• Design, synthesis, cytotoxic evaluation in pancreatic cancer cells line and docking studies in the Smoothened receptor of new trisubstituted purine derivatives

Different studies have shown that aberrant activation of the Hedgehog (Hh) signaling pathway could be involved in the origin of several types of human cancer, including lung, colon, and pancreas. In addition, numerous studies showed that different small molecules have an inhibitory effect on the Hh...

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Autor: Villegas-Menares, Alondra Elena
Tipo de recurso: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2021
País:Chile
OAI Identifier:oai:repositorio.anid.cl:10533/253004
Acceso en línea:https://hdl.handle.net/10533/253004
Access Level:acceso abierto
Palabra clave:Ciencias Naturales
Ciencias Químicas
Química Orgánica
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dc.title.es_CL.fl_str_mv • Design, synthesis, cytotoxic evaluation in pancreatic cancer cells line and docking studies in the Smoothened receptor of new trisubstituted purine derivatives
Diseño, síntesis, evaluación citotóxica en líneas celulares de cáncer de páncreas y estudios de acoplamiento molecular en el receptor smoothened de nuevos derivados de purinas trisustituidas
title • Design, synthesis, cytotoxic evaluation in pancreatic cancer cells line and docking studies in the Smoothened receptor of new trisubstituted purine derivatives
spellingShingle • Design, synthesis, cytotoxic evaluation in pancreatic cancer cells line and docking studies in the Smoothened receptor of new trisubstituted purine derivatives
Villegas-Menares, Alondra Elena
Ciencias Naturales
Ciencias Químicas
Química Orgánica
title_short • Design, synthesis, cytotoxic evaluation in pancreatic cancer cells line and docking studies in the Smoothened receptor of new trisubstituted purine derivatives
title_full • Design, synthesis, cytotoxic evaluation in pancreatic cancer cells line and docking studies in the Smoothened receptor of new trisubstituted purine derivatives
title_fullStr • Design, synthesis, cytotoxic evaluation in pancreatic cancer cells line and docking studies in the Smoothened receptor of new trisubstituted purine derivatives
title_full_unstemmed • Design, synthesis, cytotoxic evaluation in pancreatic cancer cells line and docking studies in the Smoothened receptor of new trisubstituted purine derivatives
title_sort • Design, synthesis, cytotoxic evaluation in pancreatic cancer cells line and docking studies in the Smoothened receptor of new trisubstituted purine derivatives
dc.creator.none.fl_str_mv Villegas-Menares, Alondra Elena
author Villegas-Menares, Alondra Elena
author_facet Villegas-Menares, Alondra Elena
author_role author
dc.contributor.advisor.none.fl_str_mv Salas-Sánchez, Cristian Osvaldo
dc.contributor.institution.es_CL.fl_str_mv PONTIFICIA UNIVERSIDAD CATOLICA DE CHILE
dc.subject.oecd1n.es_CL.fl_str_mv Ciencias Naturales
topic Ciencias Naturales
Ciencias Químicas
Química Orgánica
dc.subject.oecd2n.es_CL.fl_str_mv Ciencias Químicas
dc.subject.oecd3n.es_CL.fl_str_mv Química Orgánica
description Different studies have shown that aberrant activation of the Hedgehog (Hh) signaling pathway could be involved in the origin of several types of human cancer, including lung, colon, and pancreas. In addition, numerous studies showed that different small molecules have an inhibitory effect on the Hh signaling pathway. Specifically, these Hh modulators target the Smoothened (Smo) receptor. An example of this is the drug vismodegib, a Smo antagonist, used to treat basal cell carcinoma and medulloblastoma. However, in recent reports, resistance to this drug has been detected due to new mutations in Smo, which requires the development of new, more efficient ligands. Based on the above, in this thesis, new fifty 2,6,9-trisubstituted purine derivatives (Series I and II) were designed and synthesized based on fragments of Smo bioactive molecules. Synthetic methodologies to obtain these new compounds involved classical organic chemistry reactions. The compounds obtained were structurally characterized through different techniques. Also, cell viability was evaluated in pancreatic cancer lines, medulloblastoma, and no-neoplastic cells. These were compared with the controls vismodegib and gemcitabine, the latter used to treat pancreatic adenocarcinoma, showing that ten ligands of Series II presented an IC50 value of less than 10 μM in different pancreatic cancer cell lines. However, only four of these (11c, 16c, 16g, and 16f) presented a good selectivity index for this cancer. On the other hand, the ligands of Series I did not was determined their cytotoxicity, due to their low solubilities. A bioinformatic study to determine the different binding modes of the Series II ligands with the receptor was carried out, realizing that several of these ligands have hydrogen-bridge-type interactions with amino acids of the binding site expected in this study. For Series I ligands, a reverse docking study was carried out to find a suitable pharmacological model for this type of ligands, where adenosine A1 receptor was one of them.
