Síntesis y actividad anticancerígena de híbridos basados en benzofurano y 5-fluorouracilo

Se sintetizaron 24 nuevas moléculas híbridas basadas en 5-fluorouracilo-Pterostilbeno (5a – 5i), 5-fluorouracilo-bifenilo (7a – 7e) y Benzofurano-pterostilbeno (10d – 10h) con rendimientos finales entre 10 y 85 %. Todos los compuestos fueron caracterizados mediante métodos espectroscópicos como reso...

Full description

Autores:
Becerra Quintana, Rubén Darío
Tipo de recurso:
Fecha de publicación:
2025
Institución:
Universidad de Antioquia
Repositorio:
Repositorio UdeA
Idioma:
spa
OAI Identifier:
oai:bibliotecadigital.udea.edu.co:10495/46266
Acceso en línea:
https://hdl.handle.net/10495/46266
Palabra clave:
Estilbenos
Stilbenes
Fluorouracilo
Fluorouracil
Benzofuranos
Benzofurans
Anticarcinógenos
Anticarcinogenic agents
Relación estructura-actividad
Structure-activity relationship
Línea celular tumoral
Cell line, tumor
Espectroscopía de resonancia magnética
Magnetic resonance spectroscopy
Espectrometría de masas
Mass spectrometry
Desarrollo de medicamentos
Drug development
Neoplasias colorrectales - Tratamiento farmacológico
Colorectal neoplasms - Drug therapy
Híbridos moleculares
Pterostilbeno
https://id.nlm.nih.gov/mesh/D013267
https://id.nlm.nih.gov/mesh/D005472
https://id.nlm.nih.gov/mesh/D001572
https://id.nlm.nih.gov/mesh/D016588
https://id.nlm.nih.gov/mesh/D013329
https://id.nlm.nih.gov/mesh/D045744
https://id.nlm.nih.gov/mesh/D009682
https://id.nlm.nih.gov/mesh/D013058
https://id.nlm.nih.gov/mesh/D000076722
https://id.nlm.nih.gov/mesh/D015179
ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades
Rights
openAccess
License
http://creativecommons.org/licenses/by-nc-sa/4.0/
id UDEA2_f3f26f63f8e891e8c01803914ae5b720
oai_identifier_str oai:bibliotecadigital.udea.edu.co:10495/46266
network_acronym_str UDEA2
network_name_str Repositorio UdeA
repository_id_str
dc.title.spa.fl_str_mv Síntesis y actividad anticancerígena de híbridos basados en benzofurano y 5-fluorouracilo
title Síntesis y actividad anticancerígena de híbridos basados en benzofurano y 5-fluorouracilo
spellingShingle Síntesis y actividad anticancerígena de híbridos basados en benzofurano y 5-fluorouracilo
Estilbenos
Stilbenes
Fluorouracilo
Fluorouracil
Benzofuranos
Benzofurans
Anticarcinógenos
Anticarcinogenic agents
Relación estructura-actividad
Structure-activity relationship
Línea celular tumoral
Cell line, tumor
Espectroscopía de resonancia magnética
Magnetic resonance spectroscopy
Espectrometría de masas
Mass spectrometry
Desarrollo de medicamentos
Drug development
Neoplasias colorrectales - Tratamiento farmacológico
Colorectal neoplasms - Drug therapy
Híbridos moleculares
Pterostilbeno
https://id.nlm.nih.gov/mesh/D013267
https://id.nlm.nih.gov/mesh/D005472
https://id.nlm.nih.gov/mesh/D001572
https://id.nlm.nih.gov/mesh/D016588
https://id.nlm.nih.gov/mesh/D013329
https://id.nlm.nih.gov/mesh/D045744
https://id.nlm.nih.gov/mesh/D009682
https://id.nlm.nih.gov/mesh/D013058
https://id.nlm.nih.gov/mesh/D000076722
https://id.nlm.nih.gov/mesh/D015179
ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades
title_short Síntesis y actividad anticancerígena de híbridos basados en benzofurano y 5-fluorouracilo
title_full Síntesis y actividad anticancerígena de híbridos basados en benzofurano y 5-fluorouracilo
title_fullStr Síntesis y actividad anticancerígena de híbridos basados en benzofurano y 5-fluorouracilo
title_full_unstemmed Síntesis y actividad anticancerígena de híbridos basados en benzofurano y 5-fluorouracilo
title_sort Síntesis y actividad anticancerígena de híbridos basados en benzofurano y 5-fluorouracilo
dc.creator.fl_str_mv Becerra Quintana, Rubén Darío
dc.contributor.advisor.none.fl_str_mv Yepes Pérez, Andrés Felipe
Cardona Galeano, Wilson Isidro
dc.contributor.author.none.fl_str_mv Becerra Quintana, Rubén Darío
dc.contributor.researchgroup.none.fl_str_mv Química de Plantas Colombianas
dc.contributor.jury.none.fl_str_mv Herrera Calderón, Oscar
Escobar Peláez, Gustavo Adolfo
dc.subject.decs.none.fl_str_mv Estilbenos
Stilbenes
Fluorouracilo
Fluorouracil
Benzofuranos
Benzofurans
Anticarcinógenos
Anticarcinogenic agents
Relación estructura-actividad
Structure-activity relationship
Línea celular tumoral
Cell line, tumor
Espectroscopía de resonancia magnética
Magnetic resonance spectroscopy
Espectrometría de masas
Mass spectrometry
Desarrollo de medicamentos
Drug development
Neoplasias colorrectales - Tratamiento farmacológico
Colorectal neoplasms - Drug therapy
topic Estilbenos
Stilbenes
Fluorouracilo
Fluorouracil
Benzofuranos
Benzofurans
Anticarcinógenos
Anticarcinogenic agents
Relación estructura-actividad
Structure-activity relationship
Línea celular tumoral
Cell line, tumor
Espectroscopía de resonancia magnética
Magnetic resonance spectroscopy
Espectrometría de masas
Mass spectrometry
Desarrollo de medicamentos
Drug development
Neoplasias colorrectales - Tratamiento farmacológico
Colorectal neoplasms - Drug therapy
Híbridos moleculares
Pterostilbeno
https://id.nlm.nih.gov/mesh/D013267
https://id.nlm.nih.gov/mesh/D005472
https://id.nlm.nih.gov/mesh/D001572
https://id.nlm.nih.gov/mesh/D016588
https://id.nlm.nih.gov/mesh/D013329
https://id.nlm.nih.gov/mesh/D045744
https://id.nlm.nih.gov/mesh/D009682
https://id.nlm.nih.gov/mesh/D013058
https://id.nlm.nih.gov/mesh/D000076722
https://id.nlm.nih.gov/mesh/D015179
ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades
dc.subject.proposal.spa.fl_str_mv Híbridos moleculares
Pterostilbeno
dc.subject.meshuri.none.fl_str_mv https://id.nlm.nih.gov/mesh/D013267
https://id.nlm.nih.gov/mesh/D005472
https://id.nlm.nih.gov/mesh/D001572
https://id.nlm.nih.gov/mesh/D016588
https://id.nlm.nih.gov/mesh/D013329
https://id.nlm.nih.gov/mesh/D045744
https://id.nlm.nih.gov/mesh/D009682
https://id.nlm.nih.gov/mesh/D013058
https://id.nlm.nih.gov/mesh/D000076722
https://id.nlm.nih.gov/mesh/D015179
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 Se sintetizaron 24 nuevas moléculas híbridas basadas en 5-fluorouracilo-Pterostilbeno (5a – 5i), 5-fluorouracilo-bifenilo (7a – 7e) y Benzofurano-pterostilbeno (10d – 10h) con rendimientos finales entre 10 y 85 %. Todos los compuestos fueron caracterizados mediante métodos espectroscópicos como resonancia magnética nuclear de 1H y 13C y espectrometría de masas de alta resolución. Todos los híbridos sintetizados fueron evaluados en la línea celular de adenocarcinoma SW480 y en la línea celular no maligna NCM460, donde, se pudieron destacar la actividad inhibitoria de los compuestos 5g, 5h, 10d y 10h siendo estos dos últimos los que presentaron una mayor selectividad los compuestos de partida y el medicamento de referencia 5-FU.
