Nuevos triconjugados moleculares incorporando melatonina/isatina/N-acilhidrazona como potenciales agentes en el tratamiento del cáncer colorrectal
El cáncer es una de las principales causas de muerte en el mundo, siendo el cáncer de mama, pulmón y colon los más recurrentes en la sociedad. El cáncer colorrectal es el tercer cáncer más incidente y el segundo más mortífero, a pesar de que se cuenta con una amplia gama de regímenes para combatir d...
- Autores:
-
Gutiérrez Palacio, Sara Melisa
- Tipo de recurso:
- Trabajo de grado de pregrado
- Fecha de publicación:
- 2025
- Institución:
- Universidad de Antioquia
- Repositorio:
- Repositorio UdeA
- Idioma:
- spa
- OAI Identifier:
- oai:bibliotecadigital.udea.edu.co:10495/45828
- Acceso en línea:
- https://hdl.handle.net/10495/45828
- Palabra clave:
- Recto - Cáncer - Tratamiento
Rectum - Cancer - Treatment
Melatonina
Melatonin
Isatina
Isatin
Agentes antineoplásicos - Desarrollo
Antineoplastic agents - Development
Compuestos heterocíclicos
Heterocyclic compounds
Relaciones estructura-actividad (Bioquímica)
Structure-activity relationships (Biochemistry)
Línea celular tumoral
Cell line, tumor
Ensayos de selección de medicamentos antitumorales
Drug screening assays, antitumor
N-acilhidrazona
Hibridación molecular
Citotoxicidad in vitro
http://id.loc.gov/authorities/subjects/sh2010010262
http://id.loc.gov/authorities/subjects/sh85083394
http://id.loc.gov/authorities/subjects/sh2007009981
http://id.loc.gov/authorities/subjects/sh97008449
http://id.loc.gov/authorities/subjects/sh85060525
http://id.loc.gov/authorities/subjects/sh85129212
https://id.nlm.nih.gov/mesh/D045744
https://id.nlm.nih.gov/mesh/D004354
ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades
- Rights
- openAccess
- License
- http://purl.org/coar/access_right/c_abf2
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| dc.title.spa.fl_str_mv |
Nuevos triconjugados moleculares incorporando melatonina/isatina/N-acilhidrazona como potenciales agentes en el tratamiento del cáncer colorrectal |
| title |
Nuevos triconjugados moleculares incorporando melatonina/isatina/N-acilhidrazona como potenciales agentes en el tratamiento del cáncer colorrectal |
| spellingShingle |
Nuevos triconjugados moleculares incorporando melatonina/isatina/N-acilhidrazona como potenciales agentes en el tratamiento del cáncer colorrectal Recto - Cáncer - Tratamiento Rectum - Cancer - Treatment Melatonina Melatonin Isatina Isatin Agentes antineoplásicos - Desarrollo Antineoplastic agents - Development Compuestos heterocíclicos Heterocyclic compounds Relaciones estructura-actividad (Bioquímica) Structure-activity relationships (Biochemistry) Línea celular tumoral Cell line, tumor Ensayos de selección de medicamentos antitumorales Drug screening assays, antitumor N-acilhidrazona Hibridación molecular Citotoxicidad in vitro http://id.loc.gov/authorities/subjects/sh2010010262 http://id.loc.gov/authorities/subjects/sh85083394 http://id.loc.gov/authorities/subjects/sh2007009981 http://id.loc.gov/authorities/subjects/sh97008449 http://id.loc.gov/authorities/subjects/sh85060525 http://id.loc.gov/authorities/subjects/sh85129212 https://id.nlm.nih.gov/mesh/D045744 https://id.nlm.nih.gov/mesh/D004354 ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades |
| title_short |
Nuevos triconjugados moleculares incorporando melatonina/isatina/N-acilhidrazona como potenciales agentes en el tratamiento del cáncer colorrectal |
| title_full |
Nuevos triconjugados moleculares incorporando melatonina/isatina/N-acilhidrazona como potenciales agentes en el tratamiento del cáncer colorrectal |
