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Targeting neuronal calcium channels and GSK3β for Alzheimer’s disease with naturally-inspired Diels-Alder adducts
[Display omitted] •A molecular simplification plan led to new compounds via Diels-Alder cycloaddition.•Some derivatives acted as L/N type calcium channels blockers or GSK-3β modulators.•10 emerged as promising, safe and BBB-penetrating Cav modulator.•11 could be considered as a promising multitarget...
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Published in: | Bioorganic chemistry 2022-12, Vol.129, p.106152-106152, Article 106152 |
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creator | Bisi, Alessandra Feoli, Alessandra Trezza, Alfonso Viejo, Lucia Formaggio, Francesco Bartolini, Manuela Belluti, Federica Gobbi, Silvia Spiga, Ottavia Caprini, Marco de los Rios, Cristobal Castellano, Sabrina Rampa, Angela |
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•A molecular simplification plan led to new compounds via Diels-Alder cycloaddition.•Some derivatives acted as L/N type calcium channels blockers or GSK-3β modulators.•10 emerged as promising, safe and BBB-penetrating Cav modulator.•11 could be considered as a promising multitarget prototype.
The complexity of neurodegenerative diseases, among which Alzheimer’s disease plays a pivotal role, poses one of the tough therapeutic challenges of present time. In this perspective, a multitarget approach appears as a promising strategy to simultaneously interfere with different defective pathways. In this paper, a structural simplification plan was performed on our previously reported multipotent polycyclic compounds, in order to obtain a simpler pharmacophoric central core with improved pharmacokinetic properties, while maintaining the modulating activity on neuronal calcium channels and glycogen synthase kinase 3-beta (GSK-3β), as validated targets to combat Alzheimer’s disease. The molecular pruning approach applied here led to tetrahydroisoindole-dione (1), tetrahydromethanoisoindole-dione (2) and tetrahydroepoxyisoindole-dione (3) structures, easily affordable by Diels-Alder cycloaddition. Preliminary data indicated structure 3 as the most appropriate, thus a SAR study was performed by introducing different substituents, selected on the basis of the commercial availability of the furan derivatives required for the synthetic procedure. The results indicated compound 10 as a promising, structurally atypical, safe and BBB-penetrating Cav modulator, inhibiting both L- and N-calcium channels, likely responsible for the Ca2+ overload observed in Alzheimer’s disease. In a multitarget perspective, compound 11 appeared as an effective prototype, endowed with improved Cav inhibitory activity, with respect to the reference drug nifedipine, and encouraging modulating activity on GSK-3β. |
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•A molecular simplification plan led to new compounds via Diels-Alder cycloaddition.•Some derivatives acted as L/N type calcium channels blockers or GSK-3β modulators.•10 emerged as promising, safe and BBB-penetrating Cav modulator.•11 could be considered as a promising multitarget prototype.
