Design and synthesis of N-hydroxyalkyl substituted deferiprone: a kind of iron chelating agents for Parkinson's disease chelation therapy strategy
The blood–brain barrier (BBB) permeability of molecules needs to meet stringent requirements of Lipinski’s rule, which pose a difficulty for the rational design of efficient chelating agents for Parkinson's disease chelation therapy. Therefore, the iron chelators employed N -aliphatic alcohols...
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| Veröffentlicht in: | Journal of biological inorganic chemistry 2021-06, Vol.26 (4), p.467-478 |
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| container_title | Journal of biological inorganic chemistry |
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| creator | Zhang, Qingchun Feng, Shufan Zhao, Yulian Jin, Bo Peng, Rufang |
| description | The blood–brain barrier (BBB) permeability of molecules needs to meet stringent requirements of Lipinski’s rule, which pose a difficulty for the rational design of efficient chelating agents for Parkinson's disease chelation therapy. Therefore, the iron chelators employed
N
-aliphatic alcohols modification of deferiprone were reasonably designed in this work. The chelators not only meet Lipinski’s rule for BBB permeability, but also ensure the iron affinity. The results of solution thermodynamics demonstrated that the pFe
3+
value of
N
-hydroxyalkyl substituted deferiprone is between 19.20 and 19.36, which is comparable to that of clinical deferiprone. The results of 2,2-diphenyl-1-picrylhydrazyl radical scavenging assays indicated that the
N
-hydroxyalkyl substituted deferiprone also possesses similar radical scavenging ability in comparison to deferiprone. Meanwhile, the Cell Counting Kit-8 assays of neuron-like rat pheochromocytoma cell-line demonstrated that the
N
-hydroxyalkyl substituted deferiprone exhibits extremely low cytotoxicity and excellent H
2
O
2
-induced oxidative stress protection effect. These results indicated that
N
-hydroxyalkyl substituted deferiprone has potential application prospects as chelating agents for Parkinson's disease chelation therapy strategy.
Graphic abstract |
| doi_str_mv | 10.1007/s00775-021-01863-x |
| format | Article |
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N
-aliphatic alcohols modification of deferiprone were reasonably designed in this work. The chelators not only meet Lipinski’s rule for BBB permeability, but also ensure the iron affinity. The results of solution thermodynamics demonstrated that the pFe
3+
value of
N
-hydroxyalkyl substituted deferiprone is between 19.20 and 19.36, which is comparable to that of clinical deferiprone. The results of 2,2-diphenyl-1-picrylhydrazyl radical scavenging assays indicated that the
N
-hydroxyalkyl substituted deferiprone also possesses similar radical scavenging ability in comparison to deferiprone. Meanwhile, the Cell Counting Kit-8 assays of neuron-like rat pheochromocytoma cell-line demonstrated that the
N
-hydroxyalkyl substituted deferiprone exhibits extremely low cytotoxicity and excellent H
2
O
2
-induced oxidative stress protection effect. These results indicated that
N
-hydroxyalkyl substituted deferiprone has potential application prospects as chelating agents for Parkinson's disease chelation therapy strategy.
Graphic abstract</description><identifier>ISSN: 0949-8257</identifier><identifier>EISSN: 1432-1327</identifier><identifier>DOI: 10.1007/s00775-021-01863-x</identifier><identifier>PMID: 33963933</identifier><language>eng</language><publisher>Cham: Springer International Publishing</publisher><subject>Alcohols ; Biochemistry ; Biochemistry & Molecular Biology ; Biomedical and Life Sciences ; Blood-brain barrier ; Chelating agents ; Chelation ; Chelation therapy ; Chemistry ; Chemistry, Inorganic & Nuclear ; Cytotoxicity ; Hydrogen peroxide ; Iron ; Lead poisoning ; Life Sciences ; Life Sciences & Biomedicine ; Membrane permeability ; Microbiology ; Movement disorders ; Neurodegenerative diseases ; Original Paper ; Oxidative stress ; Parkinson's disease ; Permeability ; Pheochromocytoma ; Physical Sciences ; Science & Technology</subject><ispartof>Journal of biological inorganic chemistry, 2021-06, Vol.26 (4), p.467-478</ispartof><rights>Society for Biological Inorganic Chemistry (SBIC) 2021</rights><rights>Society for Biological Inorganic Chemistry (SBIC) 2021.