(R)-α-Lipoyl-Glycyl-L-Prolyl-L-Glutamyl Dimethyl Ester Codrug as a Multifunctional Agent with Potential Neuroprotective Activities
The (R)‐α‐lipoyl‐glycyl‐L‐prolyl‐L‐glutamyl dimethyl ester codrug (LA‐GPE, 1) was synthesized as a new multifunctional drug candidate with antioxidant and neuroprotective properties for the treatment of neurodegenerative diseases. Physicochemical properties, chemical and enzymatic stabilities were e...
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| Veröffentlicht in: | ChemMedChem 2012-11, Vol.7 (11), p.2021-2029 |
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| creator | Cacciatore, Ivana Baldassarre, Leonardo Fornasari, Erika Cornacchia, Catia Di Stefano, Antonio Sozio, Piera Cerasa, Laura Serafina Fontana, Antonella Fulle, Stefania Di Filippo, Ester Sara La Rovere, Rita Maria Laura Pinnen, Francesco |
| description | The (R)‐α‐lipoyl‐glycyl‐L‐prolyl‐L‐glutamyl dimethyl ester codrug (LA‐GPE, 1) was synthesized as a new multifunctional drug candidate with antioxidant and neuroprotective properties for the treatment of neurodegenerative diseases. Physicochemical properties, chemical and enzymatic stabilities were evaluated, along with the capacity of LA‐GPE to penetrate the blood–brain barrier (BBB) according to an in vitro parallel artificial membrane permeability assay for the BBB. We also investigated the potential effectiveness of LA‐GPE against the cytotoxicity induced by 6‐hydroxydopamine (6‐OHDA) and H2O2 on the human neuroblastoma cell line SH‐SY5Y by using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) reduction assay. Our results show that codrug 1 is stable at both pH 1.3 and 7.4, exhibits good lipophilicity (log P=1.51) and a pH‐dependent permeability profile. Furthermore, LA‐GPE was demonstrated to be significantly neuroprotective and to act as an antioxidant against H2O2‐ and 6‐OHDA‐induced neurotoxicity in SH‐SY5Y cells.
Efficacy through synergy: We report the synthesis, along with pharmacokinetic and neuroprotective profiles of a novel GPE codrug as a potential candidate for the multi‐target therapy of neurodegenerative diseases. The codrug shows good pharmacokinetic, potential antioxidant, and neuroprotective properties. |
| doi_str_mv | 10.1002/cmdc.201200320 |
| format | Article |
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Efficacy through synergy: We report the synthesis, along with pharmacokinetic and neuroprotective profiles of a novel GPE codrug as a potential candidate for the multi‐target therapy of neurodegenerative diseases. The codrug shows good pharmacokinetic, potential antioxidant, and neuroprotective properties.</description><identifier>ISSN: 1860-7179</identifier><identifier>EISSN: 1860-7187</identifier><identifier>DOI: 10.1002/cmdc.201200320</identifier><identifier>PMID: 22976949</identifier><language>eng</language><publisher>Weinheim: WILEY-VCH Verlag</publisher><subject>(R)-α-lipoic acid ; antioxidants ; Antioxidants - chemistry ; Antioxidants - pharmacokinetics ; Antioxidants - pharmacology ; Blood-Brain Barrier - metabolism ; Cell Line, Tumor ; glycyl-L-prolyl-L-glutamate ; Humans ; Hydrogen Peroxide - metabolism ; Neuroblastoma - drug therapy ; Neuroblastoma - metabolism ; neurodegenerative diseases ; neurological agents ; Neuroprotective Agents - chemistry ; Neuroprotective Agents - pharmacokinetics ; Neuroprotective Agents - pharmacology ; Oligopeptides - chemistry ; Oligopeptides - pharmacokinetics ; Oligopeptides - pharmacology ; Oxidative Stress - drug effects ; peptides ; Thioctic Acid - analogs & derivatives ; Thioctic Acid - pharmacokinetics ; Thioctic Acid - pharmacology</subject><ispartof>ChemMedChem, 2012-11, Vol.7 (11), p.2021-2029</ispartof><rights>Copyright © 2012 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim</rights><rights>Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4160-3fb3ad2b91c52f11e459652f2726337d186792e2e01739cd825fb9e1f2d6d9f93</citedby><cites>FETCH-LOGICAL-c4160-3fb3ad2b91c52f11e459652f2726337d186792e2e01739cd825fb9e1f2d6d9f93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fcmdc.201200320$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fcmdc.201200320$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22976949$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cacciatore, Ivana</creatorcontrib><creatorcontrib>Baldassarre, Leonardo</creatorcontrib><creatorcontrib>Fornasari, Erika</creatorcontrib><creatorcontrib>Cornacchia, Catia</creatorcontrib><creatorcontrib>Di Stefano, Antonio</creatorcontrib><creatorcontrib>Sozio, Piera</creatorcontrib><creatorcontrib>Cerasa, Laura Serafina</creatorcontrib><creatorcontrib>Fontana, Antonella</creatorcontrib><creatorcontrib>Fulle, Stefania</creatorcontrib><creatorcontrib>Di Filippo, Ester Sara</creatorcontrib><creatorcontrib>La Rovere, Rita Maria Laura</creatorcontrib><creatorcontrib>Pinnen, Francesco</creatorcontrib><title>(R)-α-Lipoyl-Glycyl-L-Prolyl-L-Glutamyl Dimethyl Ester Codrug as a Multifunctional Agent with Potential Neuroprotective Activities</title><title>ChemMedChem</title><addtitle>ChemMedChem</addtitle><description>The (R)‐α‐lipoyl‐glycyl‐L‐prolyl‐L‐glutamyl dimethyl ester codrug (LA‐GPE, 1) was synthesized as a new multifunctional drug candidate with antioxidant and neuroprotective properties for the treatment of neurodegenerative diseases. Physicochemical properties, chemical and enzymatic stabilities were evaluated, along with the capacity of LA‐GPE to penetrate the blood–brain barrier (BBB) according to an in vitro parallel artificial membrane permeability assay for the BBB. We also investigated the potential effectiveness of LA‐GPE against the cytotoxicity induced by 6‐hydroxydopamine (6‐OHDA) and H2O2 on the human neuroblastoma cell line SH‐SY5Y by using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) reduction assay. Our results show that codrug 1 is stable at both pH 1.3 and 7.4, exhibits good lipophilicity (log P=1.51) and a pH‐dependent permeability profile. Furthermore, LA‐GPE was demonstrated to be significantly neuroprotective and to act as an antioxidant against H2O2‐ and 6‐OHDA‐induced neurotoxicity in SH‐SY5Y cells.
Efficacy through synergy: We report the synthesis, along with pharmacokinetic and neuroprotective profiles of a novel GPE codrug as a potential candidate for the multi‐target therapy of neurodegenerative diseases. The codrug shows good pharmacokinetic, potential antioxidant, and neuroprotective properties.</description><subject>(R)-α-lipoic acid</subject><subject>antioxidants</subject><subject>Antioxidants - chemistry</subject><subject>Antioxidants - pharmacokinetics</subject><subject>Antioxidants - pharmacology</subject><subject>Blood-Brain Barrier - metabolism</subject><subject>Cell Line, Tumor</subject><subject>glycyl-L-prolyl-L-glutamate</subject><subject>Humans</subject><subject>Hydrogen Peroxide - metabolism</subject><subject>Neuroblastoma - drug therapy</subject><subject>Neuroblastoma - metabolism</subject><subject>neurodegenerative diseases</subject><subject>neurological agents</subject><subject>Neuroprotective Agents - chemistry</subject><subject>Neuroprotective Agents - pharmacokinetics</subject><subject>Neuroprotective Agents - pharmacology</subject><subject>Oligopeptides - chemistry</subject><subject>Oligopeptides - pharmacokinetics</subject><subject>Oligopeptides - pharmacology</subject><subject>Oxidative Stress - drug effects</subject><subject>peptides</subject><subject>Thioctic Acid - analogs & derivatives</subject><subject>Thioctic Acid - pharmacokinetics</subject><subject>Thioctic Acid - pharmacology</subject><issn>1860-7179</issn><issn>1860-7187</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1u1DAUhS1ERX9gyxJ5WRaZ-ieJ4-UoLUOr6VCqIpaWx7lpDc5ksB3arHmivgjPhIcpI3Zd3WPrO8e-Ogi9pWRCCWEnpmvMhBHKCOGMvEAHtCpJJmglXu60kPvoMIRvhOR5RatXaJ8xKUqZywP06_j6ffb7MZvbdT-6bOZGk8Y8u_K9-ytmboi6Gx0-tR3EuyTOQgSP677xwy3WAWt8Obho22Flou1X2uHpLawivrfxDl_1MWmbLhcw-H7t0zlhPwFPN8NGC-E12mu1C_DmaR6hLx_ObuqP2fzT7LyezjOT07QIb5dcN2wpqSlYSynkhSyTYoKVnIsmbSskAwaECi5NU7GiXUqgLWvKRraSH6HjbW76xY8BQlSdDQac0yvoh6CoqEhBGBf8eTRPj1Nayg062aLG9yF4aNXa2077UVGiNh2pTUdq11EyvHvKHpYdNDv8XykJkFvg3joYn4lT9eVp_X94tvXa1NLDzqv9d1UKLgr1dTFTF_x6cSGLG_WZ_wGSy620</recordid><startdate>201211</startdate><enddate>201211</enddate><creator>Cacciatore, Ivana</creator><creator>Baldassarre, Leonardo</creator><creator>Fornasari, Erika</creator><creator>Cornacchia, Catia</creator><creator>Di Stefano, Antonio</creator><creator>Sozio, Piera</creator><creator>Cerasa, Laura Serafina</creator><creator>Fontana, Antonella</creator><creator>Fulle, Stefania</creator><creator>Di Filippo, Ester Sara</creator><creator>La Rovere, Rita Maria Laura</creator><creator>Pinnen, Francesco</creator><general>WILEY-VCH Verlag</general><general>WILEY‐VCH Verlag</general><scope>BSCLL</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>7TK</scope></search><sort><creationdate>201211</creationdate><title>(R)-α-Lipoyl-Glycyl-L-Prolyl-L-Glutamyl Dimethyl Ester Codrug as a Multifunctional Agent with Potential Neuroprotective Activities</title><author>Cacciatore, Ivana ; Baldassarre, Leonardo ; Fornasari, Erika ; Cornacchia, Catia ; Di Stefano, Antonio ; Sozio, Piera ; Cerasa, Laura Serafina ; Fontana, Antonella ; Fulle, Stefania ; Di Filippo, Ester Sara ; La Rovere, Rita Maria Laura ; Pinnen, Francesco</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4160-3fb3ad2b91c52f11e459652f2726337d186792e2e01739cd825fb9e1f2d6d9f93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>(R)-α-lipoic acid</topic><topic>antioxidants</topic><topic>Antioxidants - chemistry</topic><topic>Antioxidants - pharmacokinetics</topic><topic>Antioxidants - pharmacology</topic><topic>Blood-Brain Barrier - metabolism</topic><topic>Cell Line, Tumor</topic><topic>glycyl-L-prolyl-L-glutamate</topic><topic>Humans</topic><topic>Hydrogen Peroxide - metabolism</topic><topic>Neuroblastoma - drug therapy</topic><topic>Neuroblastoma - metabolism</topic><topic>neurodegenerative diseases</topic><topic>neurological agents</topic><topic>Neuroprotective Agents - chemistry</topic><topic>Neuroprotective Agents - pharmacokinetics</topic><topic>Neuroprotective Agents - pharmacology</topic><topic>Oligopeptides - chemistry</topic><topic>Oligopeptides - pharmacokinetics</topic><topic>Oligopeptides - pharmacology</topic><topic>Oxidative Stress - drug effects</topic><topic>peptides</topic><topic>Thioctic Acid - analogs & derivatives</topic><topic>Thioctic Acid - pharmacokinetics</topic><topic>Thioctic Acid - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cacciatore, Ivana</creatorcontrib><creatorcontrib>Baldassarre, Leonardo</creatorcontrib><creatorcontrib>Fornasari, Erika</creatorcontrib><creatorcontrib>Cornacchia, Catia</creatorcontrib><creatorcontrib>Di Stefano, Antonio</creatorcontrib><creatorcontrib>Sozio, Piera</creatorcontrib><creatorcontrib>Cerasa, Laura