Síntese de Novos Nucleosídeos Quinolônicos não Naturais como Potenciais Agentes Antivirais
Autor(a) principal: | |
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Data de Publicação: | 2003 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Repositório Institucional da Universidade Federal Fluminense (RIUFF) |
Texto Completo: | https://app.uff.br/riuff/handle/1/19594 |
Resumo: | The interesting biological activities of synthetic quinoline derivatives as antibacterial and antiviral agents urged many research groups to construct numerous analogues of such compounds. Since the discovery of acyclovir as a potent and selective antiherpes virus agent, considerable interest has been focused in the synthesis of novel acyclonucleoside analogues in the search for more effective, selective and non toxic antiviral our antitumor agents. In this study 23 new quinolonic acyclovir analogues were synthesized: 1-[(2-hydroxyethoxy)methyl]-3-carbethoxy-4(1H)quinolone (80a-m) and 1-[(2-hydroxy-ethoxy)methyl]-4(1H)quinolone-3-carboxilic acid (81a-j,m). The quinolones were previously synthesized by known procedures. For preparing the quinolone acyclovir analogues in good yields, we introduced some modifications which significantly improved the previous described procedure of Ubasawa et all in terms of simplicity and yields. Thus, our route towards compounds type 80, employed a one pot reaction: silylation of the desired quinolone (BSTFA1%TMCS) followed by equimolar amount addition of 1,3-dioxolane, chlorotrimethylsilane and KI, at room temperature. The acyclonucleosides 80 a-m were obtained in 40-77% yields. The esthers 80 compounds were subsequently converted into the corresponding hydroxyacids: 1-[(2-hydroxy-ethoxy)methyl]-4(1H)quinolone-3-carboxilic acid (81a-j,m) in 40-70% yields. Antiviral activity of 80 and 81 on HSV-1 virus infection was assessed by virus yield assay. The carboxylic acids 81 and the esthers 80, except compounds 80g and 81g were found to reduce the virus yield in 93 to 99% at the concentration of 50 M, being the acids, in general, more effective inhibitors than their corresponding esthers. Attempts of tosylation reaction of 1-[(2-hydroxy-ethoxy)methyl]-6-methyl-3-carbethoxy-4(1H)quinolone (80a) using tosyl chloride in pyridine or p-toluenesulfonic acid, K10 failed to give the desired derivative. Reaction of 1-[(2-hydroxy-ethoxy)methyl]-6-methyl-3-carbethoxy-4(1H)quinolone (80a) with diisopropyl phosphonate chloride (92) didn t lead to the phosphate (84a) products, probably due to starting materials decomposition during the reactions. Aiming towards quinolonole seco-nucleosides, ribonucleosides 6-methyl-1-(2,3,5-tri-O-benzoyl--D-ribofuranosyl-4(1H)quinolone-3-carboethoxy (69a) was prepared by known procedures developed by our group. Compound 69a treated with NaIO4 and NaBH4 supported in resin amberlist A-21 failed to give any nucleoside product. In this study, we also applied a new methodology aiming towards 2`,3`-didehydro-2`,3`-dideoxyribonucleosides (73a). The 6-methyl-1-(-D-ribofuranosyl-4(1H)quinolone-3-carbomethoxy (93a) was transformed into 6-methyl-1-(2´,5´-di-O-acetyl-3´-bromo-3´-deoxy--D-ribofuranosyl-4(1H)quinolone-3-carbomethoxy (78a) and 6-methyl-1-(3´,5´-di-O-acetyl-2´-bromo-2´-deoxy--D-ribofuranosyl-4(1H)quinolone-3-carbomethoxy (78a´) on application of Isawa procedure. This bromoacetate product mixture was reacted with. NiCl2(PPh3)2 or Ni(acac)2. It is noteworthy that under these conditions the glycosidic bond uderwent cleavage. |
