An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors
- Autores
- Vettorazzi, Marcela Cristina; Angelina, Emilio Luis; Lima, Santiago; Gonec, Tomas; Otevrel, Jan; Marvanova, Pavlina; Padrtova, Tereza; Mokry, Petr; Bobal, Pavel; Acosta, Lina M.; Palma, Alirio; Cobo, Justo; Bobalova, Janette; Csollei, Jozef; Malik, Ivan; Alvarez, Sergio Eduardo; Spiegel, Sarah; Jampilek, Josef; Enriz, Ricardo Daniel
- Año de publicación
- 2017
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Sphingosine kinase 1 (SphK1), the enzyme that produces the bioactive sphingolipid metabolite, sphingosine-1-phosphate, is a promising new molecular target for therapeutic intervention in cancer and inflammatory diseases. In view of its importance, the main objective of this work was to find new and more potent inhibitors for this enzyme possessing different structural scaffolds than those of the known inhibitors. Our theoretical and experimental study has allowed us to identify two new structural scaffolds (three new compounds), which could be used as starting structures for the design and then the development of new inhibitors of SphK1. Our study was carried out in different steps: virtual screening, synthesis, bioassays and molecular modelling. From our results, we propose a new dihydrobenzo[b]pyrimido[5,4-f]azepine and two alkyl{3-/4-[1-hydroxy-2-(4-arylpiperazin-1-yl)ethyl]phenyl}carbamates as initial structures for the development of new inhibitors. In addition, our molecular modelling study using QTAIM calculations, allowed us to describe in detail the molecular interactions that stabilize the different Ligand-Receptor complexes. Such analyses indicate that the cationic head of the different compounds must be refined in order to obtain an increase in the binding affinity of these ligands.
Fil: Vettorazzi, Marcela Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Angelina, Emilio Luis. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas y Naturales y Agrimensura. Departamento de Química. Laboratorio de Estructura Molecular y Propiedades; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Lima, Santiago. Virginia Commonwealth University. School of Medicine; Estados Unidos
Fil: Gonec, Tomas. Veterinarni A Farmaceuticka Univerzita Brno; República Checa
Fil: Otevrel, Jan. Veterinarni A Farmaceuticka Univerzita Brno; República Checa
Fil: Marvanova, Pavlina. Veterinarni A Farmaceuticka Univerzita Brno; República Checa
Fil: Padrtova, Tereza. Veterinarni A Farmaceuticka Univerzita Brno; República Checa
Fil: Mokry, Petr. Veterinarni A Farmaceuticka Univerzita Brno; República Checa
Fil: Bobal, Pavel. Veterinarni A Farmaceuticka Univerzita Brno; República Checa
Fil: Acosta, Lina M.. Universidad Industrial Santander; Colombia
Fil: Palma, Alirio. Universidad Industrial Santander; Colombia
Fil: Cobo, Justo. Universidad de Jaén; España
Fil: Bobalova, Janette. Institute Of Analytical Chemistry Of The Czech Academy Of Sciences; República Checa
Fil: Csollei, Jozef. Comenius University; Eslovaquia
Fil: Malik, Ivan. Comenius University; Eslovaquia
Fil: Alvarez, Sergio Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina
Fil: Spiegel, Sarah. Virginia Commonwealth University. School of Medicine; Estados Unidos
Fil: Jampilek, Josef. Comenius University; Eslovaquia
Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina - Materia
-
Bioassays
Molecular Modelling
Sphingosine Kinase 1 Inhibitors
Synthesis
Virtual Screening - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
.jpg)
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/37958
Ver los metadatos del registro completo
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An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitorsVettorazzi, Marcela CristinaAngelina, Emilio LuisLima, SantiagoGonec, TomasOtevrel, JanMarvanova, PavlinaPadrtova, TerezaMokry, PetrBobal, PavelAcosta, Lina M.Palma, AlirioCobo, JustoBobalova, JanetteCsollei, JozefMalik, IvanAlvarez, Sergio EduardoSpiegel, SarahJampilek, JosefEnriz, Ricardo DanielBioassaysMolecular ModellingSphingosine Kinase 1 InhibitorsSynthesisVirtual Screeninghttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1Sphingosine kinase 1 (SphK1), the enzyme that produces the bioactive sphingolipid metabolite, sphingosine-1-phosphate, is a promising new molecular target for therapeutic intervention in cancer and inflammatory diseases. In view of its importance, the main objective of this work was to find new and more potent inhibitors for this enzyme possessing different structural scaffolds than those of the known inhibitors. Our theoretical and experimental study has allowed us to identify two new structural scaffolds (three new compounds), which could be used as starting structures for the design and then the development of new inhibitors of SphK1. Our study was carried out in different steps: virtual screening, synthesis, bioassays and molecular modelling. From our results, we propose a new dihydrobenzo[b]pyrimido[5,4-f]azepine and two alkyl{3-/4-[1-hydroxy-2-(4-arylpiperazin-1-yl)ethyl]phenyl}carbamates as initial structures for the development of new inhibitors. In addition, our molecular modelling study using QTAIM calculations, allowed us to describe in detail the molecular interactions that stabilize the different Ligand-Receptor complexes. Such analyses indicate that the cationic head of the different compounds must be refined in order to obtain an increase in the binding affinity of these ligands.Fil: Vettorazzi, Marcela Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Angelina, Emilio Luis. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas y Naturales y Agrimensura. Departamento de Química. Laboratorio de Estructura Molecular y Propiedades; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Lima, Santiago. Virginia Commonwealth University. School of Medicine; Estados UnidosFil: Gonec, Tomas. Veterinarni A Farmaceuticka Univerzita Brno; República ChecaFil: Otevrel, Jan. Veterinarni A Farmaceuticka Univerzita Brno; República ChecaFil: Marvanova, Pavlina. Veterinarni A Farmaceuticka Univerzita Brno; República ChecaFil: Padrtova, Tereza. Veterinarni A Farmaceuticka Univerzita Brno; República ChecaFil: Mokry, Petr. Veterinarni A Farmaceuticka Univerzita Brno; República ChecaFil: Bobal, Pavel. Veterinarni A Farmaceuticka Univerzita Brno; República ChecaFil: Acosta, Lina M.. Universidad Industrial Santander; ColombiaFil: Palma, Alirio. Universidad Industrial Santander; ColombiaFil: Cobo, Justo. Universidad de Jaén; EspañaFil: Bobalova, Janette. Institute Of Analytical Chemistry Of The Czech Academy Of Sciences; República ChecaFil: Csollei, Jozef. Comenius University; EslovaquiaFil: Malik, Ivan. Comenius University; EslovaquiaFil: Alvarez, Sergio Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Spiegel, Sarah. Virginia Commonwealth University. School of Medicine; Estados UnidosFil: Jampilek, Josef. Comenius University; EslovaquiaFil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaElsevier France-editions Scientifiques Medicales Elsevier2017-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/37958Vettorazzi, Marcela Cristina; Angelina, Emilio Luis; Lima, Santiago; Gonec, Tomas; Otevrel, Jan; et al.; An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors; Elsevier France-editions Scientifiques Medicales Elsevier; European Journal of Medical Chemistry; 139; 10-2017; 461-4810223-5234CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0223523417306207info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ejmech.2017.08.017info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:46:47Zoai:ri.conicet.gov.ar:11336/37958instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:46:47.651CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
| dc.title.none.fl_str_mv |
An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors |
| title |
An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors |
| spellingShingle |
An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors Vettorazzi, Marcela Cristina Bioassays Molecular Modelling Sphingosine Kinase 1 Inhibitors Synthesis Virtual Screening |
| title_short |
An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors |
| title_full |
An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors |
| title_fullStr |
An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors |
| title_full_unstemmed |
An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors |
| title_sort |
An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors |
| dc.creator.none.fl_str_mv |
Vettorazzi, Marcela Cristina Angelina, Emilio Luis Lima, Santiago Gonec, Tomas Otevrel, Jan Marvanova, Pavlina Padrtova, Tereza Mokry, Petr Bobal, Pavel Acosta, Lina M. Palma, Alirio Cobo, Justo Bobalova, Janette Csollei, Jozef Malik, Ivan Alvarez, Sergio Eduardo Spiegel, Sarah Jampilek, Josef Enriz, Ricardo Daniel |
| author |
Vettorazzi, Marcela Cristina |
| author_facet |
Vettorazzi, Marcela Cristina Angelina, Emilio Luis Lima, Santiago Gonec, Tomas Otevrel, Jan Marvanova, Pavlina Padrtova, Tereza Mokry, Petr Bobal, Pavel Acosta, Lina M. Palma, Alirio Cobo, Justo Bobalova, Janette Csollei, Jozef Malik, Ivan Alvarez, Sergio Eduardo Spiegel, Sarah Jampilek, Josef Enriz, Ricardo Daniel |
| author_role |
author |
| author2 |
Angelina, Emilio Luis Lima, Santiago Gonec, Tomas Otevrel, Jan Marvanova, Pavlina Padrtova, Tereza Mokry, Petr Bobal, Pavel Acosta, Lina M. Palma, Alirio Cobo, Justo Bobalova, Janette Csollei, Jozef Malik, Ivan Alvarez, Sergio Eduardo Spiegel, Sarah Jampilek, Josef Enriz, Ricardo Daniel |
| author2_role |
author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Bioassays Molecular Modelling Sphingosine Kinase 1 Inhibitors Synthesis Virtual Screening |
| topic |
Bioassays Molecular Modelling Sphingosine Kinase 1 Inhibitors Synthesis Virtual Screening |
| purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.4 https://purl.org/becyt/ford/1 |
| dc.description.none.fl_txt_mv |
