Triagem virtual e síntese de dímeros de lapachol e isatina com potencial atividade antitumoral

Detalhes bibliográficos
Autor(a) principal: Coelho, Maísa Cavalcanti
Data de Publicação: 2019
Tipo de documento: Dissertação
Idioma: por
Título da fonte: Biblioteca Digital de Teses e Dissertações da UFPB
Texto Completo: https://repositorio.ufpb.br/jspui/handle/123456789/15053
Resumo: The cancer is a disease with a considerable impact on humanity. It is estimated that by 2018 it may have affected approximately 18.1 million people worldwide. In general, existing antitumor treatments presents high toxicity and reduce patient's quality of life, making it indispensable to search for new antitumor compounds. In this research, a promising medicinal chemistry strategy is molecular hybridization, which brings together two pharmacological entities and can bring great benefits to their bioactivity and toxicity. Combined with this strategy, computational chemistry tools, such as molecular docking, if well used, can optimize this process. In molecular docking, the affinity of a linker in a macromolecule is calculated, predicting its docking tendency in this target. The present study aimed the in silico evaluation of a library of hybrids and their intermediates with structures based on isatin and lapachol, as well as to synthesize the most promising compounds. The protein NADPH quinone oxidurredutase (NQO1) was chosen as the target protein because it is highly expressed in tumor cells. The AutoDock4 program was used in virtual screening by molecular docking. System validation was done by redocking the native ligand, and the RMSD was equal to 0.51. In general, all the dimers tested had an excellent antitumor potential against NQO1, with binding energies (EL) between -10 and -9 kcal/mol, same range as dicumarol (36), being 31a-31c and 35a-35c more promising, with EL in the range of -11 kcal/mol, just like the native E6A ligand (28). For the production of dimers, lapachol was extracted by Soxhlet and acid-base extraction. Intermediates were synthesized according to literature protocols, but the use of microwaves was also tested. Lapachol was obtained pure with a better yield in Soxhlet extraction (0.76%) than the acid-base one (0.14%). The synthesis of lapachol dimers 31a-31c, 35a-35c and 33a-33c did not lead to the final products, only to intermediates 29 (67.2% yield), 30a (quantitative yield), and 32a-32c (11.69 %, 27.23% and 31.6% yield). In contrast, the isatin dimers 23a-23c and 26a-26c were synthesized in yields of 41, 29 and 20% for 23a-23c and 29.5%, 26% and 17%, respectively, for 26a-26c. Intermediates 22a-22c were produced in 50% yield. The perspective is that these isatin homo and heterodimers 23a-23c and 26a-26c as well as the potentially active intermediates 32a-32c and 29 have their syntheses optimized and sent for in vitro tests of antitumor activity in order to confirm their potential and to relate the data obtained in silico and in vitro.
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spelling Triagem virtual e síntese de dímeros de lapachol e isatina com potencial atividade antitumoralHibridização molecularDocking molecularAtividade anticâncerMolecular hybridizationMolecular dockingAntitumor activityCNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICAThe cancer is a disease with a considerable impact on humanity. It is estimated that by 2018 it may have affected approximately 18.1 million people worldwide. In general, existing antitumor treatments presents high toxicity and reduce patient's quality of life, making it indispensable to search for new antitumor compounds. In this research, a promising medicinal chemistry strategy is molecular hybridization, which brings together two pharmacological entities and can bring great benefits to their bioactivity and toxicity. Combined with this strategy, computational chemistry tools, such as molecular docking, if well used, can optimize this process. In molecular docking, the affinity of a linker in a macromolecule is calculated, predicting its docking tendency in this target. The present study aimed the in silico evaluation of a library of hybrids and their intermediates with structures based on isatin and lapachol, as well as to synthesize the most promising compounds. The protein NADPH quinone oxidurredutase (NQO1) was chosen as the target protein because it is highly expressed in tumor cells. The AutoDock4 program was used in virtual screening by molecular docking. System validation was done by redocking the native ligand, and the RMSD was equal to 0.51. In general, all the dimers tested had an excellent antitumor potential against NQO1, with binding energies (EL) between -10 and -9 kcal/mol, same range as dicumarol (36), being 31a-31c and 35a-35c more promising, with EL in the range of -11 kcal/mol, just like the native E6A ligand (28). For the production of dimers, lapachol was extracted by Soxhlet and acid-base extraction. Intermediates were synthesized according to literature protocols, but the use of microwaves was also tested. Lapachol was obtained pure with a better yield in Soxhlet extraction (0.76%) than