Relationship between structure and P-glycoprotein inhibitory activity of dimeric peptides related to the Dmt-Tic pharmacophore
Relationships between structure and P-gp inhibitory activity of dimeric peptides related to the opioid Dmt-Tic pharmacophore were investigated. To develop novel inhibitors of P-glycoprotein (P-gp), dimeric peptides related to an opioid peptide containing the Dmt-Tic pharmacophore were synthesized an...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2012-03, Vol.22 (6), p.2192-2194 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Ambo, Akihiro Ohkatsu, Hiromichi Minamizawa, Motoko Watanabe, Hideko Sugawara, Shigeki Nitta, Kazuo Tsuda, Yuko Okada, Yoshio Sasaki, Yusuke |
| description | Relationships between structure and P-gp inhibitory activity of dimeric peptides related to the opioid Dmt-Tic pharmacophore were investigated.
To develop novel inhibitors of P-glycoprotein (P-gp), dimeric peptides related to an opioid peptide containing the Dmt-Tic pharmacophore were synthesized and their P-gp inhibitory activities were analyzed. Of the 30 analogs synthesized, Nα,Nε-[(CH3)2Mle-Tic]2Lys-NH2 and its d-Lys analog were found to exhibit potent P-gp inhibitory activity, twice that of verapamil, in doxorubicin-resistant K562 cells. Structure–activity studies indicated that the correct hydrophobicity and spacer length between two aromatic rings are important structural elements in this series of analogs for inhibition of P-gp. |
| doi_str_mv | 10.1016/j.bmcl.2012.01.107 |
| format | Article |
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To develop novel inhibitors of P-glycoprotein (P-gp), dimeric peptides related to an opioid peptide containing the Dmt-Tic pharmacophore were synthesized and their P-gp inhibitory activities were analyzed. Of the 30 analogs synthesized, Nα,Nε-[(CH3)2Mle-Tic]2Lys-NH2 and its d-Lys analog were found to exhibit potent P-gp inhibitory activity, twice that of verapamil, in doxorubicin-resistant K562 cells. Structure–activity studies indicated that the correct hydrophobicity and spacer length between two aromatic rings are important structural elements in this series of analogs for inhibition of P-gp.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2012.01.107</identifier><identifier>PMID: 22365753</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - pharmacology ; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors ; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism ; Biological and medical sciences ; Biological Transport ; Dimeric peptide analogs ; Dipeptides - chemical synthesis ; Dipeptides - pharmacology ; Dmt-Tic pharmacophore ; Doxorubicin - pharmacology ; Drug Resistance, Neoplasm - drug effects ; Humans ; K562 Cells ; Medical sciences ; P-glycoprotein inhibitory activity ; Pharmacology. Drug treatments ; Solid-Phase Synthesis Techniques ; Structure-Activity Relationship ; Tetrahydroisoquinolines - chemical synthesis ; Tetrahydroisoquinolines - pharmacology ; Verapamil - pharmacology</subject><ispartof>Bioorganic & medicinal chemistry letters, 2012-03, Vol.22 (6), p.2192-2194</ispartof><rights>2012 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2012 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c483t-b0bee2afd5609efe46672a48223ff3856f86c428b1e52c47f8567d50f5d8a1a3</citedby><cites>FETCH-LOGICAL-c483t-b0bee2afd5609efe46672a48223ff3856f86c428b1e52c47f8567d50f5d8a1a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2012.01.107$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>315,781,785,3551,27928,27929,45999</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25696936$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22365753$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ambo, Akihiro</creatorcontrib><creatorcontrib>Ohkatsu, Hiromichi</creatorcontrib><creatorcontrib>Minamizawa, Motoko</creatorcontrib><creatorcontrib>Watanabe, Hideko</creatorcontrib><creatorcontrib>Sugawara, Shigeki</creatorcontrib><creatorcontrib>Nitta, Kazuo</creatorcontrib><creatorcontrib>Tsuda, Yuko</creatorcontrib><creatorcontrib>Okada, Yoshio</creatorcontrib><creatorcontrib>Sasaki, Yusuke</creatorcontrib><title>Relationship between structure and P-glycoprotein inhibitory activity of dimeric peptides related to the Dmt-Tic pharmacophore</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Relationships between structure and P-gp inhibitory activity of dimeric peptides related to the opioid Dmt-Tic pharmacophore were investigated.
