Publicação
Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases
| Resumo: | Neurotransmitter depletion and mitochondrial dysfunction are among the multiple pathological events that lead to neurodegeneration. Following our previous studies related with the development of multitarget mitochondriotropic antioxidants, this study aims to evaluate whether the π-system extension on the chemical scaffolds of AntiOXCIN2 and AntiOXCIN3 affects their bioactivity and safety profiles. After the synthesis of four triphenylphosphonium (TPP+) conjugates (compounds 2-5), we evaluated their antioxidant properties and their effect on neurotransmitter-metabolizing enzymes. All compounds were potent equine butyrylcholinesterase (eqBChE) and moderate electric eel acetylcholinesterase (eeAChE) inhibitors, with catechols 4 and 5 presenting lower IC50 values than AntiOXCIN2 and AntiOXCIN3, respectively. However, differences in the inhibition potency and selectivity of compounds 2-5 towards non-human and human cholinesterases (ChEs) were observed. Co-crystallization studies with compounds 2-5 in complex with human ChEs (hChEs) showed that these compounds exhibit different binging modes to hAChE and hBChE. Unlike AntiOXCINs, compounds 2-5 displayed moderate human monoamine oxidase (hMAO) inhibitory activity. Moreover, compounds 4 and 5 presented higher ORAC-FL indexes and lower oxidation potential values than the corresponding AntiOXCINs. Catechols 4 and 5 exhibited broader safety windows in differentiated neuroblastoma cells than benzodioxole derivatives 2 and 3. Compound 4 is highlighted as a safe mitochondria-targeted antioxidant with dual ChE/MAO inhibitory activity. Overall, this work is a contribution for the development of dual therapeutic agents addressing both mitochondrial oxidative stress and neurotransmitter depletion. |
|---|---|
| Autores principais: | Chavarria, Daniel |
| Outros Autores: | Da Silva, Ophelie; Benfeito, Sofia; Barreiro, Sandra; Garrido, Jorge; Cagide, Fernando; Soares, Pedro; Remião, Fernando; Brazzolotto, Xavier; Nachon, Florian; Oliveira, Paulo J.; Dias, José; Borges, Fernanda |
| Assunto: | neurodegenerative diseases piperine triphenylphosphonium cholinesterases monoamine oxidase mitochondria-targeted antioxidants |
| Ano: | 2021 |
| País: | Portugal |
| Tipo de documento: | artigo |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Coimbra |
| Idioma: | inglês |
| Origem: | Estudo Geral - Universidade de Coimbra |
| _version_ | 1868797499686256640 |
|---|---|
| author | Chavarria, Daniel |
| author2 | Da Silva, Ophelie Benfeito, Sofia Barreiro, Sandra Garrido, Jorge Cagide, Fernando Soares, Pedro Remião, Fernando Brazzolotto, Xavier Nachon, Florian Oliveira, Paulo J. Dias, José Borges, Fernanda |
| author2_role | author author author author author author author author author author author author |
| author_facet | Chavarria, Daniel Da Silva, Ophelie Benfeito, Sofia Barreiro, Sandra Garrido, Jorge Cagide, Fernando Soares, Pedro Remião, Fernando Brazzolotto, Xavier Nachon, Florian Oliveira, Paulo J. Dias, José Borges, Fernanda |
| author_role | author |
| contributor_name_str_mv | Estudo Geral |
| country_str | PT |
| creators_json_txt | [{\"Person.name\":\"Chavarria, Daniel\"},{\"Person.name\":\"Da Silva, Ophelie\"},{\"Person.name\":\"Benfeito, Sofia\"},{\"Person.name\":\"Barreiro, Sandra\"},{\"Person.name\":\"Garrido, Jorge\"},{\"Person.name\":\"Cagide, Fernando\"},{\"Person.name\":\"Soares, Pedro\"},{\"Person.name\":\"Remião, Fernando\"},{\"Person.name\":\"Brazzolotto, Xavier\"},{\"Person.name\":\"Nachon, Florian\"},{\"Person.name\":\"Oliveira, Paulo J.\"},{\"Person.name\":\"Dias, José\"},{\"Person.name\":\"Borges, Fernanda\"}] |
| datacite.contributors.contributor.contributorName.fl_str_mv | Estudo Geral |
| datacite.creators.creator.creatorName.fl_str_mv | Chavarria, Daniel Da Silva, Ophelie Benfeito, Sofia Barreiro, Sandra Garrido, Jorge Cagide, Fernando Soares, Pedro Remião, Fernando Brazzolotto, Xavier Nachon, Florian Oliveira, Paulo J. Dias, José Borges, Fernanda |
