Orally Bioavailable Metal Chelators and Radical Scavengers: Multifunctional Antioxidants for the Coadjutant Treatment of Neurodegenerative Diseases
Neurodegenerative diseases are associated with oxidative stress that is induced by the presence of reactive oxygen species and the abnormal cellular accumulation of transition metals. Here, a new series of orally bioavailable multifunctional antioxidants (MFAO-2s) possessing a 2-diacetylamino-5-hydr...
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| Veröffentlicht in: | Journal of medicinal chemistry 2015-11, Vol.58 (22), p.8796-8805 |
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| container_title | Journal of medicinal chemistry |
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| creator | Kawada, Hiroyoshi Kador, Peter F |
| description | Neurodegenerative diseases are associated with oxidative stress that is induced by the presence of reactive oxygen species and the abnormal cellular accumulation of transition metals. Here, a new series of orally bioavailable multifunctional antioxidants (MFAO-2s) possessing a 2-diacetylamino-5-hydroxypyrimidine moiety is described. These MFAO-2s demonstrate both free radical and metal attenuating properties that are similar to the original published MFAO-1s that are based on 1-N,N′-dimethylsulfamoyl-1-4-(2-pyrimidyl)piperazine. Oral bioavailability studies in C57BL/6 mice demonstrate that the MFAO-2s accumulate in the brain at significantly higher levels than the MFAO-1s while achieving similar neural retina levels. The MFAO-2s protect human neuroblastoma and retinal pigmented epithelial cells against hydroxyl radicals in a dose-dependent manner by maintaining cell viability and intracellular glutathione levels. The MFAO-2s outperform clioquinol, a metal attenuator that has been investigated for the treatment of Alzheimer’s disease. |
| doi_str_mv | 10.1021/acs.jmedchem.5b00272 |
| format | Article |
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Here, a new series of orally bioavailable multifunctional antioxidants (MFAO-2s) possessing a 2-diacetylamino-5-hydroxypyrimidine moiety is described. These MFAO-2s demonstrate both free radical and metal attenuating properties that are similar to the original published MFAO-1s that are based on 1-N,N′-dimethylsulfamoyl-1-4-(2-pyrimidyl)piperazine. Oral bioavailability studies in C57BL/6 mice demonstrate that the MFAO-2s accumulate in the brain at significantly higher levels than the MFAO-1s while achieving similar neural retina levels. The MFAO-2s protect human neuroblastoma and retinal pigmented epithelial cells against hydroxyl radicals in a dose-dependent manner by maintaining cell viability and intracellular glutathione levels. 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Med. Chem</addtitle><description>Neurodegenerative diseases are associated with oxidative stress that is induced by the presence of reactive oxygen species and the abnormal cellular accumulation of transition metals. Here, a new series of orally bioavailable multifunctional antioxidants (MFAO-2s) possessing a 2-diacetylamino-5-hydroxypyrimidine moiety is described. These MFAO-2s demonstrate both free radical and metal attenuating properties that are similar to the original published MFAO-1s that are based on 1-N,N′-dimethylsulfamoyl-1-4-(2-pyrimidyl)piperazine. Oral bioavailability studies in C57BL/6 mice demonstrate that the MFAO-2s accumulate in the brain at significantly higher levels than the MFAO-1s while achieving similar neural retina levels. The MFAO-2s protect human neuroblastoma and retinal pigmented epithelial cells against hydroxyl radicals in a dose-dependent manner by maintaining cell viability and intracellular glutathione levels. The MFAO-2s outperform clioquinol, a metal attenuator that has been investigated for the treatment of Alzheimer’s disease.</description><subject>Alzheimer Disease - drug therapy</subject><subject>Animals</subject><subject>Antioxidants - pharmacokinetics</subject><subject>Antioxidants - pharmacology</subject><subject>Biological Availability</subject><subject>Brain - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival - drug effects</subject><subject>Chelating Agents - pharmacokinetics</subject><subject>Chelating Agents - pharmacology</subject><subject>Clioquinol - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Epithelial Cells - metabolism</subject><subject>Female</subject><subject>Free Radical Scavengers - pharmacokinetics</subject><subject>Free Radical Scavengers - pharmacology</subject><subject>Glutathione - metabolism</subject><subject>Humans</subject><subject>Male</subject><subject>Metals - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Neurodegenerative Diseases - drug therapy</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - pharmacology</subject><subject>Retina - metabolism</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UctuFDEQtBCILIE_QMhHLrNpe97cwoaXlBAJwnnUY7ezXnnGwfasku_ghzHshiOnLlVXdau7GHstYC1AijNUcb2bSKstTet6BJCtfMJWopZQVB1UT9kqc7KQjSxP2IsYdwBQClk-ZyeygaaDulyxX9cBnXvg763HPVqHoyN-RQkd32zJYfIhcpw1_4baqsx-V7in-ZZCfMevFpesWWaVrJ9z73zO4N5qnFPkxgeetsQ3HvVuSZnjN4EwTZSRN_wrLcFruqWZAia7J35hI2Gk-JI9M-givTrWU_bj44ebzefi8vrTl835ZYFl1aWirjRVEnWrRtN3kppR9U0NOCrINwPUmpRpzdhqGHvRtaLsTd9qA5XU2MmxPGVvD3Pvgv-5UEzDZKMi53Amv8RBtGXTtG0p6yytDlIVfIyBzHAX7IThYRAw_IljyHEMj3EMxziy7c1xwzLm3j_T4_-zAA6Cv3a_hPzG-P-ZvwEWU52u</recordid><startdate>20151125</startdate><enddate>20151125</enddate><creator>Kawada, Hiroyoshi</creator><creator>Kador, Peter F</creator><general>American Chemical Society</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></search><sort><creationdate>20151125</creationdate><title>Orally Bioavailable Metal Chelators and Radical Scavengers: Multifunctional Antioxidants for the Coadjutant Treatment of Neurodegenerative Diseases</title><author>Kawada, Hiroyoshi ; Kador, Peter F</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a348t-54de42ad7cbf982e6bc9650abc0262005decf7fb7d0b9187139f97df042da82b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Alzheimer Disease - drug therapy</topic><topic>Animals</topic><topic>Antioxidants - pharmacokinetics</topic><topic>Antioxidants - pharmacology</topic><topic>Biological Availability</topic><topic>Brain - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Cell Survival - drug effects</topic><topic>Chelating Agents - pharmacokinetics</topic><topic>Chelating Agents - pharmacology</topic><topic>Clioquinol - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Epithelial Cells - metabolism</topic><topic>Female</topic><topic>Free Radical Scavengers - pharmacokinetics</topic><topic>Free Radical Scavengers - pharmacology</topic><topic>Glutathione - metabolism</topic><topic>Humans</topic><topic>Male</topic><topic>Metals - metabolism</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Neurodegenerative Diseases - drug therapy</topic><topic>Pyrimidines - chemistry</topic><topic>Pyrimidines - pharmacology</topic><topic>Retina - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kawada, Hiroyoshi</creatorcontrib><creatorcontrib>Kador, Peter F</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><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kawada, Hiroyoshi</au><au>Kador, Peter F</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Orally Bioavailable Metal Chelators and Radical Scavengers: Multifunctional Antioxidants for the Coadjutant Treatment of Neurodegenerative Diseases</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2015-11-25</date><risdate>2015</risdate><volume>58</volume><issue>22</issue><spage>8796</spage><epage>8805</epage><pages>8796-8805</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Neurodegenerative diseases are associated with oxidative stress that is induced by the presence of reactive oxygen species and the abnormal cellular accumulation of transition metals. Here, a new series of orally bioavailable multifunctional antioxidants (MFAO-2s) possessing a 2-diacetylamino-5-hydroxypyrimidine moiety is described. These MFAO-2s demonstrate both free radical and metal attenuating properties that are similar to the original published MFAO-1s that are based on 1-N,N′-dimethylsulfamoyl-1-4-(2-pyrimidyl)piperazine. Oral bioavailability studies in C57BL/6 mice demonstrate that the MFAO-2s accumulate in the brain at significantly higher levels than the MFAO-1s while achieving similar neural retina levels. 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| source | American Chemical Society; MEDLINE |
| subjects | Alzheimer Disease - drug therapy Animals Antioxidants - pharmacokinetics Antioxidants - pharmacology Biological Availability Brain - metabolism Cell Line, Tumor Cell Survival - drug effects Chelating Agents - pharmacokinetics Chelating Agents - pharmacology Clioquinol - pharmacology Dose-Response Relationship, Drug Epithelial Cells - metabolism Female Free Radical Scavengers - pharmacokinetics Free Radical Scavengers - pharmacology Glutathione - metabolism Humans Male Metals - metabolism Mice Mice, Inbred C57BL Neurodegenerative Diseases - drug therapy Pyrimidines - chemistry Pyrimidines - pharmacology Retina - metabolism |
| title | Orally Bioavailable Metal Chelators and Radical Scavengers: Multifunctional Antioxidants for the Coadjutant Treatment of Neurodegenerative Diseases |
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