publishDate 2025
dc.date.accessioned.none.fl_str_mv 2025-06-05T16:21:29Z
dc.date.issued.none.fl_str_mv 2025
dc.type.none.fl_str_mv Trabajo de grado - Maestría
dc.type.redcol.none.fl_str_mv http://purl.org/redcol/resource_type/TM
dc.type.content.none.fl_str_mv Text
dc.type.coarversion.none.fl_str_mv http://purl.org/coar/version/c_b1a7d7d4d402bcce
dc.type.driver.none.fl_str_mv info:eu-repo/semantics/masterThesis
dc.type.version.none.fl_str_mv info:eu-repo/semantics/draft
status_str draft
dc.identifier.citation.none.fl_str_mv Rubén Becerra-Quintana. (2025). Síntesis y actividad anticancerígena de híbridos basados en benzofurano y 5-fluorouracilo [Tesis de maestría]. Universidad de Antioquia, Medellín, Colombia.
dc.identifier.uri.none.fl_str_mv https://hdl.handle.net/10495/46266
identifier_str_mv Rubén Becerra-Quintana. (2025). Síntesis y actividad anticancerígena de híbridos basados en benzofurano y 5-fluorouracilo [Tesis de maestría]. Universidad de Antioquia, Medellín, Colombia.
url https://hdl.handle.net/10495/46266
dc.language.iso.none.fl_str_mv spa
language spa
dc.relation.references.none.fl_str_mv Abbas, A. A., & Dawood, K. M. (2023). Anticancer therapeutic potential of benzofuran scaffolds. RSC Advances, 13(16), 11096–11120.
Abraham, J., Ocen, J., & Staffurth, J. (2022). Hormonal therapy for cancer. Medicine.
Adhikari, S., Bhattacharya, A., Adhikary, S., Singh, V., Gadad, S. S., Roy, S., & Das, C. (2022). The paradigm of drug resistance in cancer: an epigenetic perspective. Bioscience Reports, 42(4), BSR20211812.
Albert, S., Horbach, R., Deising, H. B., Siewert, B., & Csuk, R. (2011). Synthesis and antimicrobial activity of (E) stilbene derivatives. Bioorganic & Medicinal Chemistry, 19(17), 5155–5166.
Błaszczyk, A., Sady, S., & Sielicka, M. (2019). The stilbene profile in edible berries. Phytochemistry Reviews, 18, 37–67.
Braga, A., Rocha, I., & Faria, N. (2019). Microbial hosts as a promising platform for polyphenol production. Natural Bio-Active Compounds: Volume 1: Production and Applications, 71–103.
Cao, W., Qin, K., Li, F., & Chen, W. (2024). Comparative study of cancer profiles between 2020 and 2022 using global cancer statistics (GLOBOCAN). Journal of the National Cancer Center.
Cardona-G, W., Herrera-R, A., Castrillón-L, W., & Ramírez-Malule, H. (2021). Chemistry and anticancer activity of hybrid molecules and derivatives based on 5-fluorouracil. Current Medicinal Chemistry, 28(27), 5551–5601.
Cascella, M., Bimonte, S., Barbieri, A., Del Vecchio, V., Caliendo, D., Schiavone, V., Fusco, R., Granata, V., Arra, C., & Cuomo, A. (2018). Dissecting the mechanisms and molecules underlying the potential carcinogenicity of red and processed meat in colorectal cancer (CRC): an overview on the current state of knowledge. Infectious Agents and Cancer, 13, 1–8.
Chang, T.-C., Yeh, C.-T., Adebayo, B. O., Lin, Y.-C., Deng, L., Rao, Y. K., Huang, C.-C., Lee, W.-H., Wu, A. T. H., & Hsiao, M. (2015). 4-Acetylantroquinonol B inhibits colorectal cancer tumorigenesis and suppresses cancer stem-like phenotype. Toxicology and Applied Pharmacology, 288(2), 258–268.
Chen, Y., Wang, G., Yuan, Y., Zou, G., Yang, W., Tan, Q., Kang, W., & She, Z. (2022). Metabolites with cytotoxic activities from the mangrove endophytic fungus Fusarium sp. 2ST2. Frontiers in Chemistry, 10, 842405.
Das, P. K., Islam, F., & Lam, A. K. (2020). The roles of cancer stem cells and therapy resistance in colorectal carcinoma. Cells, 9(6), 1392.
Dharavath, R., Sarasija, M., Ram Reddy, M., Naga Prathima, K., Nagarju, N., Ramakrishna, K., Ashok, D., & Daravath, S. (2022). Microwave-assisted synthesis and evaluation of their antiproliferative, antimicrobial, activities and DNA Binding studies of (3-Methyl-7 H-furo [2, 3-f] chromen-2-yl)(aryl) methanones. Medicinal Chemistry Research, 31(6), 993–1002.
Eldehna, W. M., Salem, R., Elsayed, Z. M., Al-Warhi, T., Knany, H. R., Ayyad, R. R., Traiki, T. Bin, Abdulla, M.-H., Ahmad, R., & Abdel-Aziz, H. A. (2021). Development of novel benzofuran-isatin conjugates as potential antiproliferative agents with apoptosis inducing mechanism in Colon cancer. Journal of Enzyme Inhibition and Medicinal Chemistry, 36(1), 1423–1434.
Fan, X., He, H., Li, J., Luo, G., Zheng, Y., Zhou, J.-K., He, J., Pu, W., & Zhao, Y. (2019). Discovery of 4, 6-bis (benzyloxy)-3-phenylbenzofuran as a novel Pin1 inhibitor to suppress hepatocellular carcinoma via upregulating microRNA biogenesis. Bioorganic & Medicinal Chemistry, 27(11), 2235–2244.
Fraction, L. V. E. (n.d.). FULL PRESCRIBING INFORMATION.
Gandomani, H. S., Aghajani, M., Mohammadian-Hafshejani, A., Tarazoj, A. A., Pouyesh, V., & Salehiniya, H. (2017). Colorectal cancer in the world: incidence, mortality and risk factors. Biomedical Research and Therapy, 4(10), 1656–1675.
Gao, S., Zhang, H., Li, N., Zhang, L., Zhu, Z., & Xu, C. (2024). Pterostilbene: A natural neuroprotective stilbene with anti-Alzheimer’s disease properties. Journal of Pharmaceutical Analysis, 101043.
Gao, Y., Ma, C., Feng, X., Liu, Y., & Haimiti, X. (2020). BF12, a novel benzofuran, exhibits antitumor activity by inhibiting microtubules and the PI3K/Akt/mTOR signaling pathway in human cervical cancer cells. Chemistry & Biodiversity, 17(3), e1900622.
Grandhi, N., Patel, B., & Aranha, O. (2023). Advances in Systemic Chemotherapy and Immunotherapy for Metastatic Colorectal Cancer. Seminars in Colon and Rectal Surgery, 100972.
Grau, L., Soucek, R., & Pujol, M. D. (2023). Resveratrol derivatives: Synthesis and their biological activities. European Journal of Medicinal Chemistry, 246, 114962.
Grygorenko, O. O., Volochnyuk, D. M., Ryabukhin, S. V, & Judd, D. B. (2020). The symbiotic relationship between drug discovery and organic chemistry. Chemistry–A European Journal, 26(6), 1196–1237.
Guan, X.-W., Xu, X.-H., Feng, S.-L., Tang, Z.-B., Chen, S.-W., & Hui, L. (2016). Synthesis of hybrid 4-deoxypodophyllotoxin–5-fluorouracil compounds that inhibit cellular migration and induce cell cycle arrest. Bioorganic & Medicinal Chemistry Letters, 26(6), 1561–1566.
Guan, X.-Y., Al-Misba’a, Z., & Huang, K.-W. (2015). Efficient and selective α-bromination of carbonyl compounds with N-bromosuccinimide under microwave. Arabian Journal of Chemistry, 8(6), 892–896.
Han, S., Sang, Y., Wu, Y., Tao, Y., Pannecouque, C., De Clercq, E., Zhuang, C., & Chen, F.-E. (2019). Molecular hybridization-inspired optimization of diarylbenzopyrimidines as HIV-1 nonnucleoside reverse transcriptase inhibitors with improved activity against K103N and E138K mutants and pharmacokinetic profiles. ACS Infectious Diseases, 6(5), 787–801.