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>4</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000648374100001</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c375t-7976e52e5cebe82abfbea5624ccb969c8c284ae641800de19789b6dbc0ecca583</citedby><cites>FETCH-LOGICAL-c375t-7976e52e5cebe82abfbea5624ccb969c8c284ae641800de19789b6dbc0ecca583</cites><orcidid>0000-0003-4063-9645</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00775-021-01863-x$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00775-021-01863-x$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>315,781,785,27929,27930,39263,41493,42562,51324</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33963933$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Qingchun</creatorcontrib><creatorcontrib>Feng, Shufan</creatorcontrib><creatorcontrib>Zhao, Yulian</creatorcontrib><creatorcontrib>Jin, Bo</creatorcontrib><creatorcontrib>Peng, Rufang</creatorcontrib><title>Design and synthesis of N-hydroxyalkyl substituted deferiprone: a kind of iron chelating agents for Parkinson's disease chelation therapy strategy</title><title>Journal of biological inorganic chemistry</title><addtitle>J Biol Inorg Chem</addtitle><addtitle>J BIOL INORG CHEM</addtitle><addtitle>J Biol Inorg Chem</addtitle><description>The blood–brain barrier (BBB) permeability of molecules needs to meet stringent requirements of Lipinski’s rule, which pose a difficulty for the rational design of efficient chelating agents for Parkinson's disease chelation therapy. Therefore, the iron chelators employed
N
-aliphatic alcohols modification of deferiprone were reasonably designed in this work. The chelators not only meet Lipinski’s rule for BBB permeability, but also ensure the iron affinity. The results of solution thermodynamics demonstrated that the pFe
3+
value of
N
-hydroxyalkyl substituted deferiprone is between 19.20 and 19.36, which is comparable to that of clinical deferiprone. The results of 2,2-diphenyl-1-picrylhydrazyl radical scavenging assays indicated that the
N
-hydroxyalkyl substituted deferiprone also possesses similar radical scavenging ability in comparison to deferiprone. Meanwhile, the Cell Counting Kit-8 assays of neuron-like rat pheochromocytoma cell-line demonstrated that the
N
-hydroxyalkyl substituted deferiprone exhibits extremely low cytotoxicity and excellent H
2
O
2
-induced oxidative stress protection effect. These results indicated that
N
-hydroxyalkyl substituted deferiprone has potential application prospects as chelating agents for Parkinson's disease chelation therapy strategy.
Graphic abstract</description><subject>Alcohols</subject><subject>Biochemistry</subject><subject>Biochemistry & Molecular Biology</subject><subject>Biomedical and Life Sciences</subject><subject>Blood-brain barrier</subject><subject>Chelating agents</subject><subject>Chelation</subject><subject>Chelation therapy</subject><subject>Chemistry</subject><subject>Chemistry, Inorganic & Nuclear</subject><subject>Cytotoxicity</subject><subject>Hydrogen peroxide</subject><subject>Iron</subject><subject>Lead poisoning</subject><subject>Life Sciences</subject><subject>Life Sciences & Biomedicine</subject><subject>Membrane permeability</subject><subject>Microbiology</subject><subject>Movement disorders</subject><subject>Neurodegenerative diseases</subject><subject>Original Paper</subject><subject>Oxidative stress</subject><subject>Parkinson's disease</subject><subject>Permeability</subject><subject>Pheochromocytoma</subject><subject>Physical Sciences</subject><subject>Science & Technology</subject><issn>0949-8257</issn><issn>1432-1327</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>HGBXW</sourceid><recordid>eNqNkU1v1DAQhiMEokvhD3BAljiAhAL-jBNuaPmUKuAA58hxJrtus87W44jN3-AXM3TbInFAXGzZep7xjN-ieCz4S8G5fYW0WFNyKUou6kqVhzvFSmglS6GkvVuseKObspbGnhQPEM8558oIc784UaqpVKPUqvj5FjBsInOxZ7jEvKUjsmlgn8vt0qfpsLjxYhkZzh3mkOcMPethgBT2aYrwmjl2EcglI9AF81sYXQ5xw9wGYkY2TIl9dYkgnOIzZH1AcAg3ICn0ZnL7hWFOLsNmeVjcG9yI8Oh6Py2-v3_3bf2xPPvy4dP6zVnplTW5tI2twEgwHjqopeuGDpyppPa-a6rG117W2kGlRc15D6KxddNVfec5eO9MrU6L58e6NMnlDJjbXUAP4-giTDO20khN_2WtJvTpX-j5NKdI3RGlhdJWmIYoeaR8mhATDO0-hZ1LSyt4-zux9phYS4m1V4m1B5KeXJeeux30t8pNRATUR-AHdNOAPkD0cItRppWuldVUn3OxDvnqU9fTHDOpL_5fJVodaSQibiD9GfIf_f8CuNbGAQ</recordid><startdate>20210601</startdate><enddate>20210601</enddate><creator>Zhang, Qingchun</creator><creator>Feng, Shufan</creator><creator>Zhao, Yulian</creator><creator>Jin, Bo</creator><creator>Peng, Rufang</creator><general>Springer International Publishing</general><general>Springer Nature</general><general>Springer Nature B.V</general><scope>BLEPL</scope><scope>DTL</scope><scope>HGBXW</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-4063-9645</orcidid></search><sort><creationdate>20210601</creationdate><title>Design and synthesis of N-hydroxyalkyl substituted deferiprone: a kind of iron chelating agents for Parkinson's disease chelation therapy strategy</title><author>Zhang, Qingchun ; Feng, Shufan ; Zhao, Yulian ; Jin, Bo ; Peng, Rufang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c375t-7976e52e5cebe82abfbea5624ccb969c8c284ae641800de19789b6dbc0ecca583</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Alcohols</topic><topic>Biochemistry</topic><topic>Biochemistry & Molecular Biology</topic><topic>Biomedical and Life Sciences</topic><topic>Blood-brain barrier</topic><topic>Chelating agents</topic><topic>Chelation</topic><topic>Chelation therapy</topic><topic>Chemistry</topic><topic>Chemistry, Inorganic & Nuclear</topic><topic>Cytotoxicity</topic><topic>Hydrogen peroxide</topic><topic>Iron</topic><topic>Lead poisoning</topic><topic>Life Sciences</topic><topic>Life Sciences & Biomedicine</topic><topic>Membrane permeability</topic><topic>Microbiology</topic><topic>Movement disorders</topic><topic>Neurodegenerative diseases</topic><topic>Original Paper</topic><topic>Oxidative stress</topic><topic>Parkinson's disease</topic><topic>Permeability</topic><topic>Pheochromocytoma</topic><topic>Physical Sciences</topic><topic>Science & Technology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Qingchun</creatorcontrib><creatorcontrib>Feng, Shufan</creatorcontrib><creatorcontrib>Zhao, Yulian</creatorcontrib><creatorcontrib>Jin, Bo</creatorcontrib><creatorcontrib>Peng, Rufang</creatorcontrib><collection>Web of Science Core Collection</collection><collection>Science Citation Index Expanded</collection><collection>Web of Science - Science Citation Index Expanded - 2021</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of biological inorganic chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Qingchun</au><au>Feng, Shufan</au><au>Zhao, Yulian</au><au>Jin, Bo</au><au>Peng, Rufang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design and synthesis of N-hydroxyalkyl substituted deferiprone: a kind of iron chelating agents for Parkinson's disease chelation therapy strategy</atitle><jtitle>Journal of biological inorganic chemistry</jtitle><stitle>J Biol Inorg Chem</stitle><stitle>J BIOL INORG CHEM</stitle><addtitle>J Biol Inorg Chem</addtitle><date>2021-06-01</date><risdate>2021</risdate><volume>26</volume><issue>4</issue><spage>467</spage><epage>478</epage><pages>467-478</pages><issn>0949-8257</issn><eissn>1432-1327</eissn><abstract>The blood–brain barrier (BBB) permeability of molecules needs to meet stringent requirements of Lipinski’s rule, which pose a difficulty for the rational design of efficient chelating agents for Parkinson's disease chelation therapy. Therefore, the iron chelators employed
N
-aliphatic alcohols modification of deferiprone were reasonably designed in this work. The chelators not only meet Lipinski’s rule for BBB permeability, but also ensure the iron affinity. The results of solution thermodynamics demonstrated that the pFe
3+
value of
N
-hydroxyalkyl substituted deferiprone is between 19.20 and 19.36, which is comparable to that of clinical deferiprone. The results of 2,2-diphenyl-1-picrylhydrazyl radical scavenging assays indicated that the
N
-hydroxyalkyl substituted deferiprone also possesses similar radical scavenging ability in comparison to deferiprone. Meanwhile, the Cell Counting Kit-8 assays of neuron-like rat pheochromocytoma cell-line demonstrated that the
N
-hydroxyalkyl substituted deferiprone exhibits extremely low cytotoxicity and excellent H
2
O
2
-induced oxidative stress protection effect. These results indicated that
N
-hydroxyalkyl substituted deferiprone has potential application prospects as chelating agents for Parkinson's disease chelation therapy strategy.
Graphic abstract</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><pmid>33963933</pmid><doi>10.1007/s00775-021-01863-x</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0003-4063-9645</orcidid></addata></record> |
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| source | SpringerNature Journals; Web of Science - Science Citation Index Expanded - 2021<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /> |
| subjects | Alcohols Biochemistry Biochemistry & Molecular Biology Biomedical and Life Sciences Blood-brain barrier Chelating agents Chelation Chelation therapy Chemistry Chemistry, Inorganic & Nuclear Cytotoxicity Hydrogen peroxide Iron Lead poisoning Life Sciences Life Sciences & Biomedicine Membrane permeability Microbiology Movement disorders Neurodegenerative diseases Original Paper Oxidative stress Parkinson's disease Permeability Pheochromocytoma Physical Sciences Science & Technology |
| title | Design and synthesis of N-hydroxyalkyl substituted deferiprone: a kind of iron chelating agents for Parkinson's disease chelation therapy strategy |
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