The complexity of neurodegenerative diseases, among which Alzheimer’s disease plays a pivotal role, poses one of the tough therapeutic challenges of present time. In this perspective, a multitarget approach appears as a promising strategy to simultaneously interfere with different defective pathways. In this paper, a structural simplification plan was performed on our previously reported multipotent polycyclic compounds, in order to obtain a simpler pharmacophoric central core with improved pharmacokinetic properties, while maintaining the modulating activity on neuronal calcium channels and glycogen synthase kinase 3-beta (GSK-3β), as validated targets to combat Alzheimer’s disease. The molecular pruning approach applied here led to tetrahydroisoindole-dione (1), tetrahydromethanoisoindole-dione (2) and tetrahydroepoxyisoindole-dione (3) structures, easily affordable by Diels-Alder cycloaddition. Preliminary data indicated structure 3 as the most appropriate, thus a SAR study was performed by introducing different substituents, selected on the basis of the commercial availability of the furan derivatives required for the synthetic procedure. The results indicated compound 10 as a promising, structurally atypical, safe and BBB-penetrating Cav modulator, inhibiting both L- and N-calcium channels, likely responsible for the Ca2+ overload observed in Alzheimer’s disease. In a multitarget perspective, compound 11 appeared as an effective prototype, endowed with improved Cav inhibitory activity, with respect to the reference drug nifedipine, and encouraging modulating activity on GSK-3β.</description><identifier>ISSN: 0045-2068</identifier><identifier>EISSN: 1090-2120</identifier><identifier>DOI: 10.1016/j.bioorg.2022.106152</identifier><identifier>PMID: 36155094</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Alzheimer Disease - drug therapy ; Alzheimer’s disease ; Ca2+ channels ; Calcium Channels ; Diels-Alder adducts ; Docking simulation ; Glycogen Synthase Kinase 3 beta ; GSK-3β ; Humans ; Molecular Docking Simulation ; Molecular dynamics simulation ; Neurons</subject><ispartof>Bioorganic chemistry, 2022-12, Vol.129, p.106152-106152, Article 106152</ispartof><rights>2022 Elsevier Inc.</rights><rights>Copyright © 2022 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c2074-6faefab330f796e57a06407325ca449c9ab4b518535ba3eafac95c110555bab83</citedby><cites>FETCH-LOGICAL-c2074-6faefab330f796e57a06407325ca449c9ab4b518535ba3eafac95c110555bab83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36155094$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bisi, Alessandra</creatorcontrib><creatorcontrib>Feoli, Alessandra</creatorcontrib><creatorcontrib>Trezza, Alfonso</creatorcontrib><creatorcontrib>Viejo, Lucia</creatorcontrib><creatorcontrib>Formaggio, Francesco</creatorcontrib><creatorcontrib>Bartolini, Manuela</creatorcontrib><creatorcontrib>Belluti, Federica</creatorcontrib><creatorcontrib>Gobbi, Silvia</creatorcontrib><creatorcontrib>Spiga, Ottavia</creatorcontrib><creatorcontrib>Caprini, Marco</creatorcontrib><creatorcontrib>de los Rios, Cristobal</creatorcontrib><creatorcontrib>Castellano, Sabrina</creatorcontrib><creatorcontrib>Rampa, Angela</creatorcontrib><title>Targeting neuronal calcium channels and GSK3β for Alzheimer’s disease with naturally-inspired Diels-Alder adducts</title><title>Bioorganic chemistry</title><addtitle>Bioorg Chem</addtitle><description>[Display omitted]
•A molecular simplification plan led to new compounds via Diels-Alder cycloaddition.•Some derivatives acted as L/N type calcium channels blockers or GSK-3β modulators.•10 emerged as promising, safe and BBB-penetrating Cav modulator.•11 could be considered as a promising multitarget prototype.
