Synthesis and evaluation of sesquiterpene lactone inhibitors of phospholipase A 2 from Bothrops jararacussu
Autor(a) principal: | |
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Data de Publicação: | 2010 |
Outros Autores: | , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | LOCUS Repositório Institucional da UFV |
Texto Completo: | https://doi.org/10.1016/j.toxicon.2010.10.010 http://www.locus.ufv.br/handle/123456789/14510 |
Resumo: | Several sesquiterpene lactone were synthesized and their inhibitive activities on phospholipase A2 (PLA2) from Bothrops jararacussu venom were evaluated. Compounds Lac01 and Lac02 were efficient against PLA2 edema-inducing, enzymatic and myotoxic activities and it reduces around 85% of myotoxicity and around 70% of edema-inducing activity. Lac05–Lac08 presented lower efficiency in inhibiting the biological activities studied and reduce the myotoxic and edema-inducing activities around only 15%. The enzymatic activity was significantly reduced. The values of inhibition constants (KI) for Lac01 and Lac02 were approximately 740 μM, and for compounds Lac05–Lac08 the inhibition constants were approximately 7.622–9.240 μM. The enzymatic kinetic studies show that the sesquiterpene lactones inhibit PLA2 in a non-competitive manner. Some aspects of the structure–activity relationships (topologic, molecular and electronic parameters) were obtained using ab initio quantum calculations and analyzed by chemometric methods (HCA and PCA). The quantum chemistry calculations show that compounds with a higher capacity of inhibiting PLA2 (Lac01–Lac04) present lower values of highest occupied molecular orbital (HOMO) energy and molecular volume (VOL) and bigger values of hydrophobicity (LogP). These results indicate some topologic aspects of the binding site of sesquiterpene lactone derivatives and PLA2. |
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Alvarenga, E.S. deSilva, S.A.Barosa, L.C.A.Demuner, A.J.Parreira, A.G.Ribeiro, R.I.M.A.Marcussi, S.Ferreira, J.M.S.Resende, R.R.Granjeiro, P.A.Silva, J.A.Soares, A.M.Marangoni, S.Silva, S.L. Da2017-12-06T17:26:36Z2017-12-06T17:26:36Z2010-10-310041-0101https://doi.org/10.1016/j.toxicon.2010.10.010http://www.locus.ufv.br/handle/123456789/14510Several sesquiterpene lactone were synthesized and their inhibitive activities on phospholipase A2 (PLA2) from Bothrops jararacussu venom were evaluated. Compounds Lac01 and Lac02 were efficient against PLA2 edema-inducing, enzymatic and myotoxic activities and it reduces around 85% of myotoxicity and around 70% of edema-inducing activity. Lac05–Lac08 presented lower efficiency in inhibiting the biological activities studied and reduce the myotoxic and edema-inducing activities around only 15%. The enzymatic activity was significantly reduced. The values of inhibition constants (KI) for Lac01 and Lac02 were approximately 740 μM, and for compounds Lac05–Lac08 the inhibition constants were approximately 7.622–9.240 μM. The enzymatic kinetic studies show that the sesquiterpene lactones inhibit PLA2 in a non-competitive manner. Some aspects of the structure–activity relationships (topologic, molecular and electronic parameters) were obtained using ab initio quantum calculations and analyzed by chemometric methods (HCA and PCA). The quantum chemistry calculations show that compounds with a higher capacity of inhibiting PLA2 (Lac01–Lac04) present lower values of highest occupied molecular orbital (HOMO) energy and molecular volume (VOL) and bigger values of hydrophobicity (LogP). These results indicate some topologic aspects of the binding site of sesquiterpene lactone derivatives and PLA2.engToxiconv.57(1), p. 100–108, January 2011Bothrops jararacussuDFTChemometricsPLA2Sesquiterpene lactoneSynthesis and evaluation of sesquiterpene lactone inhibitors of phospholipase A 2 from Bothrops jararacussuinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfinfo:eu-repo/semantics/openAccessreponame:LOCUS Repositório Institucional da UFVinstname:Universidade Federal de Viçosa (UFV)instacron:UFVORIGINAL1-s2.0-S0041010110003910-main.pdf1-s2.0-S0041010110003910-main.pdftexto completoapplication/pdf674040https://locus.ufv.br//bitstream/123456789/14510/1/1-s2.0-S0041010110003910-main.pdf9658704c5e93d2b38402194169b5fe43MD51LICENSElicense.txtlicense.txttext/plain; charset=utf-81748https://locus.ufv.br//bitstream/123456789/14510/2/license.txt8a4605be74aa9ea9d79846c1fba20a33MD52THUMBNAIL1-s2.0-S0041010110003910-main.pdf.jpg1-s2.0-S0041010110003910-main.pdf.jpgIM Thumbnailimage/jpeg5187https://locus.ufv.br//bitstream/123456789/14510/3/1-s2.0-S0041010110003910-main.pdf.jpge7fcf18bd88fe9f8ab9b2dbc65071bbfMD53123456789/145102017-12-06 22:01:15.195oai:locus.ufv.br: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Repositório InstitucionalPUBhttps://www.locus.ufv.br/oai/requestfabiojreis@ufv.bropendoar:21452017-12-07T01:01:15LOCUS Repositório Institucional da UFV - Universidade Federal de Viçosa (UFV)false |