the acid-base one (0.14%). The synthesis of lapachol dimers 31a-31c, 35a-35c and 33a-33c did not lead to the final products, only to intermediates 29 (67.2% yield), 30a (quantitative yield), and 32a-32c (11.69 %, 27.23% and 31.6% yield). In contrast, the isatin dimers 23a-23c and 26a-26c were synthesized in yields of 41, 29 and 20% for 23a-23c and 29.5%, 26% and 17%, respectively, for 26a-26c. Intermediates 22a-22c were produced in 50% yield. The perspective is that these isatin homo and heterodimers 23a-23c and 26a-26c as well as the potentially active intermediates 32a-32c and 29 have their syntheses optimized and sent for in vitro tests of antitumor activity in order to confirm their potential and to relate the data obtained in silico and in vitro.NenhumaUma das doenças com impacto considerável na humanidade é o câncer, que provavelmente terá atingido 18,1 milhões de pessoas no mundo em 2018. Os tratamentos antitumorais existentes, em geral, apresentam alta toxicidade e reduzem qualidade de vida do paciente, tornando indispensável a busca por novos compostos antitumorais. Nesta investigação, uma estratégia da química medicinal promissora é a hibridização molecular, que reúne duas entidades farmacológicas e pode trazer grandes benefícios à sua bioatividade e toxicidade. Aliado à esta estratégia, as ferramentas da química computacional, como o docking molecular, se bem utilizadas, podem otimizar este processo. No docking molecular, é calculada a afinidade de um ligante em uma macromolécula, prevendo a tendência de docking dele neste alvo. O presente estudo objetivou a avaliação in silico de uma biblioteca de híbridos e seus intermediários com estruturas baseadas na isatina e no lapachol, bem como sintetizar os compostos mais promissores. A proteína NADP(H) oxidurredutase (NQO1) foi escolhida como proteína alvo, por ser altamente expressa em células tumorais. O programa AutoDock4 foi utilizado na triagem virtual por docking molecular. A validação do sistema foi feita através do redocking do ligante nativo E6A, sendo o RMSD obtido igual a 0,51. Em geral, todos os dímeros testados apresentaram ótimo potencial antitumoral frente à NQO1, com energias de ligação (EL) entre 10 e -9 kcal/mol, mesma faixa que o dicumarol (36), sendo 31a-31c e 35a-35c os mais promissores, com EL na faixa de -11 kcal/mol, tal qual o ligante nativo E6A (28). Para a produção dos dímeros, o lapachol foi extraído por Soxhlet e extração ácido-básica. Os intermediários foram sintetizados de acordo com protocolos da literatura, mas também foi testado o uso de micro-ondas. O lapachol foi obtido puro com melhor rendimento na extração por Soxhlet (0,76%) em relação à ácido-base (0,14%). A síntese dos dímeros de lapachol 31a31c, 35a-35c e 33a-33c não levou aos produtos finais, apenas aos intermediários 29 (67,2% de rendimento), 30a (rendimento quantitativo), e 32a-32c (11,69%, 27,23% e 31,6% de rendimento). Em contrapartida, os dímeros de isatina 23a-23c e 26a-26c foram sintetizados com rendimentos de 41, 29 e 20% para 23a-23c e de 29,5%, 26% e 17%, respectivamente, para 26a-26c. Os intermediários 22a-22c foram produzidos com rendimento na faixa de 50%. A perspectiva é que estes homo e heterodímeros de isatina 23a-23c e 26a-26c, assim como os intermediários potencialmente ativos 32a-32c e 29 tenham suas sínteses otimizadas e sejam enviados para testes in vitro de atividade antitumoral, a fim de confirmar seu potencial e relacionar os dados obtidos in silico e in vitro.Universidade Federal da ParaíbaBrasilQuímicaPrograma de Pós-Graduação em QuímicaUFPBVasconcellos, Mário Luiz de Almeida Araujohttp://lattes.cnpq.br/1010366111082767Alencar Filho, Edilson Beserra deCoelho, Maísa Cavalcanti2019-07-11T19:49:57Z2019-07-112019-07-11T19:49:57Z2019-02-19info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesishttps://repositorio.ufpb.br/jspui/handle/123456789/15053porAttribution-NoDerivs 3.0 Brazilhttp://creativecommons.org/licenses/by-nd/3.0/br/info:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da UFPBinstname:Universidade Federal da Paraíba (UFPB)instacron:UFPB2019-07-11T19:49:57Zoai:repositorio.ufpb.br:123456789/15053Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufpb.br/PUBhttp://tede.biblioteca.ufpb.br:8080/oai/requestdiretoria@ufpb.br|| diretoria@ufpb.bropendoar:2019-07-11T19:49:57Biblioteca Digital de Teses e Dissertações da UFPB - Universidade Federal da Paraíba (UFPB)false
dc.title.none.fl_str_mv Triagem virtual e síntese de dímeros de lapachol e isatina com potencial atividade antitumoral
title Triagem virtual e síntese de dímeros de lapachol e isatina com potencial atividade antitumoral
spellingShingle Triagem virtual e síntese de dímeros de lapachol e isatina com potencial atividade antitumoral
Coelho, Maísa Cavalcanti
Hibridização molecular
Docking molecular
Atividade anticâncer
Molecular hybridization
Molecular docking
Antitumor activity
CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA
title_short Triagem virtual e síntese de dímeros de lapachol e isatina com potencial atividade antitumoral
title_full Triagem virtual e síntese de dímeros de lapachol e isatina com potencial atividade antitumoral