Sphingosine kinase 1 (SphK1), the enzyme that produces the bioactive sphingolipid metabolite, sphingosine-1-phosphate, is a promising new molecular target for therapeutic intervention in cancer and inflammatory diseases. In view of its importance, the main objective of this work was to find new and more potent inhibitors for this enzyme possessing different structural scaffolds than those of the known inhibitors. Our theoretical and experimental study has allowed us to identify two new structural scaffolds (three new compounds), which could be used as starting structures for the design and then the development of new inhibitors of SphK1. Our study was carried out in different steps: virtual screening, synthesis, bioassays and molecular modelling. From our results, we propose a new dihydrobenzo[b]pyrimido[5,4-f]azepine and two alkyl{3-/4-[1-hydroxy-2-(4-arylpiperazin-1-yl)ethyl]phenyl}carbamates as initial structures for the development of new inhibitors. In addition, our molecular modelling study using QTAIM calculations, allowed us to describe in detail the molecular interactions that stabilize the different Ligand-Receptor complexes. Such analyses indicate that the cationic head of the different compounds must be refined in order to obtain an increase in the binding affinity of these ligands. Fil: Vettorazzi, Marcela Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Angelina, Emilio Luis. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas y Naturales y Agrimensura. Departamento de Química. Laboratorio de Estructura Molecular y Propiedades; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Lima, Santiago. Virginia Commonwealth University. School of Medicine; Estados Unidos Fil: Gonec, Tomas. Veterinarni A Farmaceuticka Univerzita Brno; República Checa Fil: Otevrel, Jan. Veterinarni A Farmaceuticka Univerzita Brno; República Checa Fil: Marvanova, Pavlina. Veterinarni A Farmaceuticka Univerzita Brno; República Checa Fil: Padrtova, Tereza. Veterinarni A Farmaceuticka Univerzita Brno; República Checa Fil: Mokry, Petr. Veterinarni A Farmaceuticka Univerzita Brno; República Checa Fil: Bobal, Pavel. Veterinarni A Farmaceuticka Univerzita Brno; República Checa Fil: Acosta, Lina M.. Universidad Industrial Santander; Colombia Fil: Palma, Alirio. Universidad Industrial Santander; Colombia Fil: Cobo, Justo. Universidad de Jaén; España Fil: Bobalova, Janette. Institute Of Analytical Chemistry Of The Czech Academy Of Sciences; República Checa Fil: Csollei, Jozef. Comenius University; Eslovaquia Fil: Malik, Ivan. Comenius University; Eslovaquia Fil: Alvarez, Sergio Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina Fil: Spiegel, Sarah. Virginia Commonwealth University. School of Medicine; Estados Unidos Fil: Jampilek, Josef. Comenius University; Eslovaquia Fil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentina |
| description |
Sphingosine kinase 1 (SphK1), the enzyme that produces the bioactive sphingolipid metabolite, sphingosine-1-phosphate, is a promising new molecular target for therapeutic intervention in cancer and inflammatory diseases. In view of its importance, the main objective of this work was to find new and more potent inhibitors for this enzyme possessing different structural scaffolds than those of the known inhibitors. Our theoretical and experimental study has allowed us to identify two new structural scaffolds (three new compounds), which could be used as starting structures for the design and then the development of new inhibitors of SphK1. Our study was carried out in different steps: virtual screening, synthesis, bioassays and molecular modelling. From our results, we propose a new dihydrobenzo[b]pyrimido[5,4-f]azepine and two alkyl{3-/4-[1-hydroxy-2-(4-arylpiperazin-1-yl)ethyl]phenyl}carbamates as initial structures for the development of new inhibitors. In addition, our molecular modelling study using QTAIM calculations, allowed us to describe in detail the molecular interactions that stabilize the different Ligand-Receptor complexes. Such analyses indicate that the cationic head of the different compounds must be refined in order to obtain an increase in the binding affinity of these ligands. |
| publishDate |
2017 |
| dc.date.none.fl_str_mv |
2017-10 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/37958 Vettorazzi, Marcela Cristina; Angelina, Emilio Luis; Lima, Santiago; Gonec, Tomas; Otevrel, Jan; et al.; An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors; Elsevier France-editions Scientifiques Medicales Elsevier; European Journal of Medical Chemistry; 139; 10-2017; 461-481 0223-5234 CONICET Digital CONICET |
| url |
http://hdl.handle.net/11336/37958 |
| identifier_str_mv |
Vettorazzi, Marcela Cristina; Angelina, Emilio Luis; Lima, Santiago; Gonec, Tomas; Otevrel, Jan; et al.; An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors; Elsevier France-editions Scientifiques Medicales Elsevier; European Journal of Medical Chemistry; 139; 10-2017; 461-481 0223-5234 CONICET Digital CONICET |
| dc.language.none.fl_str_mv |
eng |
| language |
eng |
| dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0223523417306207 info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ejmech.2017.08.017 |
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info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
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openAccess |
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https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
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application/pdf application/pdf application/pdf application/pdf application/pdf |
| dc.publisher.none.fl_str_mv |
Elsevier France-editions Scientifiques Medicales Elsevier |
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Elsevier France-editions Scientifiques Medicales Elsevier |
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reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
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dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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