Hapeshi, A., Benarroch, J. M., Clarke, D. J., & Waterfield, N. R. (2018). Iso-propyl stilbene: A life-cycle signal? BioRxiv, 498857.
Hernández, C., Moreno, G., Herrera-R, A., & Cardona-G, W. (2021). New hybrids based on curcumin and resveratrol: Synthesis, cytotoxicity and antiproliferative activity against colorectal cancer cells. Molecules, 26(9), 2661.
Herrera-R, A., Castrillón, W., Otero, E., Ruiz, E., Carda, M., Agut, R., Naranjo, T., Moreno, G., Maldonado, M. E., & Cardona-G, W. (2018). Synthesis and antiproliferative activity of 3-and 7-styrylcoumarins. Medicinal Chemistry Research, 27, 1893–1905.
Housman, G., Byler, S., Heerboth, S., Lapinska, K., Longacre, M., Snyder, N., & Sarkar, S. (2014). Drug resistance in cancer: an overview. Cancers, 6(3), 1769–1792.
Hsieh, M.-T., Huang, L.-J., Wu, T.-S., Lin, H.-Y., Morris-Natschke, S. L., Lee, K.-H., & Kuo, S.-C. (2018). Synthesis and antitumor activity of bis (hydroxymethyl) propionate analogs of pterostilbene in cisplatin-resistant human oral cancer cells. Bioorganic & Medicinal Chemistry, 26(14), 3909–3916.
Hu, Q.-F., Wang, Y.-D., Zhu, D.-L., Yu, Z.-H., Zhan, J.-B., Xing, H.-H., Ma, H.-Y., Yang, Y., Li, Y.-K., & Chen, Z.-Y. (2016). Three new biphenyls from the twigs of Garcinia tetralata and their anti-tobacco mosaic virus activity. Journal of Asian Natural Products Research, 18(12), 1115–1121.
Ito, K., Tatsumi, T., Takahashi, K., Shimizu, Y., Yamatsugu, K., & Kanai, M. (2020). A stable and cleavable O-linked spacer for drug delivery systems. Chemical and Pharmaceutical Bulletin, 68(3), 212–215.
Jaferian, S., Negahdari, B., & Eatemadi, A. (2016). Colon cancer targeting using conjugates biomaterial 5-flurouracil. Biomedicine & Pharmacotherapy, 84, 780–788.
Jain, Z. J., Gide, P. S., & Kankate, R. S. (2017). Biphenyls and their derivatives as synthetically and pharmacologically important aromatic structural moieties. Arabian Journal of Chemistry, 10, S2051–S2066.
Ji, B.-K., Gao, X.-M., Cui, D., Wang, S.-S., Huang, W.-Z., Li, Y.-K., Mei, S.-X., Yang, Z., Li, G.-P., & Jiang, M.-Y. (2017). Two new biphenyls from the stems of Garcinia tetralata. Natural Product Research, 31(13), 1544–1550.
Jin, L.-P., Xie, Q., Huang, E.-F., Wang, L., Zhang, B.-Q., Hu, J.-S., Wan, D. C.-C., Jin, Z., & Hu, C. (2020). Design, synthesis, and biological activity of a novel series of benzofuran derivatives against oestrogen receptor-dependent breast cancer cell lines. Bioorganic Chemistry, 95, 103566.
Kato, K., Takahashi, M., Oh-Hashi, K., Ando, K., & Hirata, Y. (2022). Quercetin and resveratrol inhibit ferroptosis independently of Nrf2–ARE activation in mouse hippocampal HT22 cells. Food and Chemical Toxicology, 113586.
Kumar, M., Verma, S., Sharma, M., Poonam, & Rathi, B. (2023). Metal‐Catalysed Synthesis of Benzofused Five‐Membered N/O/S‐Heterocycles, a Progressive Area in Synthetic Organic Chemistry. European Journal of Organic Chemistry, 26(46), e202300877.
Lara-Ochoa, F., Sandoval-Minero, L. C., & Espinosa-Pérez, G. (2015). A new synthesis of resveratrol. Tetrahedron Letters, 56(44), 5977–5979.
Larsen, R. D., King, A. O., Chen, C. Y., Corley, E. G., Foster, B. S., Roberts, F. E., Yang, C., Lieberman, D. R., Reamer, R. A., & Tschaen, D. M. (1994). Efficient synthesis of losartan, a nonpeptide angiotensin II receptor antagonist. The Journal of Organic Chemistry, 59(21), 6391–6394.
Laudadio, G., Fusini, G., Casotti, G., Evangelisti, C., Angelici, G., & Carpita, A. (2019). Synthesis of Pterostilbene through supported-catalyst promoted Mizoroki-Heck reaction, and its transposition in continuous flow reactor. Journal of Flow Chemistry, 9, 133–143.
Lee, J. H., Yun, C. W., Han, Y., Kim, S., Jeong, D., Kwon, H. Y., Kim, H., Baek, M., & Lee, S. H. (2018). Melatonin and 5‐fluorouracil co‐suppress colon cancer stem cells by regulating cellular prion protein‐Oct4 axis. Journal of Pineal Research, 65(4), e12519.
Liman, W., Ait Lahcen, N., Oubahmane, M., Hdoufane, I., Cherqaoui, D., Daoud, R., & El Allali, A. (2022). Hybrid Molecules as Potential Drugs for the Treatment of HIV: Design and Applications. Pharmaceuticals, 15(9), 1092.
Liu, J., Mi, C., Tang, X., Cao, Y., Li, Z., & Huang, W. (2014). Facile microwave-assisted synthesis of substituted benzofuran derivatives. Research on Chemical Intermediates, 40, 2083–2090.
Ma, Z., Zhou, M., Ma, L., & Zhang, M. (2020). Synthesis of benzofurans from the cyclodehydration of α-phenoxy ketones mediated by Eaton’s reagent. Journal of Chemical Research, 44(7–8), 426–436.
Mansinho, A., Boni, V., Miguel, M., & Calvo, E. (2019). New designs in early clinical drug development. Annals of Oncology, 30(9), 1460–1465.
Marjaneh, R. M., Rahmani, F., Hassanian, S. M., Rezaei, N., Hashemzehi, M., Bahrami, A., Ariakia, F., Fiuji, H., Sahebkar, A., & Avan, A. (2018). Phytosomal curcumin inhibits tumor growth in colitis‐associated colorectal cancer. Journal of Cellular Physiology, 233(10), 6785–6798.
Masrul, M., & Nindrea, R. D. (2019). Dietary fibre protective against colorectal cancer patients in Asia: a meta-analysis. Open Access Macedonian Journal of Medical Sciences, 7(10), 1723.
MEDDEB, A., ELLEUCH, H., & AYARI, S. (2024). An efficient one-pot synthesis of benzofurans from functionalized tetrahydronaphtalenes. Tetrahedron, 134074.
Mishra, S., & Singh, P. (2016). Hybrid molecules: The privileged scaffolds for various pharmaceuticals. European Journal of Medicinal Chemistry, 124, 500–536.
Mo, C., Chadha, B., & Kuang, C. (2024). An Evolving Landscape: New Therapies for Metastatic Colorectal Cancer. Clinical Colorectal Cancer.
Mokenapelli, S., Thalari, G., Vadiyaala, N., Yerrabelli, J. R., Irlapati, V. K., Gorityala, N., Sagurthi, S. R., & Chitneni, P. R. (2020). Synthesis, cytotoxicity, and molecular docking of substituted 3‐(2‐methylbenzofuran‐3‐yl)‐5‐(phenoxymethyl)‐1, 2, 4‐oxadiazoles. Archiv Der Pharmazie, 353(6), 2000006.
Moreno-Quintero, G., Betancur-Zapata, E., Herrera-Ramírez, A., & Cardona-Galeano, W. (2023). New Hybrid Scaffolds Based on 5-FU/Curcumin: Synthesis, Cytotoxic, Antiproliferative and Pro-Apoptotic Effect. Pharmaceutics, 15(4), 1221.
Moreno-Quintero, G., Castrillón-Lopez, W., Herrera-Ramirez, A., Yepes-Pérez, A. F., Quintero-Saumeth, J., & Cardona-Galeano, W. (2022). Synthesis and Chemopreventive Potential of 5-FU/Genistein Hybrids on Colorectal Cancer Cells. Pharmaceuticals, 15(10), 1299.