The complexity of neurodegenerative diseases, among which Alzheimer’s disease plays a pivotal role, poses one of the tough therapeutic challenges of present time. In this perspective, a multitarget approach appears as a promising strategy to simultaneously interfere with different defective pathways. In this paper, a structural simplification plan was performed on our previously reported multipotent polycyclic compounds, in order to obtain a simpler pharmacophoric central core with improved pharmacokinetic properties, while maintaining the modulating activity on neuronal calcium channels and glycogen synthase kinase 3-beta (GSK-3β), as validated targets to combat Alzheimer’s disease. The molecular pruning approach applied here led to tetrahydroisoindole-dione (1), tetrahydromethanoisoindole-dione (2) and tetrahydroepoxyisoindole-dione (3) structures, easily affordable by Diels-Alder cycloaddition. Preliminary data indicated structure 3 as the most appropriate, thus a SAR study was performed by introducing different substituents, selected on the basis of the commercial availability of the furan derivatives required for the synthetic procedure. The results indicated compound 10 as a promising, structurally atypical, safe and BBB-penetrating Cav modulator, inhibiting both L- and N-calcium channels, likely responsible for the Ca2+ overload observed in Alzheimer’s disease. In a multitarget perspective, compound 11 appeared as an effective prototype, endowed with improved Cav inhibitory activity, with respect to the reference drug nifedipine, and encouraging modulating activity on GSK-3β.</description><subject>Alzheimer Disease - drug therapy</subject><subject>Alzheimer’s disease</subject><subject>Ca2+ channels</subject><subject>Calcium Channels</subject><subject>Diels-Alder adducts</subject><subject>Docking simulation</subject><subject>Glycogen Synthase Kinase 3 beta</subject><subject>GSK-3β</subject><subject>Humans</subject><subject>Molecular Docking Simulation</subject><subject>Molecular dynamics simulation</subject><subject>Neurons</subject><issn>0045-2068</issn><issn>1090-2120</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNp9kEGO1DAQRS0EYpqBGyDkJZs0ZcdOOhuk1sAMiJFYMKytilPpdstxGjsBDSuuMdfgIByCk-BWBpasSvp6_5f0GHsuYC1AVK8O69aNY9ytJUiZo0po-YCtBDRQSCHhIVsBKF1IqDZn7ElKBwAhVF09ZmdlhjU0asWmG4w7mlzY8UBzHAN6btFbNw_c7jEE8olj6PjVpw_lr5-8HyPf-u97cgPF3z_uEu9cIkzEv7lpzwNOc0TvbwsX0tFF6vgblyeKre8ocuy62U7pKXvUo0_07P6es8-Xb28u3hXXH6_eX2yvCyuhVkXVI_XYliX0dVORrhEqBXUptUWlGttgq1otNrrULZaEPdpGWyFA6xy0m_KcvVx2j3H8MlOazOCSJe8x0DgnI2uxqfKcPKFqQW0cU4rUm2N0A8ZbI8CcfJuDWXybk2-z-M61F_cf5nag7l_pr-AMvF6ALIG-OoomWUfBUpfl2Ml0o_v_hz9Mk5XG</recordid><startdate>202212</startdate><enddate>202212</enddate><creator>Bisi, Alessandra</creator><creator>Feoli, Alessandra</creator><creator>Trezza, Alfonso</creator><creator>Viejo, Lucia</creator><creator>Formaggio, Francesco</creator><creator>Bartolini, Manuela</creator><creator>Belluti, Federica</creator><creator>Gobbi, Silvia</creator><creator>Spiga, Ottavia</creator><creator>Caprini, Marco</creator><creator>de los Rios, Cristobal</creator><creator>Castellano, Sabrina</creator><creator>Rampa, Angela</creator><general>Elsevier Inc</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>202212</creationdate><title>Targeting neuronal calcium channels and GSK3β for Alzheimer’s disease with naturally-inspired Diels-Alder adducts</title><author>Bisi, Alessandra ; Feoli, Alessandra ; Trezza, Alfonso ; Viejo, Lucia ; Formaggio, Francesco ; Bartolini, Manuela ; Belluti, Federica ; Gobbi, Silvia ; Spiga, Ottavia ; Caprini, Marco ; de los Rios, Cristobal ; Castellano, Sabrina ; Rampa, Angela</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c2074-6faefab330f796e57a06407325ca449c9ab4b518535ba3eafac95c110555bab83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Alzheimer Disease - drug therapy</topic><topic>Alzheimer’s disease</topic><topic>Ca2+ channels</topic><topic>Calcium Channels</topic><topic>Diels-Alder adducts</topic><topic>Docking simulation</topic><topic>Glycogen Synthase Kinase 3 beta</topic><topic>GSK-3β</topic><topic>Humans</topic><topic>Molecular Docking