{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T18:51:02Z","timestamp":1776106262412,"version":"3.50.1"},"reference-count":105,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T00:00:00Z","timestamp":1776038400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007637","name":"Departamento Administrativo de Ciencia, Tecnolog\u00c3a e Innovaci\u00c3\u00b3n","doi-asserted-by":"publisher","award":["621-2022"],"award-info":[{"award-number":["621-2022"]}],"id":[{"id":"10.13039\/100007637","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Colorectal cancer (CRC) remains one of the most prevalent and lethal malignancies worldwide, highlighting the urgent need for developing effective treatments. Molecular hybridization is a promising strategy for identifying new bioactive compounds. This study focused on designing and synthesizing a novel series of benzofuran-pterostilbene hybrid molecules. These compounds were successfully obtained, and their structures were elucidated by spectroscopic analysis. In addition, the activity of the hybrids was evaluated against colorectal adenocarcinoma cells. After the treatments, hybrids\n                    <jats:bold>6d<\/jats:bold>\n                    and\n                    <jats:bold>6e<\/jats:bold>\n                    exhibited the highest activity, with GI\n                    <jats:sub>50<\/jats:sub>\n                    values of 11.93\u2009\u00b1\u20092.38 \u00b5M and 4.74\u2009\u00b1\u20090.38 \u00b5M, respectively, suggesting antiproliferative effects and measurable cytotoxicity under the tested conditions. Additionally, Hoechst 33342 fluorescence imaging revealed chromatin condensation and nuclear fragmentation, along with a diffuse DiOC\u2086 fluorescence pattern relative to the control, suggesting a form of programmed cell death, which was further supported by flow cytometric analysis showing an increased proportion of hypodiploid cells following propidium iodide staining. In parallel, wound-healing assays demonstrated impaired migration and cytotoxic effects that affected cell viability and structural integrity. Molecular docking simulations showed that compounds\n                    <jats:bold>6d<\/jats:bold>\n                    and\n                    <jats:bold>6e<\/jats:bold>\n                    bind strongly to mutant p53, CDK4, and PARP-1 proteins, which, in turn, may explain at the molecular level the\n                    <jats:italic>in vitro<\/jats:italic>\n                    cytotoxic effect of these compounds in SW480 colon cancer cells. Lastly, pharmacokinetic and toxicological modelling suggests that hybrids\n                    <jats:bold>6d<\/jats:bold>\n                    and\n                    <jats:bold>6e<\/jats:bold>\n                    possess optimal biopharmaceutical profiles with no major safety concerns. All these findings highlight the potential of the benzofuran-pterostilbene scaffold, with compounds\n                    <jats:bold>6d<\/jats:bold>\n                    and\n                    <jats:bold>6e<\/jats:bold>\n                    emerging as strong candidates for further evaluation against colorectal cancer.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0344602","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T17:26:36Z","timestamp":1776101196000},"page":"e0344602","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel benzofuran\/pterostilbene hybrids trigger programmed cell death and impair migration in CRC cells"],"prefix":"10.1371","volume":"21","author":[{"given":"Angie","family":"Herrera-Ram\u00edrez","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rub\u00e9n","family":"Becerra-Quintana","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andr\u00e9s