Obrador, E., Salvador-Palmer, R., Jihad-Jebbar, A., López-Blanch, R., Dellinger, T. H., Dellinger, R. W., & Estrela, J. M. (2021). Pterostilbene in cancer therapy. Antioxidants, 10(3), 492.
Obuch, J. C., & Ahnen, D. J. (2016). Colorectal cancer: genetics is changing everything. Gastroenterology Clinics, 45(3), 459–476.
Ocvirk, S., Wilson, A. S., Appolonia, C. N., Thomas, T. K., & O’Keefe, S. J. D. (2019). Fiber, fat, and colorectal cancer: new insight into modifiable dietary risk factors. Current Gastroenterology Reports, 21, 1–7.
Paul, K., Bindal, S., & Luxami, V. (2013). Synthesis of new conjugated coumarin–benzimidazole hybrids and their anticancer activity. Bioorganic & Medicinal Chemistry Letters, 23(12), 3667–3672.
Pawełczyk, A., Sowa-Kasprzak, K., Olender, D., & Zaprutko, L. (2018). Molecular consortia—Various structural and synthetic concepts for more effective therapeutics synthesis. International Journal of Molecular Sciences, 19(4), 1104.
Peeters, M., Cervantes, A., Moreno Vera, S., & Taieb, J. (2018). Trifluridine/tipiracil: an emerging strategy for the management of gastrointestinal cancers. Future Oncology, 14(16), 1629–1645.
Pradhan, R., Chatterjee, S., Hembram, K. C., Sethy, C., Mandal, M., & Kundu, C. N. (2021). Nano formulated Resveratrol inhibits metastasis and angiogenesis by reducing inflammatory cytokines in oral cancer cells by targeting tumor associated macrophages. The Journal of Nutritional Biochemistry, 92, 108624.
Raiguru, B. P., Mohapatra, S., Nayak, S., Sahal, D., Yadav, M., & Acharya, B. N. (2022). Flavone-stilbene hybrids: Synthesis and evaluation as potential antimalarial agents. European Journal of Medicinal Chemistry Reports, 4, 100029.
Ranasinghe, R., Mathai, M., & Zulli, A. (2022). A synopsis of modern-day colorectal cancer: Where we stand. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 1877(2), 188699.
Rifaldi, Sukandar, E. R., Fadlan, A., Fatmawati, S., Purnomo, A. S., Wairata, J., & Ersam, T. (2023). A new biphenyl from the stem bark of Garcinia macrantha AC Sm. Natural Product Research, 1–6.
Ross, M. H., & Pawlina, W. (2020). Ross Histologia: texto y atlas: correlación con biología molecular y celular. Wolters Klumer.
Roy, A. (2016). Reigniting pharmaceutical innovation through holistic drug targeting. Drug Discovery, 45.
Ruan, B., Rong, M., Ming, Z., Wang, K., Liu, X., Deng, L., Zhang, X., Xu, K., Shi, C., & Gao, T. (2023). Discovery of pterostilbene analogs as novel NLRP3 inflammasome inhibitors for potential treatment of DSS-induced colitis in mice. Bioorganic Chemistry, 133, 106429.
Rupasinghe, H. P. V. (2015). Application of NMR spectroscopy in plant polyphenols associated with human health. In Applications of NMR spectroscopy (pp. 3–92). Elsevier.
Saha, S., Ghosh, S., Ghosh, S., Nandi, S., & Nayak, A. (2024). Unraveling the complexities of colorectal cancer and its promising therapies–An updated review. International Immunopharmacology, 143, 113325.
Sasmal, P., Babasahib, S. K., Kumar, B. R. P., & Raghavendra, N. M. (2022). Biphenyl-based small molecule inhibitors: Novel cancer immunotherapeutic agents targeting PD-1/PD-L1 interaction. Bioorganic & Medicinal Chemistry, 117001.
Sellers, R. S., & Morton, D. (2014). The colon: from banal to brilliant. Toxicologic Pathology, 42(1), 67–81.
Sethy, C., & Kundu, C. N. (2021). 5-Fluorouracil (5-FU) resistance and the new strategy to enhance the sensitivity against cancer: Implication of DNA repair inhibition. Biomedicine & Pharmacotherapy, 137, 111285.
Shirley, M. (2018). Fruquintinib: first global approval. Drugs, 78, 1757–1761.
Soltan, O. M., Shoman, M. E., Abdel-Aziz, S. A., Narumi, A., Konno, H., & Abdel-Aziz, M. (2021). Molecular hybrids: A five-year survey on structures of multiple targeted hybrids of protein kinase inhibitors for cancer therapy. European Journal of Medicinal Chemistry, 225, 113768.
Tang, K.-W., Hsu, C.-Y., Aljuffali, I. A., Alalaiwe, A., Lai, W.-N., Gu, P.-Y., Tseng, C.-H., & Fang, J.-Y. (2024). Skin delivery of synthetic benzoyl pterostilbenes suppresses atopic dermatitis-like inflammation through the inhibition of keratinocyte and macrophage activation. Biomedicine & Pharmacotherapy, 170, 116073.
Teka, T., Lele, Z., Xiaoyan, G., Li, Y., Lifeng, H., & Xiaohui, Y. (2022). Stilbenes: Source plants, chemistry, biosynthesis, pharmacology, application and problems related to their clinical Application-A comprehensive review. Phytochemistry, 113128.
Tian, B., & Liu, J. (2020). Resveratrol: A review of plant sources, synthesis, stability, modification and food application. Journal of the Science of Food and Agriculture, 100(4), 1392–1404.
Tyunin, A. P., Nityagovsky, N. N., Grigorchuk, V. P., & Kiselev, K. V. (2018). Stilbene content and expression of stilbene synthase genes in cell cultures of Vitis amurensis treated with cinnamic and caffeic acids. Biotechnology and Applied Biochemistry, 65(2), 150–155.
Van Chinh, L., Ngoc Hung, T., Thi Nga, N., Le Cuong, H., Tien Chinh, V., Un Kim, S., & Khac Vu, T. (2015). New Chalcones Containing 5-Fluorouracil Exhibiting in vitro Anti-Cancer Activity. Letters in Organic Chemistry, 12(4), 251–261.
van der Velden, D. L., Opdam, F. L., & Voest, E. E. (2016). TAS-102 for treatment of advanced colorectal cancers that are no longer responding to other therapies. Clinical Cancer Research, 22(12), 2835–2839.
Vázquez, C., Orlova, M., Angriman, F., Minatta, J. N., Scibona, P., Verzura, M. A., Jáuregui, E. G., Díaz de Arce, H., Pallotta, M. G., & Belloso, W. H. (2017). Prediction of severe toxicity in adult patients under treatment with 5-fluorouracil: a prospective cohort study. Anti-Cancer Drugs, 28(9), 1039–1046.
Virostko, J., Capasso, A., Yankeelov, T. E., & Goodgame, B. (2019). Recent trends in the age at diagnosis of colorectal cancer in the US National Cancer Data Base, 2004‐2015. Cancer, 125(21), 3828–3835.
Vodenkova, S., Buchler, T., Cervena, K., Veskrnova, V., Vodicka, P., & Vymetalkova, V. (2020). 5-fluorouracil and other fluoropyrimidines in colorectal cancer: Past, present and future. Pharmacology & Therapeutics, 206, 107447.
Wang, J., Fan, X.-Y., Yang, L.-Y., He, H., Huang, R., Jiang, F.-L., & Liu, Y. (2016). Conjugated 5-fluorouracil with mitochondria-targeting lipophilic cation: design, synthesis and biological evaluation. MedChemComm, 7(10).
Wang, X.-D., Wang, J.-X., Yu, B.-Y., Zhang, S.-Q., & Hu, M.-H. (2023). Non-fused imidazole-biphenyl analogs repress triple-negative breast cancer growth by mainly stabilizing the c-MYC G-quadruplex via a multi-site binding mode. Bioorganic & Medicinal Chemistry, 88, 117336.
