyclosporin A-like ABCB1 nontransported substrates.</description><subject>Antineoplastic agents</subject><subject>ATP Binding Cassette Transporter, Sub-Family B</subject><subject>ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors</subject><subject>Binding Sites - drug effects</subject><subject>Biological and medical sciences</subject><subject>Caco-2 Cells</subject><subject>Cell Membrane Permeability - drug effects</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Design</subject><subject>Fluoresceins - chemistry</subject><subject>Fluoresceins - metabolism</subject><subject>General aspects</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Molecular Structure</subject><subject>Pharmacology. Drug treatments</subject><subject>Phenyl Ethers - chemical synthesis</subject><subject>Phenyl Ethers - chemistry</subject><subject>Phenyl Ethers - pharmacology</subject><subject>Receptor, Serotonin, 5-HT1A - drug effects</subject><subject>Receptors, Dopamine D2 - drug effects</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>Tumor Cells, Cultured</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0MFuEzEQBmALgWhoOfACyBcqejAdj7O7NrcmbaFSgaKEE0KW4_WyDpt1am-k5sKz4ypReuHkX_ankecn5A2HDxyQny9XEkChXD4jI14gsLGE8XMyAkBkWKI4Iq9SWgKA4ChekiOuoBBSyhH5i-zne8G-uKEND9t16_ptl_O2O3vM-eoXm5jkanoxmU44velbv_BDiOkjvWoaZwcaGnrpc4yuH2i23tKZrx2btsb3iYaezlvnI5340IXf3pqO3sWwdnHwLp2QF43pknu9P4_Jj-ur-fQzu_326WZ6ccuMkHxgpZBVXUNta26kMWjzuoWSleWqGaNBYwteoVosuKgRAQtly7I0BhyAVSDFMTndzV3HcL9xadArn6zrOtO7sEm6VLIsACHDsx20MaQUXaPX0a9M3GoO-rFsfSg727f7oZvFytVPct9uBu_2wKS8dxNNb306OARVFpXA7NjO-TS4h8O7iX90WYmq0PO7mf6K38czCTOtnuYam_QybGKfu_vPB_8ByBehDA</recordid><startdate>20081211</startdate><enddate>20081211</enddate><creator>Colabufo, Nicola Antonio</creator><creator>Berardi, Francesco</creator><creator>Perrone, Roberto</creator><creator>Rapposelli, Simona</creator><creator>Digiacomo, Maria</creator><creator>Vanni, Michael</creator><creator>Balsamo, Aldo</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</scope><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></search><sort><creationdate>20081211</creationdate><title>2-[(3-Methoxyphenylethyl)phenoxy]-Based ABCB1 Inhibitors: Effect of Different Basic Side-Chains on Their Biological Properties</title><author>Colabufo, Nicola Antonio ; Berardi, Francesco ; Perrone, Roberto ; Rapposelli, Simona ; Digiacomo, Maria ; Vanni, Michael ; Balsamo, Aldo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a381t-6387dd0dcd1a8aa2c0095987c19f42a2ac51729bb13d220259c666aa0e00c9083</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Antineoplastic agents</topic><topic>ATP Binding Cassette Transporter, Sub-Family B</topic><topic>ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors</topic><topic>Binding Sites - drug effects</topic><topic>Biological and medical sciences</topic><topic>Caco-2 Cells</topic><topic>Cell Membrane Permeability - drug effects</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Design</topic><topic>Fluoresceins - chemistry</topic><topic>Fluoresceins - metabolism</topic><topic>General aspects</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Molecular Structure</topic><topic>Pharmacology. Drug treatments</topic><topic>Phenyl Ethers - chemical synthesis</topic><topic>Phenyl Ethers - chemistry</topic><topic>Phenyl Ethers - pharmacology</topic><topic>Receptor, Serotonin, 5-HT1A - drug effects</topic><topic>Receptors, Dopamine D2 - drug effects</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Colabufo, Nicola Antonio</creatorcontrib><creatorcontrib>Berardi, Francesco</creatorcontrib><creatorcontrib>Perrone, Roberto</creatorcontrib><creatorcontrib>Rapposelli, Simona</creatorcontrib><creatorcontrib>Digiacomo, Maria</creatorcontrib><creatorcontrib>Vanni, Michael</creatorcontrib><creatorcontrib>Balsamo, Aldo</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><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><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Colabufo, Nicola Antonio</au><au>Berardi, Francesco</au><au>Perrone, Roberto</au><au>Rapposelli, Simona</au><au>Digiacomo, Maria</au><au>Vanni, Michael</au><au>Balsamo, Aldo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>2-[(3-Methoxyphenylethyl)phenoxy]-Based ABCB1 Inhibitors: Effect of Different Basic Side-Chains on Their Biological Properties</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2008-12-11</date><risdate>2008</risdate><volume>51</volume><issue>23</issue><spage>7602</spage><epage>7613</epage><pages>7602-7613</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Recently, 2-[(3-methoxyphenylethyl)phenoxy]-moiety has been selected for the design and synthesis of new small ABCB1 inhibitors. In the present paper, this moiety has been linked through a spacer of 2−5 carbon atoms to the nitrogen of three different basic nuclei such as: (i) N-4-arylpiperazine, (ii) N-4-methylpiperazine, and (iii) 6,7-dimethoxytetrahydroisoquinoline. The results demonstrated that all the selected basic nuclei were well tolerated and that, globally, the best inhibitory activity for each series was obtained when the spacer between the 2-[(3-methoxyphenylethyl)phenoxy] moiety and the basic nucleus consisted of a four-carbon chain. Among the synthesized compounds, N-4-methylpiperazine- 10c (IC50 = 0.15 μM) and tetrahydroisoquinoline-derivatives 11c (IC50 = 0.08 μM) with the spacer n = 4 for both series, displayed the best potency to inhibit ABCB1 activity. Moreover, for each compound, the ABCB1 interacting mechanism has been evaluated by three combined biological assays. N-4-methylpiperazine- (10a−d) and tetrahydroisoquinoline- (11a−d) derivatives were Cyclosporin A-like ABCB1 nontransported substrates.</abstract><cop>Columbus, OH</cop><pub>American Chemical Society</pub><pmid>19053888</pmid><doi>10.1021/jm800928j</doi><tpages>12</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2008-12, Vol.51 (23), p.7602-7613 |
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| source | MEDLINE; ACS_美国化学学会期刊（与NSTL共建） |
| subjects | Antineoplastic agents ATP Binding Cassette Transporter, Sub-Family B ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors Binding Sites - drug effects Biological and medical sciences Caco-2 Cells Cell Membrane Permeability - drug effects Dose-Response Relationship, Drug Drug Design Fluoresceins - chemistry Fluoresceins - metabolism General aspects Humans Medical sciences Molecular Structure Pharmacology. Drug treatments Phenyl Ethers - chemical synthesis Phenyl Ethers - chemistry Phenyl Ethers - pharmacology Receptor, Serotonin, 5-HT1A - drug effects Receptors, Dopamine D2 - drug effects Stereoisomerism Structure-Activity Relationship Tumor Cells, Cultured |
| title | 2-[(3-Methoxyphenylethyl)phenoxy]-Based ABCB1 Inhibitors: Effect of Different Basic Side-Chains on Their Biological Properties |
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