F.","family":"Yepes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5374-1211","authenticated-orcid":true,"given":"Wilson","family":"Cardona-Galeano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,4,13]]},"reference":[{"key":"pone.0344602.ref001","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"H Sung","year":"2021","journal-title":"CA Cancer J Clin"},{"issue":"12","key":"pone.0344602.ref002","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1038\/s41575-019-0189-8","article-title":"Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies","volume":"16","author":"N Keum","year":"2019","journal-title":"Nat Rev Gastroenterol Hepatol"},{"issue":"7","key":"pone.0344602.ref003","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1038\/s41416-018-0264-x","article-title":"The colorectal cancer epidemic: challenges and opportunities for primary, secondary and tertiary prevention","volume":"119","author":"H Brenner","year":"2018","journal-title":"Br J Cancer"},{"key":"pone.0344602.ref004","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S1636-5410(16)81792-4","article-title":"C\u00e1ncer de colon","author":"AL Pointet","year":"2017","journal-title":"EMC - Tratado de Medicina"},{"key":"pone.0344602.ref005","doi-asserted-by":"crossref","first-page":"393","DOI":"10.4236\/ijcm.2014.57054","article-title":"Anti-colorectal cancer chemotherapy-induced diarrhoea: current treatments and side-effects","volume":"5","author":"RM McQuade","year":"2014","journal-title":"Int J Clin Med"},{"issue":"9","key":"pone.0344602.ref006","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1517\/13543776.2013.801455","article-title":"Benzofuran derivatives: a patent review","volume":"23","author":"KM Dawood","year":"2013","journal-title":"Expert Opin Ther Pat"},{"key":"pone.0344602.ref007","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1515\/znc-2002-7-828","article-title":"Aurones interfere with Leishmania major mitochondrial fumarate reductase","volume":"57","author":"O Kayser","year":"2002","journal-title":"Z Naturforsch C J Biosci"},{"issue":"6","key":"pone.0344602.ref008","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/S0031-9422(00)00225-9","article-title":"nor-Lignans from the leaves of Styrax ferrugineus (Styracaceae) with antibacterial and antifungal activity","volume":"55","author":"PM Pauletti","year":"2000","journal-title":"Phytochemistry"},{"issue":"8","key":"pone.0344602.ref009","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1002\/ptr.887","article-title":"Antiinflammatory activity of the antirheumatic herbal drug, gravel root (Eupatorium purpureum): further biological activities and constituents","volume":"15","author":"S Habtemariam","year":"2001","journal-title":"Phytother Res"},{"issue":"14","key":"pone.0344602.ref010","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1016\/S0960-894X(01)00319-5","article-title":"Design and synthesis of novel benzofurans as a new class of antifungal agents targeting fungal N-myristoyltransferase. Part 1","volume":"11","author":"M Masubuchi","year":"2001","journal-title":"Bioorg Med Chem Lett"},{"issue":"16","key":"pone.0344602.ref011","doi-asserted-by":"crossref","first-page":"11096","DOI":"10.1039\/D3RA01383A","article-title":"Anticancer therapeutic potential of benzofuran scaffolds","volume":"13","author":"AA Abbas","year":"2023","journal-title":"RSC Adv"},{"key":"pone.0344602.ref012","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/j.bmcl.2003.10.039","article-title":"4-Hydroxy-3-methyl-6-phenylbenzofuran-2-carboxylic acid ethyl ester derivatives as potent anti-tumor agents","volume":"14","author":"I Hayakawa","year":"2004","journal-title":"Bioorganic & Medicinal Chemistry Letters"},{"issue":"9","key":"pone.0344602.ref013","doi-asserted-by":"crossref","first-page":"2196","DOI":"10.3390\/cancers14092196","article-title":"Structure-Activity Relationship of Benzofuran Derivatives with Potential Anticancer Activity","volume":"14","author":"J Farhat","year":"2022","journal-title":"Cancers (Basel)"},{"key":"pone.0344602.ref014","doi-asserted-by":"crossref","first-page":"139121","DOI":"10.1016\/j.molstruc.2024.139121","article-title":"Exploring the potential therapeutic role of benzofuran derivatives in cancer treatment","volume":"1317","author":"A Bendi","year":"2024","journal-title":"J Mol Struct"},{"issue":"8","key":"pone.0344602.ref015","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1016\/j.bcp.2007.02.010","article-title":"Novel heterocyclic-substituted benzofuran histamine H3 receptor antagonists: in vitro properties, drug-likeness, and behavioral activity","volume":"73","author":"M Cowart","year":"2007","journal-title":"Biochem Pharmacol"},{"key":"pone.0344602.ref016","unstructured":"fda c d e r. Highlights of prescribing information. [Cited 2025 December 14]. www.fda.gov\/medwatch"},{"issue":"13","key":"pone.0344602.ref017","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1055\/s-0028-1088301","article-title":"Biological\/chemopreventive activity of stilbenes and their effect on colon cancer","volume":"74","author":"AM Rimando","year":"2008","journal-title":"Planta Med"},{"issue":"20","key":"pone.0344602.ref018","doi-asserted-by":"crossref","first-page":"10964","DOI":"10.1021\/jf202846b","article-title":"Inhibitory effects of resveratrol and pterostilbene on human colon cancer cells: a side-by-side comparison","volume":"59","author":"W Nutakul","year":"2011","journal-title":"J Agric Food Chem"},{"key":"pone.0344602.ref019","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1016\/j.biopha.2018.11.075","article-title":"Resveratrol: from enhanced biosynthesis and bioavailability to multitargeting chronic diseases","volume":"109","author":"N Pannu","year":"2019","journal-title":"Biomed Pharmacother"},{"key":"pone.0344602.ref020","doi-asserted-by":"crossref","DOI":"10.3390\/pharmaceutics17010134","article-title":"Resveratrol\u2014A promising therapeutic agent with problematic properties","volume":"17","author":"L Radeva","year":"2025","journal-title":"Pharmaceutics"},{"issue":"1","key":"pone.0344602.ref021","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1021\/ar7000843","article-title":"Hybrid molecules with a dual mode of action: dream or reality?","volume":"41","author":"B Meunier","year":"2008","journal-title":"Acc Chem Res"},{"issue":"9","key":"pone.0344602.ref022","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.2174\/1568026616666160927160620","article-title":"Hybrid Compounds as Direct Multitarget Ligands: A Review","volume":"17","author":"M de Oliveira Pedrosa","year":"2017","journal-title":"Curr Top Med Chem"},{"issue":"1","key":"pone.0344602.ref023","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/nrd1609","article-title":"Multicomponent therapeutics for networked systems","volume":"4","author":"CT Keith","year":"2005","journal-title":"Nat Rev Drug Discov"},{"key":"pone.0344602.ref024","article-title":"Bibliometric analysis of recent research on 5-fluorouracil (2015\u20132020)","author":"RM Howard","year":"2022","journal-title":"J Appl Pharm Sci"},{"issue":"27","key":"pone.0344602.ref025","doi-asserted-by":"crossref","first-page":"5551","DOI":"10.2174\/0929867328666210211164314","article-title":"Chemistry and Anticancer Activity of Hybrid Molecules and Derivatives based on 5-Fluorouracil","volume":"28","author":"W Cardona-G","year":"2021","journal-title":"Curr Med Chem"},{"key":"pone.0344602.ref026","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.ejmech.2017.07.033","article-title":"Recent advances (2015-2016) in anticancer hybrids","volume":"142","author":"N Kerru","year":"2017","journal-title":"Eur J Med Chem"},{"issue":"1","key":"pone.0344602.ref027","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1080\/14756366.2021.1944127","article-title":"Development of novel benzofuran-isatin conjugates as potential antiproliferative agents with apoptosis inducing mechanism in Colon