Yuan, S., Wang, D.-S., Liu, H., Zhang, S.-N., Yang, W.-G., Lv, M., Zhou, Y.-X., Zhang, S.-Y., Song, J., & Liu, H.-M. (2023). New drug approvals for 2021: Synthesis and clinical applications. European Journal of Medicinal Chemistry, 245, 114898.
Zhang, R., Song, X.-Q., Liu, R.-P., Ma, Z.-Y., & Xu, J.-Y. (2019). Fuplatin: An efficient and low-toxic dual-prodrug. Journal of Medicinal Chemistry, 62(9), 4543–4554.
Zheng, H.-C. (2017). The molecular mechanisms of chemoresistance in cancers. Oncotarget, 8(35), 59950.
dc.rights.uri.none.fl_str_mv http://creativecommons.org/licenses/by-nc-sa/4.0/
dc.rights.accessrights.none.fl_str_mv info:eu-repo/semantics/openAccess
dc.rights.license.en.fl_str_mv Attribution-NonCommercial-ShareAlike 4.0 International
dc.rights.coar.none.fl_str_mv http://purl.org/coar/access_right/c_abf2
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.extent.none.fl_str_mv 124 páginas
dc.format.mimetype.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Universidad de Antioquia
dc.publisher.program.none.fl_str_mv Maestría en Ciencias Químicas
dc.publisher.department.none.fl_str_mv Instituto de Química
dc.publisher.place.none.fl_str_mv Medellín, Colombia
dc.publisher.faculty.none.fl_str_mv Facultad de Ciencias Exactas y Naturales
dc.publisher.branch.none.fl_str_mv Campus Medellín - Ciudad Universitaria
publisher.none.fl_str_mv Universidad de Antioquia
institution Universidad de Antioquia
bitstream.url.fl_str_mv https://bibliotecadigital.udea.edu.co/bitstreams/8bb7318a-1650-4b19-9bb9-6e851a9aa98a/download
https://bibliotecadigital.udea.edu.co/bitstreams/2b1a7400-f238-420c-9fb8-ed31c8695c83/download
https://bibliotecadigital.udea.edu.co/bitstreams/726a3a08-7ad0-43b2-82b6-485ee22d8be5/download
https://bibliotecadigital.udea.edu.co/bitstreams/5ec16da1-cb29-44db-a7f2-1f1d0840c41b/download
https://bibliotecadigital.udea.edu.co/bitstreams/727f138f-68b7-4d10-8dab-644a070598e9/download
bitstream.checksum.fl_str_mv 0c8269127f69e5282e2081c9800f0cfb
b76e7a76e24cf2f94b3ce0ae5ed275d0
5643bfd9bcf29d560eeec56d584edaa9
2f3a57848e5855d52c0b459c71e676b2
3db5bbe03626dbd5e93df5415a2ede7d
bitstream.checksumAlgorithm.fl_str_mv MD5
MD5
MD5
MD5
MD5
repository.name.fl_str_mv Repositorio Institucional de la Universidad de Antioquia
repository.mail.fl_str_mv aplicacionbibliotecadigitalbiblioteca@udea.edu.co
_version_ 1851052461420183552
spelling Yepes Pérez, Andrés FelipeCardona Galeano, Wilson IsidroBecerra Quintana, Rubén DaríoQuímica de Plantas ColombianasHerrera Calderón, OscarEscobar Peláez, Gustavo Adolfo2025-06-05T16:21:29Z2025Rubén Becerra-Quintana. (2025). Síntesis y actividad anticancerígena de híbridos basados en benzofurano y 5-fluorouracilo [Tesis de maestría]. Universidad de Antioquia, Medellín, Colombia.https://hdl.handle.net/10495/46266Se sintetizaron 24 nuevas moléculas híbridas basadas en 5-fluorouracilo-Pterostilbeno (5a – 5i), 5-fluorouracilo-bifenilo (7a – 7e) y Benzofurano-pterostilbeno (10d – 10h) con rendimientos finales entre 10 y 85 %. Todos los compuestos fueron caracterizados mediante métodos espectroscópicos como resonancia magnética nuclear de 1H y 13C y espectrometría de masas de alta resolución. Todos los híbridos sintetizados fueron evaluados en la línea celular de adenocarcinoma SW480 y en la línea celular no maligna NCM460, donde, se pudieron destacar la actividad inhibitoria de los compuestos 5g, 5h, 10d y 10h siendo estos dos últimos los que presentaron una mayor selectividad los compuestos de partida y el medicamento de referencia 5-FU.A total of 24 new hybrid molecules were synthesized based on 5-fluorouracil–pterostilbene (5a–5i), 5-fluorouracil–biphenyl (7a–7e), and benzofuran–pterostilbene (10d–10h), with final yields ranging from 10% to 85%. All compounds were characterized using spectroscopic methods such as 1H and 13C nuclear magnetic resonance (NMR) and highresolution mass spectrometry. All synthesized hybrids were evaluated against the SW480 adenocarcinoma cell line and the non-malignant NCM460 cell line. Among them, compounds 5g, 5h, 10d, and 10h exhibited notable inhibitory activity, with the latter two showing greater selectivity compared to the starting compounds and the reference drug 5-FU.Química MedicinalCOL0015329MaestríaMagíster en Ciencias Químicas124 páginasapplication/pdfspaUniversidad de AntioquiaMaestría en Ciencias QuímicasInstituto de QuímicaMedellín, ColombiaFacultad de Ciencias Exactas y NaturalesCampus Medellín - Ciudad Universitariahttp://creativecommons.org/licenses/by-nc-sa/4.0/info:eu-repo/semantics/openAccessAttribution-NonCommercial-ShareAlike 4.0 Internationalhttp://purl.org/coar/access_right/c_abf2Síntesis y actividad anticancerígena de híbridos basados en benzofurano y 5-fluorouraciloTrabajo de grado - Maestríahttp://purl.org/redcol/resource_type/TMTexthttp://purl.org/coar/version/c_b1a7d7d4d402bcceinfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/draftAbbas, A. A., & Dawood, K. M. (2023). Anticancer therapeutic potential of benzofuran scaffolds. RSC Advances, 13(16), 11096–11120.Abraham, J., Ocen, J., & Staffurth, J. (2022). Hormonal therapy for cancer. Medicine.Adhikari, S., Bhattacharya, A., Adhikary, S., Singh, V., Gadad, S. S., Roy, S., & Das, C. (2022). The paradigm of drug resistance in cancer: an epigenetic perspective. Bioscience Reports, 42(4), BSR20211812.Albert, S., Horbach, R., Deising, H. B., Siewert, B., & Csuk, R. (2011). Synthesis and antimicrobial activity of (E) stilbene derivatives. Bioorganic & Medicinal Chemistry, 19(17), 5155–5166.Błaszczyk, A., Sady, S., & Sielicka, M. (2019). The stilbene profile in edible berries. Phytochemistry Reviews, 18, 37–67.Braga, A., Rocha, I., & Faria, N. (2019). Microbial hosts as a promising platform for polyphenol production. Natural Bio-Active Compounds: Volume 1: Production and Applications, 71–103.Cao, W., Qin, K., Li, F., & Chen, W. (2024). Comparative study of cancer profiles between 2020 and 2022 using global cancer statistics (GLOBOCAN). Journal of the National Cancer Center.Cardona-G, W., Herrera-R, A., Castrillón-L, W., & Ramírez-Malule, H. (2021). Chemistry and anticancer activity of hybrid molecules and derivatives based on 5-fluorouracil. Current Medicinal Chemistry, 28(27), 5551–5601.Cascella, M., Bimonte, S., Barbieri, A., Del Vecchio, V., Caliendo, D., Schiavone, V., Fusco, R., Granata, V., Arra, C., & Cuomo, A. (2018). Dissecting the mechanisms and molecules underlying the potential carcinogenicity of red and processed meat in colorectal cancer (CRC): an overview on the current state of knowledge. Infectious Agents and Cancer, 13, 1–8.Chang, T.