Simulation</topic><topic>Molecular dynamics simulation</topic><topic>Neurons</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bisi, Alessandra</creatorcontrib><creatorcontrib>Feoli, Alessandra</creatorcontrib><creatorcontrib>Trezza, Alfonso</creatorcontrib><creatorcontrib>Viejo, Lucia</creatorcontrib><creatorcontrib>Formaggio, Francesco</creatorcontrib><creatorcontrib>Bartolini, Manuela</creatorcontrib><creatorcontrib>Belluti, Federica</creatorcontrib><creatorcontrib>Gobbi, Silvia</creatorcontrib><creatorcontrib>Spiga, Ottavia</creatorcontrib><creatorcontrib>Caprini, Marco</creatorcontrib><creatorcontrib>de los Rios, Cristobal</creatorcontrib><creatorcontrib>Castellano, Sabrina</creatorcontrib><creatorcontrib>Rampa, Angela</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>Bioorganic chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bisi, Alessandra</au><au>Feoli, Alessandra</au><au>Trezza, Alfonso</au><au>Viejo, Lucia</au><au>Formaggio, Francesco</au><au>Bartolini, Manuela</au><au>Belluti, Federica</au><au>Gobbi, Silvia</au><au>Spiga, Ottavia</au><au>Caprini, Marco</au><au>de los Rios, Cristobal</au><au>Castellano, Sabrina</au><au>Rampa, Angela</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeting neuronal calcium channels and GSK3β for Alzheimer’s disease with naturally-inspired Diels-Alder adducts</atitle><jtitle>Bioorganic chemistry</jtitle><addtitle>Bioorg Chem</addtitle><date>2022-12</date><risdate>2022</risdate><volume>129</volume><spage>106152</spage><epage>106152</epage><pages>106152-106152</pages><artnum>106152</artnum><issn>0045-2068</issn><eissn>1090-2120</eissn><abstract>[Display omitted]
•A molecular simplification plan led to new compounds via Diels-Alder cycloaddition.•Some derivatives acted as L/N type calcium channels blockers or GSK-3β modulators.•10 emerged as promising, safe and BBB-penetrating Cav modulator.•11 could be considered as a promising multitarget prototype.
The complexity of neurodegenerative diseases, among which Alzheimer’s disease plays a pivotal role, poses one of the tough therapeutic challenges of present time. In this perspective, a multitarget approach appears as a promising strategy to simultaneously interfere with different defective pathways. In this paper, a structural simplification plan was performed on our previously reported multipotent polycyclic compounds, in order to obtain a simpler pharmacophoric central core with improved pharmacokinetic properties, while maintaining the modulating activity on neuronal calcium channels and glycogen synthase kinase 3-beta (GSK-3β), as validated targets to combat Alzheimer’s disease. The molecular pruning approach applied here led to tetrahydroisoindole-dione (1), tetrahydromethanoisoindole-dione (2) and tetrahydroepoxyisoindole-dione (3) structures, easily affordable by Diels-Alder cycloaddition. Preliminary data indicated structure 3 as the most appropriate, thus a SAR study was performed by introducing different substituents, selected on the basis of the commercial availability of the furan derivatives required for the synthetic procedure. The results indicated compound 10 as a promising, structurally atypical, safe and BBB-penetrating Cav modulator, inhibiting both L- and N-calcium channels, likely responsible for the Ca2+ overload observed in Alzheimer’s disease. In a multitarget perspective, compound 11 appeared as an effective prototype, endowed with improved Cav inhibitory activity, with respect to the reference drug nifedipine, and encouraging modulating activity on GSK-3β.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>36155094</pmid><doi>10.1016/j.bioorg.2022.106152</doi><tpages>1</tpages></addata></record> |
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subjects | Alzheimer Disease - drug therapy Alzheimer’s disease Ca2+ channels Calcium Channels Diels-Alder adducts Docking simulation Glycogen Synthase Kinase 3 beta GSK-3β Humans Molecular Docking Simulation Molecular dynamics simulation Neurons |
title | Targeting neuronal calcium channels and GSK3β for Alzheimer’s disease with naturally-inspired Diels-Alder adducts |
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