cancer","volume":"36","author":"WM Eldehna","year":"2021","journal-title":"J Enzyme Inhib Med Chem"},{"issue":"11","key":"pone.0344602.ref028","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.4103\/1735-1995.172835","article-title":"Benzofuran as a promising scaffold for the synthesis of antimicrobial and antibreast cancer agents: A review","volume":"20","author":"G Khodarahmi","year":"2015","journal-title":"J Res Med Sci"},{"key":"pone.0344602.ref029","doi-asserted-by":"crossref","DOI":"10.1002\/ardp.202000006","article-title":"Synthesis, cytotoxicity, and molecular docking of substituted 3\u2010(2\u2010methylbenzofuran\u20103\u2010yl)\u20105\u2010(phenoxymethyl)\u20101,2,4\u2010oxadiazoles","volume":"353","author":"S Mokenapelli","year":"2020","journal-title":"Arch Pharm (Weinheim)"},{"key":"pone.0344602.ref030","doi-asserted-by":"crossref","first-page":"3151","DOI":"10.2217\/fon-2021-0202","article-title":"FRESCO-2: A Global Phase III Study Investigating the Efficacy and Safety of Fruquintinib in Metastatic Colorectal Cancer","volume":"17","author":"A Dasari","year":"2021","journal-title":"Future Oncology"},{"key":"pone.0344602.ref031","doi-asserted-by":"crossref","DOI":"10.1016\/j.annonc.2022.08.021","article-title":"LBA25 FRESCO-2: A global phase III multiregional clinical trial (MRCT) evaluating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer","volume":"33","author":"NA Dasari","year":"2022","journal-title":"Annals of Oncology"},{"key":"pone.0344602.ref032","doi-asserted-by":"crossref","first-page":"2774","DOI":"10.1158\/1538-7445.AM2012-2774","article-title":"Abstract 2774: Anti-cancer activity of the tumor-selective, hypoxia-inducing, agent BNC105 in platinum resistant ovarian cancer","volume":"72","author":"TC Lavranos","year":"2012","journal-title":"Cancer Research"},{"issue":"5","key":"pone.0344602.ref033","doi-asserted-by":"crossref","first-page":"903","DOI":"10.3324\/haematol.2016.154377","article-title":"Safety and efficacy of abexinostat, a pan-histone deacetylase inhibitor, in non-Hodgkin lymphoma and chronic lymphocytic leukemia: results of a phase II study","volume":"102","author":"V Ribrag","year":"2017","journal-title":"Haematologica"},{"issue":"5","key":"pone.0344602.ref034","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1158\/1535-7163.MCT-05-0442","article-title":"CRA-024781: a novel synthetic inhibitor of histone deacetylase enzymes with antitumor activity in vitro and in vivo","volume":"5","author":"JJ Buggy","year":"2006","journal-title":"Mol Cancer Ther"},{"issue":"10","key":"pone.0344602.ref035","doi-asserted-by":"crossref","first-page":"3354","DOI":"10.1158\/1078-0432.CCR-08-2365","article-title":"PCI-24781 induces caspase and reactive oxygen species-dependent apoptosis through NF-kappaB mechanisms and is synergistic with bortezomib in lymphoma cells","volume":"15","author":"S Bhalla","year":"2009","journal-title":"Clin Cancer Res"},{"key":"pone.0344602.ref036","doi-asserted-by":"crossref","first-page":"923398","DOI":"10.3389\/fphar.2022.923398","article-title":"The Anticancer Effects of the Pro-Apoptotic Benzofuran-Isatin Conjugate (5a) Are Associated With p53 Upregulation and Enhancement of Conventional Chemotherapeutic Drug Efficiency in Colorectal Cancer Cell Lines","volume":"13","author":"M-A Vaali-Mohammed","year":"2022","journal-title":"Front Pharmacol"},{"key":"pone.0344602.ref037","doi-asserted-by":"crossref","first-page":"2278","DOI":"10.3390\/pharmaceutics14112278","article-title":"Resveratrol\/Hydrazone hybrids: synthesis and chemopreventive activity against colorectal cancer cells","volume":"14","author":"W Castrill\u00f3n-L\u00f3pez","year":"2022","journal-title":"Pharmaceutics"},{"issue":"9","key":"pone.0344602.ref038","doi-asserted-by":"crossref","first-page":"2661","DOI":"10.3390\/molecules26092661","article-title":"New Hybrids Based on Curcumin and Resveratrol: Synthesis, Cytotoxicity