-C., Yeh, C.-T., Adebayo, B. O., Lin, Y.-C., Deng, L., Rao, Y. K., Huang, C.-C., Lee, W.-H., Wu, A. T. H., & Hsiao, M. (2015). 4-Acetylantroquinonol B inhibits colorectal cancer tumorigenesis and suppresses cancer stem-like phenotype. Toxicology and Applied Pharmacology, 288(2), 258–268.Chen, Y., Wang, G., Yuan, Y., Zou, G., Yang, W., Tan, Q., Kang, W., & She, Z. (2022). Metabolites with cytotoxic activities from the mangrove endophytic fungus Fusarium sp. 2ST2. Frontiers in Chemistry, 10, 842405.Das, P. K., Islam, F., & Lam, A. K. (2020). The roles of cancer stem cells and therapy resistance in colorectal carcinoma. Cells, 9(6), 1392.Dharavath, R., Sarasija, M., Ram Reddy, M., Naga Prathima, K., Nagarju, N., Ramakrishna, K., Ashok, D., & Daravath, S. (2022). Microwave-assisted synthesis and evaluation of their antiproliferative, antimicrobial, activities and DNA Binding studies of (3-Methyl-7 H-furo [2, 3-f] chromen-2-yl)(aryl) methanones. Medicinal Chemistry Research, 31(6), 993–1002.Eldehna, W. M., Salem, R., Elsayed, Z. M., Al-Warhi, T., Knany, H. R., Ayyad, R. R., Traiki, T. Bin, Abdulla, M.-H., Ahmad, R., & Abdel-Aziz, H. A. (2021). Development of novel benzofuran-isatin conjugates as potential antiproliferative agents with apoptosis inducing mechanism in Colon cancer. Journal of Enzyme Inhibition and Medicinal Chemistry, 36(1), 1423–1434.Fan, X., He, H., Li, J., Luo, G., Zheng, Y., Zhou, J.-K., He, J., Pu, W., & Zhao, Y. (2019). Discovery of 4, 6-bis (benzyloxy)-3-phenylbenzofuran as a novel Pin1 inhibitor to suppress hepatocellular carcinoma via upregulating microRNA biogenesis. Bioorganic & Medicinal Chemistry, 27(11), 2235–2244.Fraction, L. V. E. (n.d.). FULL PRESCRIBING INFORMATION.Gandomani, H. S., Aghajani, M., Mohammadian-Hafshejani, A., Tarazoj, A. A., Pouyesh, V., & Salehiniya, H. (2017). Colorectal cancer in the world: incidence, mortality and risk factors. Biomedical Research and Therapy, 4(10), 1656–1675.Gao, S., Zhang, H., Li, N., Zhang, L., Zhu, Z., & Xu, C. (2024). Pterostilbene: A natural neuroprotective stilbene with anti-Alzheimer’s disease properties. Journal of Pharmaceutical Analysis, 101043.Gao, Y., Ma, C., Feng, X., Liu, Y., & Haimiti, X. (2020). BF12, a novel benzofuran, exhibits antitumor activity by inhibiting microtubules and the PI3K/Akt/mTOR signaling pathway in human cervical cancer cells. Chemistry & Biodiversity, 17(3), e1900622.Grandhi, N., Patel, B., & Aranha, O. (2023). Advances in Systemic Chemotherapy and Immunotherapy for Metastatic Colorectal Cancer. Seminars in Colon and Rectal Surgery, 100972.Grau, L., Soucek, R., & Pujol, M. D. (2023). Resveratrol derivatives: Synthesis and their biological activities. European Journal of Medicinal Chemistry, 246, 114962.Grygorenko, O. O., Volochnyuk, D. M., Ryabukhin, S. V, & Judd, D. B. (2020). The symbiotic relationship between drug discovery and organic chemistry. Chemistry–A European Journal, 26(6), 1196–1237.Guan, X.-W., Xu, X.-H., Feng, S.-L., Tang, Z.-B., Chen, S.-W., & Hui, L. (2016). Synthesis of hybrid 4-deoxypodophyllotoxin–5-fluorouracil compounds that inhibit cellular migration and induce cell cycle arrest. Bioorganic & Medicinal Chemistry Letters, 26(6), 1561–1566.Guan, X.-Y., Al-Misba’a, Z., & Huang, K.-W. (2015). Efficient and selective α-bromination of carbonyl compounds with N-bromosuccinimide under microwave. Arabian Journal of Chemistry, 8(6), 892–896.Han, S., Sang, Y., Wu, Y., Tao, Y., Pannecouque, C., De Clercq, E., Zhuang, C., & Chen, F.-E. (2019). Molecular hybridization-inspired optimization of diarylbenzopyrimidines as HIV-1 nonnucleoside reverse transcriptase inhibitors with improved activity against K103N and E138K mutants and pharmacokinetic profiles. ACS Infectious Diseases, 6(5), 787–801.Hapeshi, A., Benarroch, J. M., Clarke, D. J., & Waterfield, N. R. (2018). Iso-propyl stilbene: A life-cycle signal? BioRxiv, 498857.Hernández, C., Moreno, G., Herrera-R, A., & Cardona-G, W. (2021). New hybrids based on curcumin and resveratrol: Synthesis, cytotoxicity and antiproliferative activity against colorectal cancer cells. Molecules, 26(9), 2661.Herrera-R, A., Castrillón, W., Otero, E., Ruiz, E., Carda, M., Agut, R., Naranjo, T., Moreno, G., Maldonado, M. E., & Cardona-G, W. (2018). Synthesis and antiproliferative activity of 3-and 7-styrylcoumarins. Medicinal Chemistry Research, 27, 1893–1905.Housman, G., Byler, S., Heerboth, S., Lapinska, K., Longacre, M., Snyder, N., & Sarkar, S. (2014). Drug resistance in cancer: an overview. Cancers, 6(3), 1769–1792.Hsieh, M.-T., Huang, L.-J., Wu, T.-S., Lin, H.-Y., Morris-Natschke, S. L., Lee, K.-H., & Kuo, S.-C. (2018). Synthesis and antitumor activity of bis (hydroxymethyl) propionate analogs of pterostilbene in cisplatin-resistant human oral cancer cells. Bioorganic & Medicinal Chemistry, 26(14), 3909–3916.Hu, Q.-F., Wang, Y.-D., Zhu, D.-L., Yu, Z.-H., Zhan, J.-B., Xing, H.-H., Ma, H.-Y., Yang, Y., Li, Y.-K., & Chen, Z.-Y. (2016). Three new biphenyls from the twigs of Garcinia tetralata and their anti-tobacco mosaic virus activity. Journal of Asian Natural Products Research, 18(12), 1115–1121.Ito, K., Tatsumi, T., Takahashi, K., Shimizu, Y., Yamatsugu, K., & Kanai, M. (2020). A stable and cleavable O-linked spacer for drug delivery systems. Chemical and Pharmaceutical Bulletin, 68(3), 212–215.Jaferian, S., Negahdari, B., & Eatemadi, A. (2016). Colon cancer targeting using conjugates biomaterial 5-flurouracil. Biomedicine & Pharmacotherapy, 84, 780–788.Jain, Z. J., Gide, P. S., & Kankate, R. S. (2017). Biphenyls and their derivatives as synthetically and pharmacologically important aromatic structural moieties. Arabian Journal of Chemistry, 10, S2051–S2066.Ji, B.-K., Gao, X.-M., Cui, D., Wang, S.-S., Huang, W.-Z., Li, Y.-K., Mei, S.-X., Yang, Z., Li, G.-P., & Jiang, M.-Y. (2017). Two new biphenyls from the stems of Garcinia tetralata. Natural Product Research, 31(13), 1544–1550.Jin, L.-P., Xie, Q., Huang, E.-F., Wang, L., Zhang, B.-Q., Hu, J.-S., Wan, D. C.