| datacite.date.Accepted.fl_str_mv | 2021-02-23T00:00:00Z |
| datacite.date.available.fl_str_mv | 2021-02-23T00:00:00Z |
| datacite.rights.fl_str_mv | http://purl.org/coar/access_right/c_abf2 |
| datacite.subjects.subject.fl_str_mv | neurodegenerative diseases piperine triphenylphosphonium cholinesterases monoamine oxidase mitochondria-targeted antioxidants |
| datacite.titles.title.fl_str_mv | Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases |
| dc.contributor.none.fl_str_mv | Estudo Geral |
| dc.creator.none.fl_str_mv | Chavarria, Daniel Da Silva, Ophelie Benfeito, Sofia Barreiro, Sandra Garrido, Jorge Cagide, Fernando Soares, Pedro Remião, Fernando Brazzolotto, Xavier Nachon, Florian Oliveira, Paulo J. Dias, José Borges, Fernanda |
| dc.date.Accepted.fl_str_mv | 2021-02-23T00:00:00Z |
| dc.date.available.fl_str_mv | 2021-02-23T00:00:00Z |
| dc.format.none.fl_str_mv | application/pdf |
| dc.identifier.none.fl_str_mv | https://hdl.handle.net/10316/103683 |
| dc.language.none.fl_str_mv | eng |
| dc.publisher.none.fl_str_mv | MDPI |
| dc.rights.none.fl_str_mv | http://purl.org/coar/access_right/c_abf2 |
| dc.subject.none.fl_str_mv | neurodegenerative diseases piperine triphenylphosphonium cholinesterases monoamine oxidase mitochondria-targeted antioxidants |
| dc.title.fl_str_mv | Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases |
| dc.type.none.fl_str_mv | http://purl.org/coar/resource_type/c_6501 |
| description | Neurotransmitter depletion and mitochondrial dysfunction are among the multiple pathological events that lead to neurodegeneration. Following our previous studies related with the development of multitarget mitochondriotropic antioxidants, this study aims to evaluate whether the π-system extension on the chemical scaffolds of AntiOXCIN2 and AntiOXCIN3 affects their bioactivity and safety profiles. After the synthesis of four triphenylphosphonium (TPP+) conjugates (compounds 2-5), we evaluated their antioxidant properties and their effect on neurotransmitter-metabolizing enzymes. All compounds were potent equine butyrylcholinesterase (eqBChE) and moderate electric eel acetylcholinesterase (eeAChE) inhibitors, with catechols 4 and 5 presenting lower IC50 values than AntiOXCIN2 and AntiOXCIN3, respectively. However, differences in the inhibition potency and selectivity of compounds 2-5 towards non-human and human cholinesterases (ChEs) were observed. Co-crystallization studies with compounds 2-5 in complex with human ChEs (hChEs) showed that these compounds exhibit different binging modes to hAChE and hBChE. Unlike AntiOXCINs, compounds 2-5 displayed moderate human monoamine oxidase (hMAO) inhibitory activity. Moreover, compounds 4 and 5 presented higher ORAC-FL indexes and lower oxidation potential values than the corresponding AntiOXCINs. Catechols 4 and 5 exhibited broader safety windows in differentiated neuroblastoma cells than benzodioxole derivatives 2 and 3. Compound 4 is highlighted as a safe mitochondria-targeted antioxidant with dual ChE/MAO inhibitory activity. Overall, this work is a contribution for the development of dual therapeutic agents addressing both mitochondrial oxidative stress and neurotransmitter depletion. |
| dirty | 0 |
| eu_rights_str_mv | openAccess |
| format | article |
| id | estudogl_2ff70cb2881086e2ced8aefa3b31d764 |
| identifier.url.fl_str_mv | https://hdl.handle.net/10316/103683 |
| instacron_str | uc |
| institution | Universidade de Coimbra |
| instname_str | Universidade de Coimbra |
| language | eng |
| network_acronym_str | estudogl |
| network_name_str | Estudo Geral - Universidade de Coimbra |
| oai_identifier_str | oai:estudogeral.uc.pt:10316/103683 |
| organization_str_mv | urn:organizationAcronym:uc |
| person_str_mv | Chavarria, Daniel Da Silva, Ophelie Benfeito, Sofia Barreiro, Sandra Garrido, Jorge Cagide, Fernando Soares, Pedro Remião, Fernando Brazzolotto, Xavier Nachon, Florian Oliveira, Paulo J. Dias, José Borges, Fernanda |
| publishDate | 2021 |