To develop novel inhibitors of P-glycoprotein (P-gp), dimeric peptides related to an opioid peptide containing the Dmt-Tic pharmacophore were synthesized and their P-gp inhibitory activities were analyzed. Of the 30 analogs synthesized, Nα,Nε-[(CH3)2Mle-Tic]2Lys-NH2 and its d-Lys analog were found to exhibit potent P-gp inhibitory activity, twice that of verapamil, in doxorubicin-resistant K562 cells. Structure–activity studies indicated that the correct hydrophobicity and spacer length between two aromatic rings are important structural elements in this series of analogs for inhibition of P-gp.</description><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors</subject><subject>ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism</subject><subject>Biological and medical sciences</subject><subject>Biological Transport</subject><subject>Dimeric peptide analogs</subject><subject>Dipeptides - chemical synthesis</subject><subject>Dipeptides - pharmacology</subject><subject>Dmt-Tic pharmacophore</subject><subject>Doxorubicin - pharmacology</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Humans</subject><subject>K562 Cells</subject><subject>Medical sciences</subject><subject>P-glycoprotein inhibitory activity</subject><subject>Pharmacology. Drug treatments</subject><subject>Solid-Phase Synthesis Techniques</subject><subject>Structure-Activity Relationship</subject><subject>Tetrahydroisoquinolines - chemical synthesis</subject><subject>Tetrahydroisoquinolines - pharmacology</subject><subject>Verapamil - pharmacology</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU2v1CAUhonReMerf8CFYWNcdQQKtE3cmOtnchONmYU7QuFgmbSlAr1mNv52aWbUna5IXh6ecM6L0FNK9pRQ-fK47ycz7hmhbE9oyZp7aEe55FXNibiPdqSTpGo7_vUKPUrpSAjlhPOH6IqxWopG1Dv08wuMOvswp8EvuIf8A2DGKcfV5DUC1rPFn6tv48mEJYYMfsZ-Hnzvc4gnrE32dz6fcHDY-gmiN3iBJXsLCcfNDBbngPMA-M2Uq8N2P-g46aIbQoTH6IHTY4Inl_MaHd69Pdx8qG4_vf948_q2Mrytc9WTHoBpZ4UkHTjgUjZM87bM4VzdCulaaThrewqCGd64EjVWECdsq6mur9GLs7bM8H2FlNXkk4Fx1DOENalOtrQRnDb_J5kUpCNNV0h2Jk0MKUVwaol-0vGkKFFbP-qotn7U1o8itGSb_tlFv_YT2D9PfhdSgOcXQCejRxf1bHz6ywnZya6WhXt15qBs7c5DVMl4mA1YH8FkZYP_1z9-AXh1sNA</recordid><startdate>20120315</startdate><enddate>20120315</enddate><creator>Ambo, Akihiro</creator><creator>Ohkatsu, Hiromichi</creator><creator>Minamizawa, Motoko</creator><creator>Watanabe, Hideko</creator><creator>Sugawara, Shigeki</creator><creator>Nitta, Kazuo</creator><creator>Tsuda, Yuko</creator><creator>Okada, Yoshio</creator><creator>Sasaki, Yusuke</creator><general>Elsevier Ltd</general><general>Elsevier</general><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><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20120315</creationdate><title>Relationship between structure and P-glycoprotein inhibitory activity of dimeric peptides related to the Dmt-Tic pharmacophore</title><author>Ambo, Akihiro ; Ohkatsu, Hiromichi ; Minamizawa, Motoko ; Watanabe, Hideko ; Sugawara, Shigeki ; Nitta, Kazuo ; Tsuda, Yuko ; Okada, Yoshio ; Sasaki, Yusuke</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c483t-b0bee2afd5609efe46672a48223ff3856f86c428b1e52c47f8567d50f5d8a1a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors</topic><topic>ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism</topic><topic>Biological and medical sciences</topic><topic>Biological Transport</topic><topic>Dimeric peptide analogs</topic><topic>Dipeptides - chemical synthesis</topic><topic>Dipeptides - pharmacology</topic><topic>Dmt-Tic