-C., Jin, Z., & Hu, C. (2020). Design, synthesis, and biological activity of a novel series of benzofuran derivatives against oestrogen receptor-dependent breast cancer cell lines. Bioorganic Chemistry, 95, 103566.Kato, K., Takahashi, M., Oh-Hashi, K., Ando, K., & Hirata, Y. (2022). Quercetin and resveratrol inhibit ferroptosis independently of Nrf2–ARE activation in mouse hippocampal HT22 cells. Food and Chemical Toxicology, 113586.Kumar, M., Verma, S., Sharma, M., Poonam, & Rathi, B. (2023). Metal‐Catalysed Synthesis of Benzofused Five‐Membered N/O/S‐Heterocycles, a Progressive Area in Synthetic Organic Chemistry. European Journal of Organic Chemistry, 26(46), e202300877.Lara-Ochoa, F., Sandoval-Minero, L. C., & Espinosa-Pérez, G. (2015). A new synthesis of resveratrol. Tetrahedron Letters, 56(44), 5977–5979.Larsen, R. D., King, A. O., Chen, C. Y., Corley, E. G., Foster, B. S., Roberts, F. E., Yang, C., Lieberman, D. R., Reamer, R. A., & Tschaen, D. M. (1994). Efficient synthesis of losartan, a nonpeptide angiotensin II receptor antagonist. The Journal of Organic Chemistry, 59(21), 6391–6394.Laudadio, G., Fusini, G., Casotti, G., Evangelisti, C., Angelici, G., & Carpita, A. (2019). Synthesis of Pterostilbene through supported-catalyst promoted Mizoroki-Heck reaction, and its transposition in continuous flow reactor. Journal of Flow Chemistry, 9, 133–143.Lee, J. H., Yun, C. W., Han, Y., Kim, S., Jeong, D., Kwon, H. Y., Kim, H., Baek, M., & Lee, S. H. (2018). Melatonin and 5‐fluorouracil co‐suppress colon cancer stem cells by regulating cellular prion protein‐Oct4 axis. Journal of Pineal Research, 65(4), e12519.Liman, W., Ait Lahcen, N., Oubahmane, M., Hdoufane, I., Cherqaoui, D., Daoud, R., & El Allali, A. (2022). Hybrid Molecules as Potential Drugs for the Treatment of HIV: Design and Applications. Pharmaceuticals, 15(9), 1092.Liu, J., Mi, C., Tang, X., Cao, Y., Li, Z., & Huang, W. (2014). Facile microwave-assisted synthesis of substituted benzofuran derivatives. Research on Chemical Intermediates, 40, 2083–2090.Ma, Z., Zhou, M., Ma, L., & Zhang, M. (2020). Synthesis of benzofurans from the cyclodehydration of α-phenoxy ketones mediated by Eaton’s reagent. Journal of Chemical Research, 44(7–8), 426–436.Mansinho, A., Boni, V., Miguel, M., & Calvo, E. (2019). New designs in early clinical drug development. Annals of Oncology, 30(9), 1460–1465.Marjaneh, R. M., Rahmani, F., Hassanian, S. M., Rezaei, N., Hashemzehi, M., Bahrami, A., Ariakia, F., Fiuji, H., Sahebkar, A., & Avan, A. (2018). Phytosomal curcumin inhibits tumor growth in colitis‐associated colorectal cancer. Journal of Cellular Physiology, 233(10), 6785–6798.Masrul, M., & Nindrea, R. D. (2019). Dietary fibre protective against colorectal cancer patients in Asia: a meta-analysis. Open Access Macedonian Journal of Medical Sciences, 7(10), 1723.MEDDEB, A., ELLEUCH, H., & AYARI, S. (2024). An efficient one-pot synthesis of benzofurans from functionalized tetrahydronaphtalenes. Tetrahedron, 134074.Mishra, S., & Singh, P. (2016). Hybrid molecules: The privileged scaffolds for various pharmaceuticals. European Journal of Medicinal Chemistry, 124, 500–536.Mo, C., Chadha, B., & Kuang, C. (2024). An Evolving Landscape: New Therapies for Metastatic Colorectal Cancer. Clinical Colorectal Cancer.Mokenapelli, S., Thalari, G., Vadiyaala, N., Yerrabelli, J. R., Irlapati, V. K., Gorityala, N., Sagurthi, S. R., & Chitneni, P. R. (2020). Synthesis, cytotoxicity, and molecular docking of substituted 3‐(2‐methylbenzofuran‐3‐yl)‐5‐(phenoxymethyl)‐1, 2, 4‐oxadiazoles. Archiv Der Pharmazie, 353(6), 2000006.Moreno-Quintero, G., Betancur-Zapata, E., Herrera-Ramírez, A., & Cardona-Galeano, W. (2023). New Hybrid Scaffolds Based on 5-FU/Curcumin: Synthesis, Cytotoxic, Antiproliferative and Pro-Apoptotic Effect. Pharmaceutics, 15(4), 1221.Moreno-Quintero, G., Castrillón-Lopez, W., Herrera-Ramirez, A., Yepes-Pérez, A. F., Quintero-Saumeth, J., & Cardona-Galeano, W. (2022). Synthesis and Chemopreventive Potential of 5-FU/Genistein Hybrids on Colorectal Cancer Cells. Pharmaceuticals, 15(10), 1299.Obrador, E., Salvador-Palmer, R., Jihad-Jebbar, A., López-Blanch, R., Dellinger, T. H., Dellinger, R. W., & Estrela, J. M. (2021). Pterostilbene in cancer therapy. Antioxidants, 10(3), 492.Obuch, J. C., & Ahnen, D. J. (2016). Colorectal cancer: genetics is changing everything. Gastroenterology Clinics, 45(3), 459–476.Ocvirk, S., Wilson, A. S., Appolonia, C. N., Thomas, T. K., & O’Keefe, S. J. D. (2019). Fiber, fat, and colorectal cancer: new insight into modifiable dietary risk factors. Current Gastroenterology Reports, 21, 1–7.Paul, K., Bindal, S., & Luxami, V. (2013). Synthesis of new conjugated coumarin–benzimidazole hybrids and their anticancer activity. Bioorganic & Medicinal Chemistry Letters, 23(12), 3667–3672.Pawełczyk, A., Sowa-Kasprzak, K., Olender, D., & Zaprutko, L. (2018). Molecular consortia—Various structural and synthetic concepts for more effective therapeutics synthesis. International Journal of Molecular Sciences, 19(4), 1104.Peeters, M., Cervantes, A., Moreno Vera, S., & Taieb, J. (2018). Trifluridine/tipiracil: an emerging strategy for the management of gastrointestinal cancers. Future Oncology, 14(16), 1629–1645.Pradhan, R., Chatterjee, S., Hembram, K. C., Sethy, C., Mandal, M., & Kundu, C. N. (2021). Nano formulated Resveratrol inhibits metastasis and angiogenesis by reducing inflammatory cytokines in oral cancer cells by targeting tumor associated macrophages. The Journal of Nutritional Biochemistry, 92, 108624.Raiguru, B. P., Mohapatra, S., Nayak, S., Sahal, D., Yadav, M., & Acharya, B. N. (2022). Flavone-stilbene hybrids: Synthesis and evaluation as potential antimalarial agents. European Journal of Medicinal Chemistry Reports, 4, 100029.Ranasinghe, R., Mathai, M., & Zulli, A. (2022). A synopsis of modern-day colorectal cancer: Where we stand. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 1877(2), 188699.Rifaldi, Sukandar, E. R., Fadlan, A., Fatmawati, S., Purnomo, A. S., Wairata, J., & Ersam, T. (2023). A new biphenyl from the stem bark of Garcinia macrantha AC Sm. Natural Product Research, 1–6.Ross, M. H., & Pawlina, W. (2020). Ross Histologia: texto y atlas: correlación con biología molecular y celular. Wolters Klumer.Roy, A. (2016). Reigniting pharmaceutical innovation through holistic drug targeting. Drug Discovery, 45.Ruan, B., Rong, M., Ming, Z., Wang, K., Liu, X., Deng, L., Zhang, X., Xu, K., Shi, C., & Gao, T. (2023). Discovery of pterostilbene analogs as novel NLRP3 inflammasome inhibitors for potential treatment of DSS-induced colitis in mice. Bioorganic Chemistry, 133, 106429.Rupasinghe, H. P. V. (2015). Application of NMR spectroscopy in plant polyphenols associated with human health. In Applications of NMR spectroscopy (pp. 3–92). Elsevier.Saha, S., Ghosh, S., Ghosh, S., Nandi, S., & Nayak, A. (2024). Unraveling the complexities of colorectal cancer and its promising therapies–An updated review. International Immunopharmacology, 143, 113325.Sasmal, P., Babasahib, S. K., Kumar, B. R. P., & Raghavendra, N. M. (2022). Biphenyl-based small molecule inhibitors: Novel cancer immunotherapeutic agents targeting PD-1/PD-L1 interaction. Bioorganic & Medicinal Chemistry, 117001.Sellers, R. S., & Morton, D. (2014). The colon: from banal to brilliant. Toxicologic Pathology, 42(1), 67–81.Sethy, C., & Kundu, C. N. (2021). 