Design, synthesis and anticancer activity of constrained sphingolipid-phenoxazine/phenothiazine hybrid constructs targeting protein phosphatase 2A
[Display omitted] Inspired by the cytotoxicity of perphenazine toward cancer cells and its ability to activate the serine/threonine protein phosphatase 2A (PP2A), we prepared series of ether-carbon linked analogs of a constrained synthetic sphingolipid analog 3, known for its cytotoxicity, nutrient...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2019-09, Vol.29 (18), p.2681-2685 |
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| creator | Garsi, Jean-Baptiste Vece, Vito Sernissi, Lorenzo Auger-Morin, Catherine Hanessian, Stephen McCracken, Alison N. Selwan, Elizabeth Ramirez, Cuauhtemoc Dahal, Amogha Romdhane, Nadine Ben Finicle, Brendan T. Edinger, Aimee L. |
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Inspired by the cytotoxicity of perphenazine toward cancer cells and its ability to activate the serine/threonine protein phosphatase 2A (PP2A), we prepared series of ether-carbon linked analogs of a constrained synthetic sphingolipid analog 3, known for its cytotoxicity, nutrient transporter down-regulation and vacuolation properties, incorporating the tricyclic neuroleptics phenoxazine and phenothiazine to represent hybrid structures with possible synergistic cytotoxic activity. While the original activity of the lead compound 3 was diminished by fusion with the phenoxazine or phenothiazine tethered moieties, the corresponding 3-pyridyltetryl ether analog 10 showed cytotoxicity and nutrient transporter down-regulation similar to the lead compound 3, although it separated these PP2A-dependent phenotypes from that of vacuolation. |
| doi_str_mv | 10.1016/j.bmcl.2019.07.023 |
| format | Article |
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Inspired by the cytotoxicity of perphenazine toward cancer cells and its ability to activate the serine/threonine protein phosphatase 2A (PP2A), we prepared series of ether-carbon linked analogs of a constrained synthetic sphingolipid analog 3, known for its cytotoxicity, nutrient transporter down-regulation and vacuolation properties, incorporating the tricyclic neuroleptics phenoxazine and phenothiazine to represent hybrid structures with possible synergistic cytotoxic activity. While the original activity of the lead compound 3 was diminished by fusion with the phenoxazine or phenothiazine tethered moieties, the corresponding 3-pyridyltetryl ether analog 10 showed cytotoxicity and nutrient transporter down-regulation similar to the lead compound 3, although it separated these PP2A-dependent phenotypes from that of vacuolation.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2019.07.023</identifier><identifier>PMID: 31383588</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Cell Line ; Cell Survival - drug effects ; Cytotoxicity FL5.12 ; Dose-Response Relationship, Drug ; Drug Design ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Hybrid structures ; Mice ; Molecular Structure ; Nutrient transport down-regulation ; Oxazines - chemistry ; Oxazines - pharmacology ; Phenothiazines - chemistry ; Phenothiazines - pharmacology ; Protein Phosphatase 2 - antagonists & inhibitors ; Protein Phosphatase 2 - metabolism ; Sphingolipid ; Sphingolipids - chemistry ; Sphingolipids - pharmacology ; Structure-Activity Relationship ; Vacuolation</subject><ispartof>Bioorganic & medicinal chemistry letters, 2019-09, Vol.29 (18), p.2681-2685</ispartof><rights>2019</rights><rights>Copyright © 2019. Published by Elsevier Ltd.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c455t-898950732940c0a2b2b1f00198b04e35433f516bd6ec0ec1933e475be093cff03</citedby><cites>FETCH-LOGICAL-c455t-898950732940c0a2b2b1f00198b04e35433f516bd6ec0ec1933e475be093cff03</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.2019.07.023$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,315,781,785,886,3551,27929,27930,46000</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31383588$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Garsi, Jean-Baptiste</creatorcontrib><creatorcontrib>Vece, Vito</creatorcontrib><creatorcontrib>Sernissi, Lorenzo</creatorcontrib><creatorcontrib>Auger-Morin, Catherine</creatorcontrib><creatorcontrib>Hanessian, Stephen</creatorcontrib><creatorcontrib>McCracken, Alison N.