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Síntese de Novos Nucleosídeos Quinolônicos não Naturais como Potenciais Agentes AntiviraisSynthesis of New Quinolonics Nucleosides no Natural by Antivirals Potential AgentsNucleosídeosRibonucleosídeosAciclonucleosideosQuinolonasSíntese orgânicaNucleosidesRibonucleosidesAcyclonucleosideOrganic synthesisQuinolonesCNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA ORGANICAThe interesting biological activities of synthetic quinoline derivatives as antibacterial and antiviral agents urged many research groups to construct numerous analogues of such compounds. Since the discovery of acyclovir as a potent and selective antiherpes virus agent, considerable interest has been focused in the synthesis of novel acyclonucleoside analogues in the search for more effective, selective and non toxic antiviral our antitumor agents. In this study 23 new quinolonic acyclovir analogues were synthesized: 1-[(2-hydroxyethoxy)methyl]-3-carbethoxy-4(1H)quinolone (80a-m) and 1-[(2-hydroxy-ethoxy)methyl]-4(1H)quinolone-3-carboxilic acid (81a-j,m). The quinolones were previously synthesized by known procedures. For preparing the quinolone acyclovir analogues in good yields, we introduced some modifications which significantly improved the previous described procedure of Ubasawa et all in terms of simplicity and yields. Thus, our route towards compounds type 80, employed a one pot reaction: silylation of the desired quinolone (BSTFA1%TMCS) followed by equimolar amount addition of 1,3-dioxolane, chlorotrimethylsilane and KI, at room temperature. The acyclonucleosides 80 a-m were obtained in 40-77% yields. The esthers 80 compounds were subsequently converted into the corresponding hydroxyacids: 1-[(2-hydroxy-ethoxy)methyl]-4(1H)quinolone-3-carboxilic acid (81a-j,m) in 40-70% yields. Antiviral activity of 80 and 81 on HSV-1 virus infection was assessed by virus yield assay. The carboxylic acids 81 and the esthers 80, except compounds 80g and 81g were found to reduce the virus yield in 93 to 99% at the concentration of 50 M, being the acids, in general, more effective inhibitors than their corresponding esthers. Attempts of tosylation reaction of 1-[(2-hydroxy-ethoxy)methyl]-6-methyl-3-carbethoxy-4(1H)quinolone (80a) using tosyl chloride in pyridine or p-toluenesulfonic acid, K10 failed to give the desired derivative. Reaction of 1-[(2-hydroxy-ethoxy)methyl]-6-methyl-3-carbethoxy-4(1H)quinolone (80a) with diisopropyl phosphonate chloride (92) didn t lead to the phosphate (84a) products, probably due to starting materials decomposition during the reactions. Aiming towards quinolonole seco-nucleosides, ribonucleosides 6-methyl-1-(2,3,5-tri-O-benzoyl--D-ribofuranosyl-4(1H)quinolone-3-carboethoxy (69a) was prepared by known procedures developed by our group. Compound 69a treated with NaIO4 and NaBH4 supported in resin amberlist A-21 failed to give any nucleoside product. In this study, we also applied a new methodology aiming towards 2`,3`-didehydro-2`,3`-dideoxyribonucleosides (73a). The 6-methyl-1-(-D-ribofuranosyl-4(1H)quinolone-3-carbomethoxy (93a) was transformed into 6-methyl-1-(2´,5´-di-O-acetyl-3´-bromo-3´-deoxy--D-ribofuranosyl-4(1H)quinolone-3-carbomethoxy (78a) and 6-methyl-1-(3´,5´-di-O-acetyl-2´-bromo-2´-deoxy--D-ribofuranosyl-4(1H)quinolone-3-carbomethoxy (78a´) on application of Isawa procedure. This bromoacetate product mixture was reacted with. NiCl2(PPh3)2 or Ni(acac)2. It is noteworthy that under these conditions the glycosidic bond uderwent cleavage.Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorNeste trabalho foram obtidos 23 novos aciclonucleosídeos quinolônicos análogos do aciclovir, dos tipos 1-[(2-hidroxi) metil]-3-carbetoxi-4(1H)quinolona (80a-m) e ácido-3-carboxílico-1-[(2-hidroxietoxi)metil]-4(1H)quinolona (81a-j e 81m), estes últimos contendo suas hidroxilas totalmente desprotegidas. Dentre as técnicas testadas para a obtenção de 80am, a que apresentou melhores resultados foi a da prévia sililação das bases nitrogenadas utilizando-se bistrimetilsiltrifluoacetamida (BSTFA) contendo 1% de clorotrimetilsilano seguindo-se de acoplamento em um único pote reacional com 1,3-dioxolano e iodeto de potássio, na presença de trimetilsililtrifluormetanossulfonato como catalisador (TMSOTf). Foram obtidos os derivados 80a-j e 80a-m com rendimentos entre 40 e 77%, contendo a hidroxila terminal 4 desprotegida e o grupamento ácido da posição 3 do anel quinolônico protegido sob a forma de éster metílico ou etílico, de acordo com as condições empregadas. Para a obtenção dos aciclonucleosídeos 81a-j e 81m foi efetuada hidrólise usando-se solução etanólica de hidróxido de sódio, chegando-se aos produtos desejados em rendimentos que variaram entre 40 e 69%. Estes aciclonucleosídeos 80a-j, 80m, 81a-j e 81m foram testados quanto a sua atividade antiviral, frente ao vírus HSV-1, causador da herpes. Pode-se observar que os derivados do tipo 81 foram, em geral mais ativos do que os seus correspondentes ésteres 80. Quando isto não ocorreu, entre ácidos (81) e ésteres (80), com exceção das substâncias 80g e 81g, todos apresentaram excelentes graus de inibição, em uma concentração de 50 mM, inibindo entre 93 e 99% a replicação viral em células: VERO. Foram ainda efetuadas tentativas de derivatização da hidroxila da cadeia acíclica em nucleosídeos do tipo 80. A introdução do grupamento tosilato, mesilato ou clorado com o objetivo de sua substituição posterior por grupos azido, amino, etc não levaram a resultados satisfatórios nas reações realizadas. Também foram realizadas reações visando a obtenção de aciclonucleosídeos quinolônicos contendo o grupo dialquilfosfato (88) ou fosfato ácido (89) na posição terminal da cadeia acíclica (posição 4 ) sem contudo obter os produtos desejados. Prosseguindo ainda na linha de obtenção de aciclonucleosídeos quinolônicos, foram feitas reações para se chegar a 2 ,3 -seco-nucleosídeos 86 (ácido 3-carboxílico-1-b-D-(2´,3´-seco)-ribofuranosil-4(1H)quinolona) a partir dos ribonucleosídeos correspondentes. O ribonucleosídeo 3-carboxi-1-b-D-ribofuranosil-4(1H)quinolona (72) foi reagido com periodato de sódio e boroidreto de sódio suportados em resina amberliste A21 levando a produtos de decomposição da matéria-prima. Quanto ao desenvolvimento de uma nova metodologia para a obtenção de didesidro-didesoxiribonucleosídeos quinolônicos a partir do ribonucleosídeo correspondente devidamente funcionalizado, ou seja, derivados (2`,3`),(3`,2`) bromo-O-acetilados (78), a utilização para este fim de complexos de níquel no estado de oxidação zero via reação de b-eliminação redutiva não obteve sucesso, nas condições empregadas.Universidade Federal FluminensePrograma de Pós-graduação em Química OrgânicaQuímica OrgânicaBRUFFSouza, Maria Cecília Bastos Vieira deCPF:44470134791http://genos.cnpq.br:12010/dwlattes/owa/prc_imp_cv_int?f_cod=K4783203D6Ferreira, Vítor FranciscoCPF:34985220787http://genos.cnpq.br:12010/dwlattes/owa/prc_imp_cv_int?f_cod=K4783135Y6Echevarria, AureaCPF:66874238868http://genos.cnpq.br:12010/dwlattes/owa/prc_imp_cv_int?f_cod=K4787205D1Corrêa, Rodrigo JoséCPF:49999449994http://genos.cnpq.br:12010/dwlattes/owa/prc_imp_cv_int?f_cod=K4797658E3Cunha, Anna CláudiaCPF:91618983768http://genos.cnpq.br:12010/dwlattes/owa/prc_imp_cv_int?f_cod=K4728588U6Cunha, Maria Fernanda Vasconcelos daCPF:58787585787http://genos.cnpq.br:12010/dwlattes/owa/prc_imp_cv_int?f_cod=K4786691Y5Gomes, Claudia Regina Brandão2021-03-10T20:47:52Z2004-09-212021-03-10T20:47:52Z2003-03-25info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfhttps://app.uff.br/riuff/handle/1/19594porCC-BY-SAinfo:eu-repo/semantics/embargoedAccessreponame:Repositório Institucional da Universidade Federal Fluminense (RIUFF)instname:Universidade Federal Fluminense (UFF)instacron:UFF2021-03-10T20:47:52Zoai:app.uff.br:1/19594Repositório InstitucionalPUBhttps://app.uff.br/oai/requestriuff@id.uff.bropendoar:21202024-08-19T11:13:27.388788Repositório Institucional da Universidade Federal Fluminense (RIUFF) - Universidade Federal Fluminense (UFF)false |