Serafina</creatorcontrib><creatorcontrib>Fontana, Antonella</creatorcontrib><creatorcontrib>Fulle, Stefania</creatorcontrib><creatorcontrib>Di Filippo, Ester Sara</creatorcontrib><creatorcontrib>La Rovere, Rita Maria Laura</creatorcontrib><creatorcontrib>Pinnen, Francesco</creatorcontrib><collection>Istex</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>Neurosciences Abstracts</collection><jtitle>ChemMedChem</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cacciatore, Ivana</au><au>Baldassarre, Leonardo</au><au>Fornasari, Erika</au><au>Cornacchia, Catia</au><au>Di Stefano, Antonio</au><au>Sozio, Piera</au><au>Cerasa, Laura Serafina</au><au>Fontana, Antonella</au><au>Fulle, Stefania</au><au>Di Filippo, Ester Sara</au><au>La Rovere, Rita Maria Laura</au><au>Pinnen, Francesco</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>(R)-α-Lipoyl-Glycyl-L-Prolyl-L-Glutamyl Dimethyl Ester Codrug as a Multifunctional Agent with Potential Neuroprotective Activities</atitle><jtitle>ChemMedChem</jtitle><addtitle>ChemMedChem</addtitle><date>2012-11</date><risdate>2012</risdate><volume>7</volume><issue>11</issue><spage>2021</spage><epage>2029</epage><pages>2021-2029</pages><issn>1860-7179</issn><eissn>1860-7187</eissn><abstract>The (R)‐α‐lipoyl‐glycyl‐L‐prolyl‐L‐glutamyl dimethyl ester codrug (LA‐GPE, 1) was synthesized as a new multifunctional drug candidate with antioxidant and neuroprotective properties for the treatment of neurodegenerative diseases. Physicochemical properties, chemical and enzymatic stabilities were evaluated, along with the capacity of LA‐GPE to penetrate the blood–brain barrier (BBB) according to an in vitro parallel artificial membrane permeability assay for the BBB. We also investigated the potential effectiveness of LA‐GPE against the cytotoxicity induced by 6‐hydroxydopamine (6‐OHDA) and H2O2 on the human neuroblastoma cell line SH‐SY5Y by using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) reduction assay. Our results show that codrug 1 is stable at both pH 1.3 and 7.4, exhibits good lipophilicity (log P=1.51) and a pH‐dependent permeability profile. Furthermore, LA‐GPE was demonstrated to be significantly neuroprotective and to act as an antioxidant against H2O2‐ and 6‐OHDA‐induced neurotoxicity in SH‐SY5Y cells.
Efficacy through synergy: We report the synthesis, along with pharmacokinetic and neuroprotective profiles of a novel GPE codrug as a potential candidate for the multi‐target therapy of neurodegenerative diseases. The codrug shows good pharmacokinetic, potential antioxidant, and neuroprotective properties.</abstract><cop>Weinheim</cop><pub>WILEY-VCH Verlag</pub><pmid>22976949</pmid><doi>10.1002/cmdc.201200320</doi><tpages>9</tpages></addata></record> |
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| subjects | (R)-α-lipoic acid antioxidants Antioxidants - chemistry Antioxidants - pharmacokinetics Antioxidants - pharmacology Blood-Brain Barrier - metabolism Cell Line, Tumor glycyl-L-prolyl-L-glutamate Humans Hydrogen Peroxide - metabolism Neuroblastoma - drug therapy Neuroblastoma - metabolism neurodegenerative diseases neurological agents Neuroprotective Agents - chemistry Neuroprotective Agents - pharmacokinetics Neuroprotective Agents - pharmacology Oligopeptides - chemistry Oligopeptides - pharmacokinetics Oligopeptides - pharmacology Oxidative Stress - drug effects peptides Thioctic Acid - analogs & derivatives Thioctic Acid - pharmacokinetics Thioctic Acid - pharmacology |
| title | (R)-α-Lipoyl-Glycyl-L-Prolyl-L-Glutamyl Dimethyl Ester Codrug as a Multifunctional Agent with Potential Neuroprotective Activities |
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