</creatorcontrib><creatorcontrib>Selwan, Elizabeth</creatorcontrib><creatorcontrib>Ramirez, Cuauhtemoc</creatorcontrib><creatorcontrib>Dahal, Amogha</creatorcontrib><creatorcontrib>Romdhane, Nadine Ben</creatorcontrib><creatorcontrib>Finicle, Brendan T.</creatorcontrib><creatorcontrib>Edinger, Aimee L.</creatorcontrib><title>Design, synthesis and anticancer activity of constrained sphingolipid-phenoxazine/phenothiazine hybrid constructs targeting protein phosphatase 2A</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
Inspired by the cytotoxicity of perphenazine toward cancer cells and its ability to activate the serine/threonine protein phosphatase 2A (PP2A), we prepared series of ether-carbon linked analogs of a constrained synthetic sphingolipid analog 3, known for its cytotoxicity, nutrient transporter down-regulation and vacuolation properties, incorporating the tricyclic neuroleptics phenoxazine and phenothiazine to represent hybrid structures with possible synergistic cytotoxic activity. While the original activity of the lead compound 3 was diminished by fusion with the phenoxazine or phenothiazine tethered moieties, the corresponding 3-pyridyltetryl ether analog 10 showed cytotoxicity and nutrient transporter down-regulation similar to the lead compound 3, although it separated these PP2A-dependent phenotypes from that of vacuolation.</description><subject>Animals</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Cell Line</subject><subject>Cell Survival - drug effects</subject><subject>Cytotoxicity FL5.12</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Design</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Hybrid structures</subject><subject>Mice</subject><subject>Molecular Structure</subject><subject>Nutrient transport down-regulation</subject><subject>Oxazines - chemistry</subject><subject>Oxazines - pharmacology</subject><subject>Phenothiazines - chemistry</subject><subject>Phenothiazines - pharmacology</subject><subject>Protein Phosphatase 2 - antagonists & inhibitors</subject><subject>Protein Phosphatase 2 - metabolism</subject><subject>Sphingolipid</subject><subject>Sphingolipids - chemistry</subject><subject>Sphingolipids - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Vacuolation</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kd2KFDEQhYMo7rj6Al5IHsDurXTSfyDCsq4_sOCNgnchna6ermEmaZLs4PgYPvFmdtZFb7woqkLVOeHwMfZaQClANBebctjZbVmB6EtoS6jkE7YSqlGFVFA_ZSvoGyi6Xv04Yy9i3AAIBUo9Z2dSyE7WXbdivz9gpLV7y-PBpTnPkRs35kpkjbMYuLGJ9pQO3E_cehdTMORw5HGZya39lhYai2VG53-aX3lzcT-nme5ffD4MgcYH5a1NkScT1piyli_BJyTHl9lnN5NMRF5dvmTPJrON-Oqhn7PvH6-_XX0ubr5--nJ1eVNYVdcp5-r6GlpZ9QosmGqoBjHliH03gEJZKymnWjTD2KAFtKKXElVbDwi9tNME8py9P_kut8MOR4suR9vqJdDOhIP2hvS_G0ezXvu9bttOtaLNBtXJwAYfY8DpUStAHwnpjT4S0kdCGlqdCWXRm79_fZT8QZIP3p0OMGffEwYdLWFGMVJAm_To6X_-dwxYqEw</recordid><startdate>20190915</startdate><enddate>20190915</enddate><creator>Garsi, Jean-Baptiste</creator><creator>Vece, Vito</creator><creator>Sernissi, Lorenzo</creator><creator>Auger-Morin, Catherine</creator><creator>Hanessian, Stephen</creator><creator>McCracken, Alison N.</creator><creator>Selwan, Elizabeth</creator><creator>Ramirez, Cuauhtemoc</creator><creator>Dahal, Amogha</creator><creator>Romdhane, Nadine Ben</creator><creator>Finicle, Brendan T.</creator><creator>Edinger, Aimee L.</creator><general>Elsevier Ltd</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>5PM</scope></search><sort><creationdate>20190915</creationdate><title>Design, synthesis and anticancer activity of constrained sphingolipid-phenoxazine/phenothiazine hybrid constructs targeting protein phosphatase 2A</title><author>Garsi, Jean-Baptiste ; Vece, Vito ; Sernissi, Lorenzo ; Auger-Morin, Catherine ; Hanessian, Stephen ; McCracken, Alison N. ; Selwan, Elizabeth ; Ramirez, Cuauhtemoc ; Dahal, Amogha ; Romdhane, Nadine Ben ; Finicle, Brendan T. ; Edinger, Aimee L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c455t-898950732940c0a2b2b1f00198b04e35433f516bd6ec0ec1933e475be093cff03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Cell