publishDate 2021
dc.date.accessioned.none.fl_str_mv 2021-10-18T16:25:09Z
2022-08-22T17:15:58Z
dc.date.available.none.fl_str_mv 2021-10-18T16:25:09Z
2022-08-22T17:15:58Z
dc.date.issued.es_CL.fl_str_mv 2021
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identifier_str_mv 21150586
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spelling PONTIFICIA UNIVERSIDAD CATOLICA DE CHILEVillegas-Menares, Alondra Elena2021https://hdl.handle.net/10533/253004http://purl.org/coar/access_right/c_abf2Química OrgánicaCiencias QuímicasCiencias Naturales• Design, synthesis, cytotoxic evaluation in pancreatic cancer cells line and docking studies in the Smoothened receptor of new trisubstituted purine derivativesSalas-Sánchez, Cristian OsvaldoPONTIFICIA UNIVERSIDAD CATOLICA DE CHILEChileVillegas-Menares, Alondra Elena2021-10-18T16:25:09Z2022-08-22T17:15:58Z2021-10-18T16:25:09Z2022-08-22T17:15:58Z2021Different studies have shown that aberrant activation of the Hedgehog (Hh) signaling pathway could be involved in the origin of several types of human cancer, including lung, colon, and pancreas. In addition, numerous studies showed that different small molecules have an inhibitory effect on the Hh signaling pathway. Specifically, these Hh modulators target the Smoothened (Smo) receptor. An example of this is the drug vismodegib, a Smo antagonist, used to treat basal cell carcinoma and medulloblastoma. However, in recent reports, resistance to this drug has been detected due to new mutations in Smo, which requires the development of new, more efficient ligands. Based on the above, in this thesis, new fifty 2,6,9-trisubstituted purine derivatives (Series I and II) were designed and synthesized based on fragments of Smo bioactive molecules. Synthetic methodologies to obtain these new compounds involved classical organic chemistry reactions. The compounds obtained were structurally characterized through different techniques. Also, cell viability was evaluated in pancreatic cancer lines, medulloblastoma, and no-neoplastic cells. These were compared with the controls vismodegib and gemcitabine, the latter used to treat pancreatic adenocarcinoma, showing that ten ligands of Series II presented an IC50 value of less than 10 μM in different pancreatic cancer cell lines. However, only four of these (11c, 16c, 16g, and 16f) presented a good selectivity index for this cancer. On the other hand, the ligands of Series I did not was determined their cytotoxicity, due to their low solubilities. A bioinformatic study to determine the different binding modes of the Series II ligands with the receptor was carried out, realizing that several of these ligands have hydrogen-bridge-type interactions with amino acids of the binding site expected in this study. For Series I ligands, a reverse docking study was carried out to find a suitable pharmacological model for this type of ligands, where adenosine A1 receptor was one of them.Diferentes estudios han demostrado que la activación aberrante de la vía de señalización Hedgehog (Hh), estaría involucrada en el origen de diversos tipos de cáncer humanos, entre ellos, el de pulmón, colon y páncreas. Hay numerosos estudios que demuestran que diferentes moléculas pequeñas presentan un efecto inhibitorio en la vía de señalización Hedgehog (Hh). Específicamente, estos moduladores de Hh tienen como blanco farmacológico al receptor Smoothened (Smo). Ejemplo de ello, es el fármaco vismodegib, un antagonista de Smo, utilizado en el tratamiento del carcinoma de células basales y meduloblastoma. Sin embargo, en reportes recientes, se ha detectado resistencia a este fármaco debido a nuevas mutaciones en Smo, lo que