| title_fullStr |
Nuevos triconjugados moleculares incorporando melatonina/isatina/N-acilhidrazona como potenciales agentes en el tratamiento del cáncer colorrectal |
| title_full_unstemmed |
Nuevos triconjugados moleculares incorporando melatonina/isatina/N-acilhidrazona como potenciales agentes en el tratamiento del cáncer colorrectal |
| title_sort |
Nuevos triconjugados moleculares incorporando melatonina/isatina/N-acilhidrazona como potenciales agentes en el tratamiento del cáncer colorrectal |
| dc.creator.fl_str_mv |
Gutiérrez Palacio, Sara Melisa |
| dc.contributor.advisor.none.fl_str_mv |
Yepes Pérez, Andrés Felipe Cardona Galeano, Wilson Isidro |
| dc.contributor.author.none.fl_str_mv |
Gutiérrez Palacio, Sara Melisa |
| dc.contributor.researchgroup.none.fl_str_mv |
Química de Plantas Colombianas |
| dc.contributor.jury.none.fl_str_mv |
Hernández Barajas, José Gregorio Restrepo Sánchez, Nora Eugenia |
| dc.subject.lcsh.none.fl_str_mv |
Recto - Cáncer - Tratamiento Rectum - Cancer - Treatment Melatonina Melatonin Isatina Isatin Agentes antineoplásicos - Desarrollo Antineoplastic agents - Development Compuestos heterocíclicos Heterocyclic compounds Relaciones estructura-actividad (Bioquímica) Structure-activity relationships (Biochemistry) |
| topic |
Recto - Cáncer - Tratamiento Rectum - Cancer - Treatment Melatonina Melatonin Isatina Isatin Agentes antineoplásicos - Desarrollo Antineoplastic agents - Development Compuestos heterocíclicos Heterocyclic compounds Relaciones estructura-actividad (Bioquímica) Structure-activity relationships (Biochemistry) Línea celular tumoral Cell line, tumor Ensayos de selección de medicamentos antitumorales Drug screening assays, antitumor N-acilhidrazona Hibridación molecular Citotoxicidad in vitro http://id.loc.gov/authorities/subjects/sh2010010262 http://id.loc.gov/authorities/subjects/sh85083394 http://id.loc.gov/authorities/subjects/sh2007009981 http://id.loc.gov/authorities/subjects/sh97008449 http://id.loc.gov/authorities/subjects/sh85060525 http://id.loc.gov/authorities/subjects/sh85129212 https://id.nlm.nih.gov/mesh/D045744 https://id.nlm.nih.gov/mesh/D004354 ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades |
| dc.subject.decs.none.fl_str_mv |
Línea celular tumoral Cell line, tumor Ensayos de selección de medicamentos antitumorales Drug screening assays, antitumor |
| dc.subject.proposal.spa.fl_str_mv |
N-acilhidrazona Hibridación molecular Citotoxicidad in vitro |
| dc.subject.lcshuri.none.fl_str_mv |
http://id.loc.gov/authorities/subjects/sh2010010262 http://id.loc.gov/authorities/subjects/sh85083394 http://id.loc.gov/authorities/subjects/sh2007009981 http://id.loc.gov/authorities/subjects/sh97008449 http://id.loc.gov/authorities/subjects/sh85060525 http://id.loc.gov/authorities/subjects/sh85129212 |
| dc.subject.meshuri.none.fl_str_mv |
https://id.nlm.nih.gov/mesh/D045744 https://id.nlm.nih.gov/mesh/D004354 |
| dc.subject.ods.none.fl_str_mv |
ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades |
| description |
El cáncer es una de las principales causas de muerte en el mundo, siendo el cáncer de mama, pulmón y colon los más recurrentes en la sociedad. El cáncer colorrectal es el tercer cáncer más incidente y el segundo más mortífero, a pesar de que se cuenta con una amplia gama de regímenes para combatir dicha afección, los tratamientos resultan ser no selectivos y con efectos secundarios bastante nocivos para el paciente. En la búsqueda de nuevos medicamentos, la hibridación molecular es una de las estrategias más usadas por los químicos sintéticos, pues les permite agrupar en una sola