dc.title.none.fl_str_mv |
Síntese de Novos Nucleosídeos Quinolônicos não Naturais como Potenciais Agentes Antivirais Synthesis of New Quinolonics Nucleosides no Natural by Antivirals Potential Agents |
title |
Síntese de Novos Nucleosídeos Quinolônicos não Naturais como Potenciais Agentes Antivirais |
spellingShingle |
Síntese de Novos Nucleosídeos Quinolônicos não Naturais como Potenciais Agentes Antivirais Gomes, Claudia Regina Brandão Nucleosídeos Ribonucleosídeos Aciclonucleosideos Quinolonas Síntese orgânica Nucleosides Ribonucleosides Acyclonucleoside Organic synthesis Quinolones CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA ORGANICA |
title_short |
Síntese de Novos Nucleosídeos Quinolônicos não Naturais como Potenciais Agentes Antivirais |
title_full |
Síntese de Novos Nucleosídeos Quinolônicos não Naturais como Potenciais Agentes Antivirais |
title_fullStr |
Síntese de Novos Nucleosídeos Quinolônicos não Naturais como Potenciais Agentes Antivirais |
title_full_unstemmed |
Síntese de Novos Nucleosídeos Quinolônicos não Naturais como Potenciais Agentes Antivirais |
title_sort |
Síntese de Novos Nucleosídeos Quinolônicos não Naturais como Potenciais Agentes Antivirais |
author |
Gomes, Claudia Regina Brandão |
author_facet |
Gomes, Claudia Regina Brandão |
author_role |
author |
dc.contributor.none.fl_str_mv |
Souza, Maria Cecília Bastos Vieira de CPF:44470134791 http://genos.cnpq.br:12010/dwlattes/owa/prc_imp_cv_int?f_cod=K4783203D6 Ferreira, Vítor Francisco CPF:34985220787 http://genos.cnpq.br:12010/dwlattes/owa/prc_imp_cv_int?f_cod=K4783135Y6 Echevarria, Aurea CPF:66874238868 http://genos.cnpq.br:12010/dwlattes/owa/prc_imp_cv_int?f_cod=K4787205D1 Corrêa, Rodrigo José CPF:49999449994 http://genos.cnpq.br:12010/dwlattes/owa/prc_imp_cv_int?f_cod=K4797658E3 Cunha, Anna Cláudia CPF:91618983768 http://genos.cnpq.br:12010/dwlattes/owa/prc_imp_cv_int?f_cod=K4728588U6 Cunha, Maria Fernanda Vasconcelos da CPF:58787585787 http://genos.cnpq.br:12010/dwlattes/owa/prc_imp_cv_int?f_cod=K4786691Y5 |
dc.contributor.author.fl_str_mv |
Gomes, Claudia Regina Brandão |
dc.subject.por.fl_str_mv |
Nucleosídeos Ribonucleosídeos Aciclonucleosideos Quinolonas Síntese orgânica Nucleosides Ribonucleosides Acyclonucleoside Organic synthesis Quinolones CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA ORGANICA |
topic |
Nucleosídeos Ribonucleosídeos Aciclonucleosideos Quinolonas Síntese orgânica Nucleosides Ribonucleosides Acyclonucleoside Organic synthesis Quinolones CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA::QUIMICA ORGANICA |
description |
The interesting biological activities of synthetic quinoline derivatives as antibacterial and antiviral agents urged many research groups to construct numerous analogues of such compounds. Since the discovery of acyclovir as a potent and selective antiherpes virus agent, considerable interest has been focused in the synthesis of novel acyclonucleoside analogues in the search for more effective, selective and non toxic antiviral our antitumor agents. In this study 23 new quinolonic acyclovir analogues were synthesized: 1-[(2-hydroxyethoxy)methyl]-3-carbethoxy-4(1H)quinolone (80a-m) and 1-[(2-hydroxy-ethoxy)methyl]-4(1H)quinolone-3-carboxilic acid (81a-j,m). The quinolones were previously synthesized by known procedures. For preparing the quinolone acyclovir analogues in good yields, we introduced some modifications which significantly improved the previous