5-Fluorouracil (5-FU) resistance and the new strategy to enhance the sensitivity against cancer: Implication of DNA repair inhibition. Biomedicine & Pharmacotherapy, 137, 111285.Shirley, M. (2018). Fruquintinib: first global approval. Drugs, 78, 1757–1761.Soltan, O. M., Shoman, M. E., Abdel-Aziz, S. A., Narumi, A., Konno, H., & Abdel-Aziz, M. (2021). Molecular hybrids: A five-year survey on structures of multiple targeted hybrids of protein kinase inhibitors for cancer therapy. European Journal of Medicinal Chemistry, 225, 113768.Tang, K.-W., Hsu, C.-Y., Aljuffali, I. A., Alalaiwe, A., Lai, W.-N., Gu, P.-Y., Tseng, C.-H., & Fang, J.-Y. (2024). Skin delivery of synthetic benzoyl pterostilbenes suppresses atopic dermatitis-like inflammation through the inhibition of keratinocyte and macrophage activation. Biomedicine & Pharmacotherapy, 170, 116073.Teka, T., Lele, Z., Xiaoyan, G., Li, Y., Lifeng, H., & Xiaohui, Y. (2022). Stilbenes: Source plants, chemistry, biosynthesis, pharmacology, application and problems related to their clinical Application-A comprehensive review. Phytochemistry, 113128.Tian, B., & Liu, J. (2020). Resveratrol: A review of plant sources, synthesis, stability, modification and food application. Journal of the Science of Food and Agriculture, 100(4), 1392–1404.Tyunin, A. P., Nityagovsky, N. N., Grigorchuk, V. P., & Kiselev, K. V. (2018). Stilbene content and expression of stilbene synthase genes in cell cultures of Vitis amurensis treated with cinnamic and caffeic acids. Biotechnology and Applied Biochemistry, 65(2), 150–155.Van Chinh, L., Ngoc Hung, T., Thi Nga, N., Le Cuong, H., Tien Chinh, V., Un Kim, S., & Khac Vu, T. (2015). New Chalcones Containing 5-Fluorouracil Exhibiting in vitro Anti-Cancer Activity. Letters in Organic Chemistry, 12(4), 251–261.van der Velden, D. L., Opdam, F. L., & Voest, E. E. (2016). TAS-102 for treatment of advanced colorectal cancers that are no longer responding to other therapies. Clinical Cancer Research, 22(12), 2835–2839.Vázquez, C., Orlova, M., Angriman, F., Minatta, J. N., Scibona, P., Verzura, M. A., Jáuregui, E. G., Díaz de Arce, H., Pallotta, M. G., & Belloso, W. H. (2017). Prediction of severe toxicity in adult patients under treatment with 5-fluorouracil: a prospective cohort study. Anti-Cancer Drugs, 28(9), 1039–1046.Virostko, J., Capasso, A., Yankeelov, T. E., & Goodgame, B. (2019). Recent trends in the age at diagnosis of colorectal cancer in the US National Cancer Data Base, 2004‐2015. Cancer, 125(21), 3828–3835.Vodenkova, S., Buchler, T., Cervena, K., Veskrnova, V., Vodicka, P., & Vymetalkova, V. (2020). 5-fluorouracil and other fluoropyrimidines in colorectal cancer: Past, present and future. Pharmacology & Therapeutics, 206, 107447.Wang, J., Fan, X.-Y., Yang, L.-Y., He, H., Huang, R., Jiang, F.-L., & Liu, Y. (2016). Conjugated 5-fluorouracil with mitochondria-targeting lipophilic cation: design, synthesis and biological evaluation. MedChemComm, 7(10).Wang, X.-D., Wang, J.-X., Yu, B.-Y., Zhang, S.-Q., & Hu, M.-H. (2023). Non-fused imidazole-biphenyl analogs repress triple-negative breast cancer growth by mainly stabilizing the c-MYC G-quadruplex via a multi-site binding mode. Bioorganic & Medicinal Chemistry, 88, 117336.Yuan, S., Wang, D.-S., Liu, H., Zhang, S.-N., Yang, W.-G., Lv, M., Zhou, Y.-X., Zhang, S.-Y., Song, J., & Liu, H.-M. (2023). New drug approvals for 2021: Synthesis and clinical applications. European Journal of Medicinal Chemistry, 245, 114898.Zhang, R., Song, X.-Q., Liu, R.-P., Ma, Z.-Y., & Xu, J.-Y. (2019). Fuplatin: An efficient and low-toxic dual-prodrug. Journal of Medicinal Chemistry, 62(9), 4543–4554.Zheng, H.-C. (2017). The molecular mechanisms of chemoresistance in cancers. Oncotarget, 8(35), 59950.EstilbenosStilbenesFluorouraciloFluorouracilBenzofuranosBenzofuransAnticarcinógenosAnticarcinogenic agentsRelación estructura-actividadStructure-activity relationshipLínea celular tumoralCell line, tumorEspectroscopía de resonancia magnéticaMagnetic resonance spectroscopyEspectrometría de masasMass spectrometryDesarrollo de medicamentosDrug developmentNeoplasias colorrectales - Tratamiento farmacológicoColorectal neoplasms - Drug therapyHíbridos molecularesPterostilbenohttps://id.nlm.nih.gov/mesh/D013267https://id.nlm.nih.gov/mesh/D005472https://id.nlm.nih.gov/mesh/D001572https://id.nlm.nih.gov/mesh/D016588https://id.nlm.nih.gov/mesh/D013329https://id.nlm.nih.gov/mesh/D045744https://id.nlm.nih.gov/mesh/D009682https://id.nlm.nih.gov/mesh/D013058https://id.nlm.nih.gov/mesh/D000076722https://id.nlm.nih.gov/mesh/D015179ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edadesPublicationORIGINALBecerraRuben_2025_ActividadAnticancerigenaHibridos.pdfBecerraRuben_2025_ActividadAnticancerigenaHibridos.pdfapplication/pdf10628340https://bibliotecadigital.udea.edu.co/bitstreams/8bb7318a-1650-4b19-9bb9-6e851a9aa98a/download0c8269127f69e5282e2081c9800f0cfbMD51trueAnonymousREADLICENSElicense.txtlicense.txttext/plain; charset=utf-814837https://bibliotecadigital.udea.edu.co/bitstreams/2b1a7400-f238-420c-9fb8-ed31c8695c83/downloadb76e7a76e24cf2f94b3ce0ae5ed275d0MD52falseAnonymousREADCC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-81160https://bibliotecadigital.udea.edu.co/bitstreams/726a3a08-7ad0-43b2-82b6-485ee22d8be5/download5643bfd9bcf29d560eeec56d584edaa9MD53falseAnonymousREADTEXTBecerraRuben_2025_ActividadAnticancerigenaHibridos.pdf.txtBecerraRuben_2025_ActividadAnticancerigenaHibridos.pdf.txtExtracted texttext/plain101627https://bibliotecadigital.udea.edu.co/bitstreams/5ec16da1-cb29-44db-a7f2-1f1d0840c41b/download2f3a57848e5855d52c0b459c71e676b2MD54falseAnonymousREADTHUMBNAILBecerraRuben_2025_ActividadAnticancerigenaHibridos.pdf.jpgBecerraRuben_2025_ActividadAnticancerigenaHibridos.pdf.jpgGenerated Thumbnailimage/jpeg7088https://bibliotecadigital.udea.edu.co/bitstreams/727f138f-68b7-4d10-8dab-644a070598e9/download3db5bbe03626dbd5e93df5415a2ede7dMD55falseAnonymousREAD10495/46266oai:bibliotecadigital.udea.edu.co:10495/462662025-06-06 04:07:28.318http://creativecommons.org/licenses/by-nc-sa/4.0/Attribution-NonCommercial-ShareAlike 4.0 Internationalopen.accesshttps://bibliotecadigital.udea.edu.coRepositorio Institucional de la Universidad de Antioquiaaplicacionbibliotecadigitalbiblioteca@udea.edu.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

Publicaciones similares