estructura unidades farmacofóricas de diversos núcleos privilegiados en la química medicinal. Respecto a las enfermedades oncológicas, esta metodología ha emergido como una poderosa herramienta para diseñar moléculas más selectivas, con marcada citotoxicidad y con una alta capacidad antiproliferativa en ensayos in vitro e in vivo. Siendo entonces la hibridación molecular una de las alternativas más interesantes para el desarrollo de potenciales quimioterapéuticos, una exhaustiva revisión bibliográfica reveló que sustancias como la melatonina, la isatina y las N-acilhidrazonas emergen como andamios moleculares para diseñar compuestos con promisoria actividad farmacológica, particularmente en el tratamiento del cáncer. Una vez realizado el diseño de una ruta sintética que permitiera la unión de estos tres andamios, se procedió con la síntesis de los mismos empleando reacciones clásicas de α- cloroacilación, SN2 y condensación, obteniendo rendimientos entre moderados y excelentes (20 - 99%); una vez se sintetizaron los precursores y la serie de híbridos, estos fueron inequívocamente caracterizados mediante RMN (1H, 13C y DEPT-135) y ESI-MS, luego, se determinó su pureza empleando cromatografía líquida de alta eficiencia (HPLC). Posteriormente, la serie 3a-l fue evaluada en la línea celular SW480 para determinar su capacidad inhibitoria de crecimiento, de este experimento se obtuvo que el híbrido 3e (2-OH-Ph) inhibe el crecimiento de las células tumorales en un 100% y genera una letalidad del 23.45%; para determinar la capacidad antiproliferativa en las líneas celulares SW480 y NCM460, se eligieron los híbridos 3e, 3f (R = 4-Piridil), 3g (R = 2,3-OMe-Ph) y 3l (R = NH2) por su capacidad inhibitoria y buena solubilidad en medios acuosos; este experimento mostró que los híbridos evaluados son más selectivos y menos tóxicos que el medicamento de referencia (5-FU). Finalmente, las propiedades farmacocinéticas y toxicológicas del híbrido líder (3e) fueron determinadas mediante servidores quimioinformáticos de libre acceso, demostrando que este puede ser un potencial candidato a fármaco de administración oral para el tratamiento del cáncer colorrectal. |
| publishDate |
2025 |
| dc.date.accessioned.none.fl_str_mv |
2025-05-08T14:08:25Z |
| dc.date.issued.none.fl_str_mv |
2025 |
| dc.type.none.fl_str_mv |
Trabajo de grado - Pregrado |
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http://purl.org/coar/resource_type/c_7a1f |
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http://purl.org/redcol/resource_type/TP |
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info:eu-repo/semantics/bachelorThesis |
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info:eu-repo/semantics/draft |
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http://purl.org/coar/resource_type/c_7a1f |
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draft |
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https://hdl.handle.net/10495/45828 |
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https://hdl.handle.net/10495/45828 |
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spa |
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| dc.relation.references.none.fl_str_mv |
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A., Nakatsuji, H., Li, X., Caricato, M., Marenich, A., Bloino, J., Janesko, B. G., Gomperts, R., Mennucci, B., Hratchian, H. P., Ortiz, J. V., ... Fox, D. J. (2016). Gaussian 09, Revision C.01. Gaussian, Inc., Wallingford CT. Hansen, P. E. (2021). A Spectroscopic Overview of Intramolecular Hydrogen Bonds of NH...O,S,N Type. Molecules, 26(9), 2409. https://doi.org/10.3390/molecules26092409 Harris, T. K., & Mildvan, A. S. (1999). High-Precision Measurement of Hydrogen Bond Lengths in Proteins by Nuclear Magnetic Resonance Methods. Proteins: Structure, Function, and Genetics, 35(3), 275–282. https://doi.org/10.1002/(SICI)1097- 0134(19990515)35:3<275::AID-PROT1>3.0.CO;2-V |