dc.title.en.fl_str_mv |
Synthesis and evaluation of sesquiterpene lactone inhibitors of phospholipase A 2 from Bothrops jararacussu |
title |
Synthesis and evaluation of sesquiterpene lactone inhibitors of phospholipase A 2 from Bothrops jararacussu |
spellingShingle |
Synthesis and evaluation of sesquiterpene lactone inhibitors of phospholipase A 2 from Bothrops jararacussu Alvarenga, E.S. de Bothrops jararacussu DFT Chemometrics PLA2 Sesquiterpene lactone |
title_short |
Synthesis and evaluation of sesquiterpene lactone inhibitors of phospholipase A 2 from Bothrops jararacussu |
title_full |
Synthesis and evaluation of sesquiterpene lactone inhibitors of phospholipase A 2 from Bothrops jararacussu |
title_fullStr |
Synthesis and evaluation of sesquiterpene lactone inhibitors of phospholipase A 2 from Bothrops jararacussu |
title_full_unstemmed |
Synthesis and evaluation of sesquiterpene lactone inhibitors of phospholipase A 2 from Bothrops jararacussu |
title_sort |
Synthesis and evaluation of sesquiterpene lactone inhibitors of phospholipase A 2 from Bothrops jararacussu |
author |
Alvarenga, E.S. de |
author_facet |
Alvarenga, E.S. de Silva, S.A. Barosa, L.C.A. Demuner, A.J. Parreira, A.G. Ribeiro, R.I.M.A. Marcussi, S. Ferreira, J.M.S. Resende, R.R. Granjeiro, P.A. Silva, J.A. Soares, A.M. Marangoni, S. Silva, S.L. Da |
author_role |
author |
author2 |
Silva, S.A. Barosa, L.C.A. Demuner, A.J. Parreira, A.G. Ribeiro, R.I.M.A. Marcussi, S. Ferreira, J.M.S. Resende, R.R. Granjeiro, P.A. Silva, J.A. Soares, A.M. Marangoni, S. Silva, S.L. Da |
author2_role |
author author author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Alvarenga, E.S. de Silva, S.A. Barosa, L.C.A. Demuner, A.J. Parreira, A.G. Ribeiro, R.I.M.A. Marcussi, S. Ferreira, J.M.S. Resende, R.R. Granjeiro, P.A. Silva, J.A. Soares, A.M. Marangoni, S. Silva, S.L. Da |
dc.subject.pt-BR.fl_str_mv |
Bothrops jararacussu DFT Chemometrics PLA2 Sesquiterpene lactone |
topic |
Bothrops jararacussu DFT Chemometrics PLA2 Sesquiterpene lactone |
description |
Several sesquiterpene lactone were synthesized and their inhibitive activities on phospholipase A2 (PLA2) from Bothrops jararacussu venom were evaluated. Compounds Lac01 and Lac02 were efficient against PLA2 edema-inducing, enzymatic and myotoxic activities and it reduces around 85% of myotoxicity and around 70% of edema-inducing activity. Lac05–Lac08 presented lower efficiency in inhibiting the biological activities studied and reduce the myotoxic and edema-inducing activities around only 15%. The enzymatic activity was significantly reduced. The values of inhibition constants (KI) for Lac01 and Lac02 were approximately 740 μM, and for compounds Lac05–Lac08 the inhibition constants were approximately 7.622–9.240 μM. The enzymatic kinetic studies show that the sesquiterpene lactones inhibit PLA2 in a non-competitive manner. Some aspects of the structure–activity relationships (topologic, molecular and electronic parameters) were obtained using ab initio quantum calculations and analyzed by chemometric methods (HCA and PCA). The quantum chemistry calculations show that compounds with a higher capacity of inhibiting PLA2 (Lac01–Lac04) present lower values of highest occupied molecular orbital (HOMO) energy and molecular volume (VOL) and bigger values of hydrophobicity (LogP). These results indicate some topologic aspects of the binding site of sesquiterpene lactone derivatives and PLA2. |
publishDate |
2010 |
dc.date.issued.fl_str_mv |
2010-10-31 |
dc.date.accessioned.fl_str_mv |
2017-12-06T17:26:36Z |
dc.date.available.fl_str_mv |
2017-12-06T17:26:36Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
format |
article |
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dc.identifier.uri.fl_str_mv |
https://doi.org/10.1016/j.toxicon.2010.10.010 http://www.locus.ufv.br/handle/123456789/14510 |
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0041-0101 |
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0041-0101 |
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https://doi.org/10.1016/j.toxicon.2010.10.010 http://www.locus.ufv.br/handle/123456789/14510 |
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eng |
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eng |
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v.57(1), p. 100–108, January 2011 |
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