obliga a desarrollar nuevos ligandos más eficaces. En función de lo anterior, en esta tesis se diseñaron y sintetizaron 50 nuevos derivados de purina 2,6,9-trisustituida (Series I y II), basados en fragmentos de moléculas bioactivas y con actividad sobre Smo. Las metodologías de síntesis para acceder a estos nuevos compuestos involucraron reacciones de química orgánica clásica. Los compuestos obtenidos fueron caracterizados a través de diferentes técnicas. Por un lado, se evaluó la viabilidad celular en líneas cancerígenas de páncreas, meduloblastoma y células no neoplásicas. Estos fueron comparados con los controles vismodegib y gemcitabina (fármaco utilizado para el tratamiento de adenocarcinoma pancreático), dando cuenta que 10 ligandos de la Serie II presentaron un IC50 menor a 10 μM en diferentes líneas celulares cancerígenas de páncreas, pero solo 4 de éstos (11c, 16c, 16g y 16f) presentaron un índice de selectividad razonable para futuros estudios biológicos. Para el caso de la Serie I, no se pudo evaluar su citotoxicidad debido a la baja solubilidad. Luego se realizó un estudio bioinformático para determinar los diferentes modos de unión de los ligandos de la Serie II con el receptor Smo, dando cuenta que varios de estos ligandos presentan interacciones del tipo puente de hidrógeno con aminoácidos del sitio de unión esperado en este estudio. Para ligandos de la Serie I, se realizó un estudio de anclaje reverso para encontrar un modelo farmacológico adecuado para este tipo de ligandos, siendo el receptor de adenosina A1 uno de ellos.21150586https://hdl.handle.net/10533/253004instname: Conicytreponame: Repositorio Digital RI2.0info:eu-repo/grantAgreement//21150586info:eu-repo/semantics/dataset/hdl.handle.net/10533/93488https://repositorio.uc.cl/handle/11534/62514info:eu-repo/semantics/openAccessAttribution-NonCommercial-NoDerivs 3.0 Chilehttp://creativecommons.org/licenses/by-nc-nd/3.0/cl/Ciencias NaturalesCiencias QuímicasQuímica Orgánica• Design, synthesis, cytotoxic evaluation in pancreatic cancer cells line and docking studies in the Smoothened receptor of new trisubstituted purine derivativesDiseño, síntesis, evaluación citotóxica en líneas celulares de cáncer de páncreas y estudios de acoplamiento molecular en el receptor smoothened de nuevos derivados de purinas trisustituidasinfo:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersionTesisTesishttps://hdl.handle.net/10533/2530047063bac4-1c87-454a-88ee-09a867f6c7a3virtual::62718-17063bac4-1c87-454a-88ee-09a867f6c7a3virtual::62718-1THUMBNAILTesisdoctorado_AVillegas.pdf.jpgIM Thumbnailimage/jpeg5111https://repositorio.anid.cl/bitstreams/044c680c-3299-4cef-b974-c67754faa58a/download0d045770003e6c71f6a46d5edbafb92fMD51TEXTTesisdoctorado_AVillegas.pdf.txtExtracted texttext/plain261434https://repositorio.anid.cl/bitstreams/a6a087f5-eedf-4571-9e21-3d1c87829352/downloadbeadb1f4bdaebf31a7a7670840f9f305MD52CC-LICENSElicense_rdfapplication/octet-stream1232https://repositorio.anid.cl/bitstreams/ac3da474-c169-4fe9-b334-93460ac946dc/downloadf97bcfdf58f3e17b5cec231112dab5b1MD53LICENSElicense.txttext/plain1779https://repositorio.anid.cl/bitstreams/4266f959-ab33-4a77-87b5-81e3d6cd94a4/download593a6e7305c66c56041a9f9e15a649c1MD54ORIGINALTesisdoctorado_AVillegas.pdfapplication/pdf11964322https://repositorio.anid.cl/bitstreams/63c36690-f1e6-45cc-bf4b-713e9e2ac93b/download1a6ba85f717922e46095acb3e12fb4d3MD5510533/253004oai:repositorio.anid.cl:10533/2530042023-07-24 17:27:28.366http://creativecommons.org/licenses/by-nc-nd/3.0/cl/info:eu-repo/semantics/openAccesshttps://repositorio.anid.clRepositorio ANIDaletelier@anid.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