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Yepes Pérez, Andrés FelipeCardona Galeano, Wilson IsidroGutiérrez Palacio, Sara MelisaQuímica de Plantas ColombianasHernández Barajas, José GregorioRestrepo Sánchez, Nora Eugenia2025-05-08T14:08:25Z2025https://hdl.handle.net/10495/45828El cáncer es una de las principales causas de muerte en el mundo, siendo el cáncer de mama, pulmón y colon los más recurrentes en la sociedad. El cáncer colorrectal es el tercer cáncer más incidente y el segundo más mortífero, a pesar de que se cuenta con una amplia gama de regímenes para combatir dicha afección, los tratamientos resultan ser no selectivos y con efectos secundarios bastante nocivos para el paciente. En la búsqueda de nuevos medicamentos, la hibridación molecular es una de las estrategias más usadas por los químicos sintéticos, pues les permite agrupar en una sola estructura unidades farmacofóricas de diversos núcleos privilegiados en la química medicinal. Respecto a las enfermedades oncológicas, esta metodología ha emergido como una poderosa herramienta para diseñar moléculas más selectivas, con marcada citotoxicidad y con una alta capacidad antiproliferativa en ensayos in vitro e in vivo. Siendo entonces la hibridación molecular una de las alternativas más interesantes para el desarrollo de potenciales quimioterapéuticos, una exhaustiva revisión bibliográfica reveló que sustancias como la melatonina, la isatina y las N-acilhidrazonas emergen como andamios moleculares para diseñar compuestos con promisoria actividad farmacológica, particularmente en el tratamiento del cáncer. Una vez realizado el diseño de una ruta sintética que permitiera la unión de estos tres andamios, se procedió con la síntesis de los mismos empleando reacciones clásicas de α- cloroacilación, SN2 y condensación, obteniendo rendimientos entre moderados y excelentes (20 - 99%); una vez se sintetizaron los precursores y la serie de híbridos, estos fueron inequívocamente caracterizados mediante RMN (1H, 13C y DEPT-135) y ESI-MS, luego, se determinó su pureza empleando cromatografía líquida de alta eficiencia (HPLC). Posteriormente, la serie 3a-l fue evaluada en la línea celular SW480 para determinar su capacidad inhibitoria de crecimiento, de este experimento se obtuvo que el híbrido 3e (2-OH-Ph) inhibe el crecimiento de las células tumorales en un 100% y genera una letalidad del 23.45%; para determinar la capacidad antiproliferativa en las líneas celulares SW480 y NCM460, se eligieron los híbridos 3e, 3f (R = 4-Piridil), 3g (R = 2,3-OMe-Ph) y 3l (R = NH2) por su capacidad inhibitoria y buena solubilidad en medios acuosos; este experimento mostró que los híbridos evaluados son más selectivos y menos tóxicos que el medicamento de referencia (5-FU). Finalmente, las propiedades farmacocinéticas y toxicológicas del híbrido líder (3e) fueron determinadas mediante servidores quimioinformáticos de libre acceso, demostrando que este puede ser un potencial candidato a fármaco de administración oral para el tratamiento del cáncer colorrectal.Síntesis orgánica y química medicinalCOL0015329PregradoQuímico100 páginasapplication/pdfspaUniversidad de AntioquiaQuímicaInstituto de QuímicaMedellín, ColombiaFacultad de Ciencias Exactas y NaturalesCampus Medellín - Ciudad UniversitariaRecto - Cáncer - TratamientoRectum - Cancer - TreatmentMelatoninaMelatoninIsatinaIsatinAgentes antineoplásicos - DesarrolloAntineoplastic agents - DevelopmentCompuestos heterocíclicosHeterocyclic compoundsRelaciones estructura-actividad (Bioquímica)Structure-activity relationships (Biochemistry)Línea celular tumoralCell line, tumorEnsayos de selección de medicamentos antitumoralesDrug screening assays, antitumorN-acilhidrazonaHibridación molecularCitotoxicidad in vitrohttp://id.loc.gov/authorities/subjects/sh2010010262http://id.loc.gov/authorities/subjects/sh85083394http://id.loc.gov/authorities/subjects/sh2007009981http://id.loc.gov/authorities/subjects/sh97008449http://id.loc.gov/authorities/subjects/sh85060525http://id.loc.gov/authorities/subjects/sh85129212https://id.nlm.nih.gov/mesh/D045744https://id.nlm.nih.gov/mesh/D004354ODS 3: Salud y bienestar. 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Nature, 469(7330), 314–322. https://doi.org/10.1038/nature09781Escrig Sos, J., Gómez Quiles, L., & Maiocchi, K. (2019). La 8.a edición de la clasificación AJCC-TNM: nuevas aportaciones a la estadificación del cáncer de la unión esofagogástrica. Cirugía Española, 97(8), 432–437. https://doi.org/10.1016/j.ciresp.2019.03.006American Cancer Society. (2024). Colorectal Cancer Stages. American Cancer Society. https://www.cancer.org/cancer/types/colon-rectal-cancer/detection-diagnosis- staging/staged.htmlNevárez Noboa, F. (2017). Cáncer de Colon. DR. Francisco Narváez N. https://cirujanoguayaquil.com/cancer-de-colon/International Agency For Research on Cancer. (2022). Absolute numbers, Incidence and Mortality, Both sexes, in 2022. 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World Journal of Gastrointestinal Surgery, 15(4), 495–519. https://doi.org/10.4240/wjgs.v15.i4.495Carrato, A., Gallego, J., & Dı́az-Rubio, E. (2002). Oxaliplatin: results in colorectal carcinoma. Critical Reviews in Oncology/Hematology, 44(1), 29–44. https://doi.org/10.1016/S1040-8428(01)00192-5Delaunoit, T., Goldberg, R. M., Sargent, D. J., Morton, R. F., Fuchs, C. S., Findlay, B. P., Thomas, S. P., Salim, M., Schaefer, P. L., Stella, P. J., Green, E., & Mailliard, J. A. (2004). Mortality associated with daily bolus 5‐fluorouracil/leucovorin administered in combination with either irinotecan or oxaliplatin. Cancer, 101(10), 2170–2176. https://doi.org/10.1002/cncr.20594Rothenberg, M. L., Meropol, N. J., Poplin, E. A., Van Cutsem, E., & Wadler, S. (2001). Mortality Associated With Irinotecan Plus Bolus Fluorouracil/Leucovorin: Summary Findings of an Independent Panel. Journal of Clinical Oncology, 19(18), 3801–3807. https://doi.org/10.1200/JCO.2001.19.18.3801Meunier, B. (2008). 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Proteins: Structure, Function, and Genetics, 35(3), 275–282. https://doi.org/10.1002/(SICI)1097- 0134(19990515)35:3<275::AID-PROT1>3.0.CO;2-Vinfo:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Publication60.000.000ORIGINALGutierrezSara_2025_NuevosTriconjugadosCancer.pdfGutierrezSara_2025_NuevosTriconjugadosCancer.pdfapplication/pdf7088770https://bibliotecadigital.udea.edu.co/bitstreams/a51b48b6-247f-459c-92ea-c6ebf21d2e55/downloadb7759f9ae0e4ce02536edfea6ef92c4dMD51trueAnonymousREADLICENSElicense.txtlicense.txttext/plain; charset=utf-814837https://bibliotecadigital.udea.edu.co/bitstreams/1175332d-c0d9-448f-b571-c86694addc65/downloadb76e7a76e24cf2f94b3ce0ae5ed275d0MD53falseAnonymousREADTEXTGutierrezSara_2025_NuevosTriconjugadosCancer.pdf.txtGutierrezSara_2025_NuevosTriconjugadosCancer.pdf.txtExtracted 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