Line</topic><topic>Cell Survival - drug effects</topic><topic>Cytotoxicity FL5.12</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Design</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Hybrid structures</topic><topic>Mice</topic><topic>Molecular Structure</topic><topic>Nutrient transport down-regulation</topic><topic>Oxazines - chemistry</topic><topic>Oxazines - pharmacology</topic><topic>Phenothiazines - chemistry</topic><topic>Phenothiazines - pharmacology</topic><topic>Protein Phosphatase 2 - antagonists & inhibitors</topic><topic>Protein Phosphatase 2 - metabolism</topic><topic>Sphingolipid</topic><topic>Sphingolipids - chemistry</topic><topic>Sphingolipids - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Vacuolation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Garsi, Jean-Baptiste</creatorcontrib><creatorcontrib>Vece, Vito</creatorcontrib><creatorcontrib>Sernissi, Lorenzo</creatorcontrib><creatorcontrib>Auger-Morin, Catherine</creatorcontrib><creatorcontrib>Hanessian, Stephen</creatorcontrib><creatorcontrib>McCracken, Alison N.</creatorcontrib><creatorcontrib>Selwan, Elizabeth</creatorcontrib><creatorcontrib>Ramirez, Cuauhtemoc</creatorcontrib><creatorcontrib>Dahal, Amogha</creatorcontrib><creatorcontrib>Romdhane, Nadine Ben</creatorcontrib><creatorcontrib>Finicle, Brendan T.</creatorcontrib><creatorcontrib>Edinger, Aimee L.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Garsi, Jean-Baptiste</au><au>Vece, Vito</au><au>Sernissi, Lorenzo</au><au>Auger-Morin, Catherine</au><au>Hanessian, Stephen</au><au>McCracken, Alison N.</au><au>Selwan, Elizabeth</au><au>Ramirez, Cuauhtemoc</au><au>Dahal, Amogha</au><au>Romdhane, Nadine Ben</au><au>Finicle, Brendan T.</au><au>Edinger, Aimee L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, synthesis and anticancer activity of constrained sphingolipid-phenoxazine/phenothiazine hybrid constructs targeting protein phosphatase 2A</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2019-09-15</date><risdate>2019</risdate><volume>29</volume><issue>18</issue><spage>2681</spage><epage>2685</epage><pages>2681-2685</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
Inspired by the cytotoxicity of perphenazine toward cancer cells and its ability to activate the serine/threonine protein phosphatase 2A (PP2A), we prepared series of ether-carbon linked analogs of a constrained synthetic sphingolipid analog 3, known for its cytotoxicity, nutrient transporter down-regulation and vacuolation properties, incorporating the tricyclic neuroleptics phenoxazine and phenothiazine to represent hybrid structures with possible synergistic cytotoxic activity. While the original activity of the lead compound 3 was diminished by fusion with the phenoxazine or phenothiazine tethered moieties, the corresponding 3-pyridyltetryl ether analog 10 showed cytotoxicity and nutrient transporter down-regulation similar to the lead compound 3, although it separated these PP2A-dependent phenotypes from that of vacuolation.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>31383588</pmid><doi>10.1016/j.bmcl.2019.07.023</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2019-09, Vol.29 (18), p.2681-2685 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; Access via ScienceDirect (Elsevier) |
| subjects | Animals Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Cell Line Cell Survival - drug effects Cytotoxicity FL5.12 Dose-Response Relationship, Drug Drug Design Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Hybrid structures Mice Molecular Structure Nutrient transport down-regulation Oxazines - chemistry Oxazines - pharmacology Phenothiazines - chemistry Phenothiazines - pharmacology Protein Phosphatase 2 - antagonists & inhibitors Protein Phosphatase 2 - metabolism Sphingolipid Sphingolipids - chemistry Sphingolipids - pharmacology Structure-Activity Relationship Vacuolation |
| title | Design, synthesis and anticancer activity of constrained sphingolipid-phenoxazine/phenothiazine hybrid constructs targeting protein phosphatase 2A |
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