| publisher.none.fl_str_mv | MDPI |
| reponame_str | Estudo Geral - Universidade de Coimbra |
| repository_id_str | urn:repositoryAcronym:estudogl |
| service_str_mv | urn:repositoryAcronym:estudogl |
| spelling | engMDPIengNeurotransmitter depletion and mitochondrial dysfunction are among the multiple pathological events that lead to neurodegeneration. Following our previous studies related with the development of multitarget mitochondriotropic antioxidants, this study aims to evaluate whether the π-system extension on the chemical scaffolds of AntiOXCIN2 and AntiOXCIN3 affects their bioactivity and safety profiles. After the synthesis of four triphenylphosphonium (TPP+) conjugates (compounds 2-5), we evaluated their antioxidant properties and their effect on neurotransmitter-metabolizing enzymes. All compounds were potent equine butyrylcholinesterase (eqBChE) and moderate electric eel acetylcholinesterase (eeAChE) inhibitors, with catechols 4 and 5 presenting lower IC50 values than AntiOXCIN2 and AntiOXCIN3, respectively. However, differences in the inhibition potency and selectivity of compounds 2-5 towards non-human and human cholinesterases (ChEs) were observed. Co-crystallization studies with compounds 2-5 in complex with human ChEs (hChEs) showed that these compounds exhibit different binging modes to hAChE and hBChE. Unlike AntiOXCINs, compounds 2-5 displayed moderate human monoamine oxidase (hMAO) inhibitory activity. Moreover, compounds 4 and 5 presented higher ORAC-FL indexes and lower oxidation potential values than the corresponding AntiOXCINs. Catechols 4 and 5 exhibited broader safety windows in differentiated neuroblastoma cells than benzodioxole derivatives 2 and 3. Compound 4 is highlighted as a safe mitochondria-targeted antioxidant with dual ChE/MAO inhibitory activity. Overall, this work is a contribution for the development of dual therapeutic agents addressing both mitochondrial oxidative stress and neurotransmitter depletion.application/pdfporFine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative DiseasesChavarria, DanielDa Silva, OphelieBenfeito, SofiaBarreiro, SandraGarrido, JorgeCagide, FernandoSoares, PedroRemião, FernandoBrazzolotto, XavierNachon, FlorianOliveira, Paulo J.Dias, JoséBorges, FernandaHostingInstitutionOrganizationalEstudo Gerale-mailmailto:inf@sib.uc.ptinf@sib.uc.ptISSNIsPartOf2076-3921DOIIsPartOf10.3390/antiox100203292021-02-232021-02-23T00:00:00Z2021-02-23T00:00:00ZHandlehttps://hdl.handle.net/10316/103683http://purl.org/coar/access_right/c_abf2open accessneurodegenerative diseasespiperinetriphenylphosphoniumcholinesterasesmonoamine oxidasemitochondria-targeted antioxidants2451643 bytesliteraturehttp://purl.org/coar/resource_type/c_6501journal articleapplication/pdfhttps://estudogeral.uc.pt/bitstream/10316/103683/1/antioxidants-10-00329-v3.pdf |
| spellingShingle | Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases Chavarria, Daniel neurodegenerative diseases piperine triphenylphosphonium cholinesterases monoamine oxidase mitochondria-targeted antioxidants |
| status | SINGLETON |
| subject.fl_str_mv | neurodegenerative diseases piperine triphenylphosphonium cholinesterases monoamine oxidase mitochondria-targeted antioxidants |
| title | Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases |
| title_full | Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases |
| title_fullStr | Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases |
| title_full_unstemmed | Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases |
| title_short | Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases |
| title_sort | Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases |
| topic | neurodegenerative diseases piperine triphenylphosphonium cholinesterases monoamine oxidase mitochondria-targeted antioxidants |
| topic_facet | neurodegenerative diseases piperine triphenylphosphonium cholinesterases monoamine oxidase mitochondria-targeted antioxidants |
| url | https://hdl.handle.net/10316/103683 |
| visible | 1 |