title_fullStr Triagem virtual e síntese de dímeros de lapachol e isatina com potencial atividade antitumoral
title_full_unstemmed Triagem virtual e síntese de dímeros de lapachol e isatina com potencial atividade antitumoral
title_sort Triagem virtual e síntese de dímeros de lapachol e isatina com potencial atividade antitumoral
author Coelho, Maísa Cavalcanti
author_facet Coelho, Maísa Cavalcanti
author_role author
dc.contributor.none.fl_str_mv Vasconcellos, Mário Luiz de Almeida Araujo
http://lattes.cnpq.br/1010366111082767
Alencar Filho, Edilson Beserra de
dc.contributor.author.fl_str_mv Coelho, Maísa Cavalcanti
dc.subject.por.fl_str_mv Hibridização molecular
Docking molecular
Atividade anticâncer
Molecular hybridization
Molecular docking
Antitumor activity
CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA
topic Hibridização molecular
Docking molecular
Atividade anticâncer
Molecular hybridization
Molecular docking
Antitumor activity
CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA
description The cancer is a disease with a considerable impact on humanity. It is estimated that by 2018 it may have affected approximately 18.1 million people worldwide. In general, existing antitumor treatments presents high toxicity and reduce patient's quality of life, making it indispensable to search for new antitumor compounds. In this research, a promising medicinal chemistry strategy is molecular hybridization, which brings together two pharmacological entities and can bring great benefits to their bioactivity and toxicity. Combined with this strategy, computational chemistry tools, such as molecular docking, if well used, can optimize this process. In molecular docking, the affinity of a linker in a macromolecule is calculated, predicting its docking tendency in this target. The present study aimed the in silico evaluation of a library of hybrids and their intermediates with structures based on isatin and lapachol, as well as to synthesize the most promising compounds. The protein NADPH quinone oxidurredutase (NQO1) was chosen as the target protein because it is highly expressed in tumor cells. The AutoDock4 program was used in virtual screening by molecular docking. System validation was done by redocking the native ligand, and the RMSD was equal to 0.51. In general, all the dimers tested had an excellent antitumor potential against NQO1, with binding energies (EL) between -10 and -9 kcal/mol, same range as dicumarol (36), being 31a-31c and 35a-35c more promising, with EL in the range of -11 kcal/mol, just like the native E6A ligand (28). For the production of dimers, lapachol was extracted by Soxhlet and acid-base extraction. Intermediates were synthesized according to literature protocols, but the use of microwaves was also tested. Lapachol was obtained pure with a better yield in Soxhlet extraction (0.76%) than the acid-base one (0.14%). The synthesis of lapachol dimers 31a-31c, 35a-35c and 33a-33c did not lead to the final products, only to intermediates 29 (67.2% yield), 30a (quantitative yield), and 32a-32c (11.69 %, 27.23% and 31.6% yield). In contrast, the isatin dimers 23a-23c and 26a-26c were synthesized in yields of 41, 29 and 20% for 23a-23c and 29.5%, 26% and 17%, respectively, for 26a-26c. Intermediates 22a-22c were produced in 50% yield. The perspective is that these isatin homo and heterodimers 23a-23c and 26a-26c as well as the potentially active intermediates 32a-32c and 29 have their syntheses optimized and sent for in vitro tests of antitumor activity in order to confirm their potential and to relate the data obtained in silico and in vitro.
publishDate 2019
dc.date.none.fl_str_mv 2019-07-11T19:49:57Z
2019-07-11
2019-07-11T19:49:57Z
2019-02-19
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/masterThesis
format masterThesis
status_str publishedVersion
dc.identifier.uri.fl_str_mv https://repositorio.ufpb.br/jspui/handle/123456789/15053
url https://repositorio.ufpb.br/jspui/handle/123456789/15053
dc.language.iso.fl_str_mv por
language por
dc.rights.driver.fl_str_mv Attribution-NoDerivs 3.0 Brazil
http://creativecommons.org/licenses/by-nd/3.0/br/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Attribution-NoDerivs 3.0 Brazil
http://creativecommons.org/licenses/by-nd/3.0/br/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Universidade Federal da Paraíba
Brasil
Química
Programa de Pós-Graduação em Química
UFPB
publisher.none.fl_str_mv Universidade Federal da Paraíba
Brasil
Química
Programa de Pós-Graduação em Química
UFPB
dc.source.none.fl_str_mv reponame:Biblioteca Digital de Teses e Dissertações da UFPB
instname:Universidade Federal da Paraíba (UFPB)
instacron:UFPB
instname_str Universidade Federal da Paraíba (UFPB)
instacron_str UFPB
institution UFPB
reponame_str Biblioteca Digital de Teses e Dissertações da UFPB
collection Biblioteca Digital de Teses e Dissertações da UFPB
repository.name.fl_str_mv Biblioteca Digital de Teses e Dissertações da UFPB - Universidade Federal da Paraíba (UFPB)
repository.mail.fl_str_mv diretoria@ufpb.br|| diretoria@ufpb.br
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