described procedure of Ubasawa et all in terms of simplicity and yields. Thus, our route towards compounds type 80, employed a one pot reaction: silylation of the desired quinolone (BSTFA1%TMCS) followed by equimolar amount addition of 1,3-dioxolane, chlorotrimethylsilane and KI, at room temperature. The acyclonucleosides 80 a-m were obtained in 40-77% yields. The esthers 80 compounds were subsequently converted into the corresponding hydroxyacids: 1-[(2-hydroxy-ethoxy)methyl]-4(1H)quinolone-3-carboxilic acid (81a-j,m) in 40-70% yields. Antiviral activity of 80 and 81 on HSV-1 virus infection was assessed by virus yield assay. The carboxylic acids 81 and the esthers 80, except compounds 80g and 81g were found to reduce the virus yield in 93 to 99% at the concentration of 50 M, being the acids, in general, more effective inhibitors than their corresponding esthers. Attempts of tosylation reaction of 1-[(2-hydroxy-ethoxy)methyl]-6-methyl-3-carbethoxy-4(1H)quinolone (80a) using tosyl chloride in pyridine or p-toluenesulfonic acid, K10 failed to give the desired derivative. Reaction of 1-[(2-hydroxy-ethoxy)methyl]-6-methyl-3-carbethoxy-4(1H)quinolone (80a) with diisopropyl phosphonate chloride (92) didn t lead to the phosphate (84a) products, probably due to starting materials decomposition during the reactions. Aiming towards quinolonole seco-nucleosides, ribonucleosides 6-methyl-1-(2,3,5-tri-O-benzoyl--D-ribofuranosyl-4(1H)quinolone-3-carboethoxy (69a) was prepared by known procedures developed by our group. Compound 69a treated with NaIO4 and NaBH4 supported in resin amberlist A-21 failed to give any nucleoside product. In this study, we also applied a new methodology aiming towards 2`,3`-didehydro-2`,3`-dideoxyribonucleosides (73a). The 6-methyl-1-(-D-ribofuranosyl-4(1H)quinolone-3-carbomethoxy (93a) was transformed into 6-methyl-1-(2´,5´-di-O-acetyl-3´-bromo-3´-deoxy--D-ribofuranosyl-4(1H)quinolone-3-carbomethoxy (78a) and 6-methyl-1-(3´,5´-di-O-acetyl-2´-bromo-2´-deoxy--D-ribofuranosyl-4(1H)quinolone-3-carbomethoxy (78a´) on application of Isawa procedure. This bromoacetate product mixture was reacted with. NiCl2(PPh3)2 or Ni(acac)2. It is noteworthy that under these conditions the glycosidic bond uderwent cleavage. |
publishDate |
2003 |
dc.date.none.fl_str_mv |
2003-03-25 2004-09-21 2021-03-10T20:47:52Z 2021-03-10T20:47:52Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
https://app.uff.br/riuff/handle/1/19594 |
url |
https://app.uff.br/riuff/handle/1/19594 |
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por |
language |
por |
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CC-BY-SA info:eu-repo/semantics/embargoedAccess |
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CC-BY-SA |
eu_rights_str_mv |
embargoedAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Universidade Federal Fluminense Programa de Pós-graduação em Química Orgânica Química Orgânica BR UFF |
publisher.none.fl_str_mv |
Universidade Federal Fluminense Programa de Pós-graduação em Química Orgânica Química Orgânica BR UFF |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da Universidade Federal Fluminense (RIUFF) instname:Universidade Federal Fluminense (UFF) instacron:UFF |
instname_str |
Universidade Federal Fluminense (UFF) |
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UFF |
institution |
UFF |
reponame_str |
Repositório Institucional da Universidade Federal Fluminense (RIUFF) |
collection |
Repositório Institucional da Universidade Federal Fluminense (RIUFF) |
repository.name.fl_str_mv |
Repositório Institucional da Universidade Federal Fluminense (RIUFF) - Universidade Federal Fluminense (UFF) |
repository.mail.fl_str_mv |
riuff@id.uff.br |
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