pharmacophore</topic><topic>Doxorubicin - pharmacology</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Humans</topic><topic>K562 Cells</topic><topic>Medical sciences</topic><topic>P-glycoprotein inhibitory activity</topic><topic>Pharmacology. Drug treatments</topic><topic>Solid-Phase Synthesis Techniques</topic><topic>Structure-Activity Relationship</topic><topic>Tetrahydroisoquinolines - chemical synthesis</topic><topic>Tetrahydroisoquinolines - pharmacology</topic><topic>Verapamil - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ambo, Akihiro</creatorcontrib><creatorcontrib>Ohkatsu, Hiromichi</creatorcontrib><creatorcontrib>Minamizawa, Motoko</creatorcontrib><creatorcontrib>Watanabe, Hideko</creatorcontrib><creatorcontrib>Sugawara, Shigeki</creatorcontrib><creatorcontrib>Nitta, Kazuo</creatorcontrib><creatorcontrib>Tsuda, Yuko</creatorcontrib><creatorcontrib>Okada, Yoshio</creatorcontrib><creatorcontrib>Sasaki, Yusuke</creatorcontrib><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><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ambo, Akihiro</au><au>Ohkatsu, Hiromichi</au><au>Minamizawa, Motoko</au><au>Watanabe, Hideko</au><au>Sugawara, Shigeki</au><au>Nitta, Kazuo</au><au>Tsuda, Yuko</au><au>Okada, Yoshio</au><au>Sasaki, Yusuke</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Relationship between structure and P-glycoprotein inhibitory activity of dimeric peptides related to the Dmt-Tic pharmacophore</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2012-03-15</date><risdate>2012</risdate><volume>22</volume><issue>6</issue><spage>2192</spage><epage>2194</epage><pages>2192-2194</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Relationships between structure and P-gp inhibitory activity of dimeric peptides related to the opioid Dmt-Tic pharmacophore were investigated.
To develop novel inhibitors of P-glycoprotein (P-gp), dimeric peptides related to an opioid peptide containing the Dmt-Tic pharmacophore were synthesized and their P-gp inhibitory activities were analyzed. Of the 30 analogs synthesized, Nα,Nε-[(CH3)2Mle-Tic]2Lys-NH2 and its d-Lys analog were found to exhibit potent P-gp inhibitory activity, twice that of verapamil, in doxorubicin-resistant K562 cells. Structure–activity studies indicated that the correct hydrophobicity and spacer length between two aromatic rings are important structural elements in this series of analogs for inhibition of P-gp.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>22365753</pmid><doi>10.1016/j.bmcl.2012.01.107</doi><tpages>3</tpages></addata></record> |
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| subjects | Antineoplastic Agents - chemical synthesis Antineoplastic Agents - pharmacology ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism Biological and medical sciences Biological Transport Dimeric peptide analogs Dipeptides - chemical synthesis Dipeptides - pharmacology Dmt-Tic pharmacophore Doxorubicin - pharmacology Drug Resistance, Neoplasm - drug effects Humans K562 Cells Medical sciences P-glycoprotein inhibitory activity Pharmacology. Drug treatments Solid-Phase Synthesis Techniques Structure-Activity Relationship Tetrahydroisoquinolines - chemical synthesis Tetrahydroisoquinolines - pharmacology Verapamil - pharmacology |
| title | Relationship between structure and P-glycoprotein inhibitory activity of dimeric peptides related to the Dmt-Tic pharmacophore |
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