and Antiproliferative Activity against Colorectal Cancer Cells","volume":"26","author":"C Hern\u00e1ndez","year":"2021","journal-title":"Molecules"},{"issue":"8","key":"pone.0344602.ref039","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1007\/s00044-018-2202-0","article-title":"Synthesis and antiproliferative activity of 3- and 7-styrylcoumarins","volume":"27","author":"A Herrera-R","year":"2018","journal-title":"Med Chem Res"},{"issue":"6","key":"pone.0344602.ref040","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1016\/j.arabjc.2014.01.024","article-title":"Efficient and selective \u03b1-bromination of carbonyl compounds with N-bromosuccinimide under microwave","volume":"8","author":"X-Y Guan","year":"2015","journal-title":"Arabian Journal of Chemistry"},{"key":"pone.0344602.ref041","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.1007\/s11164-013-1104-5","article-title":"Facile microwave-assisted synthesis of substituted benzofuran derivatives","volume":"40","author":"J Liu","year":"2014","journal-title":"Research on Chemical Intermediates"},{"issue":"9","key":"pone.0344602.ref042","doi-asserted-by":"crossref","first-page":"2661","DOI":"10.3390\/molecules26092661","article-title":"New hybrids based on curcumin and resveratrol: synthesis, cytotoxicity and antiproliferative activity against colorectal cancer cells","volume":"26","author":"C Hern\u00e1ndez","year":"2021","journal-title":"Molecules"},{"issue":"12","key":"pone.0344602.ref043","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.1021\/ed084p2004","article-title":"Microwave-Assisted Organic Synthesis in the Organic Teaching Lab: A Simple, Greener Wittig Reaction","volume":"84","author":"E Martin","year":"2007","journal-title":"J Chem Educ"},{"issue":"40","key":"pone.0344602.ref044","doi-asserted-by":"crossref","first-page":"6893","DOI":"10.1016\/j.tetlet.2005.08.011","article-title":"Preparation of vinylphenols from 2- and 4-hydroxybenzaldehydes","volume":"46","author":"CJ Simpson","year":"2005","journal-title":"Tetrahedron Letters"},{"issue":"6","key":"pone.0344602.ref045","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1007\/s00044-025-03401-9","article-title":"Discovery of novel pterostilbene\/biphenyl tethered 5-FU based conjugates targeting colorectal cancer: synthesis, cytotoxic and ADMET modeling studies","volume":"34","author":"R Becerra-Quintana","year":"2025","journal-title":"Med Chem Res"},{"issue":"2","key":"pone.0344602.ref046","doi-asserted-by":"crossref","first-page":"369","DOI":"10.3390\/molecules27020369","article-title":"Mechanism of Pterostilbene-Induced Cell Death in HT-29 Colon cancer cells","volume":"27","author":"J Wawszczyk","year":"2022","journal-title":"Molecules"},{"issue":"1","key":"pone.0344602.ref047","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1038\/s41420-023-01581-0","article-title":"Different types of cell death and their shift in shaping disease","volume":"9","author":"S Shen","year":"2023","journal-title":"Cell Death Discov"},{"key":"pone.0344602.ref048","article-title":"Cytoplasmic vacuolization: A fascinating morphological alteration from cellular stress to cell death","volume":"116","author":"X Wen","year":"2025","journal-title":"Cancer Sci"},{"key":"pone.0344602.ref049","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/B978-0-12-391860-4.00003-3","article-title":"Application of mesoporous silica nanoparticles in intracellular delivery of molecules and proteins","volume":"508","author":"I-J Fang","year":"2012","journal-title":"Methods Enzymol"},{"key":"pone.0344602.ref050","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/B978-0-12-417158-9.00015-7","article-title":"Phospholipid Scrambling on the Plasma Membrane","volume":"544","author":"J Suzuki","year":"2014","journal-title":"Methods Enzymol"},{"key":"pone.0344602.ref051","unstructured":"Mitochondria - The Cell - NCBI Bookshelf. [Cited 2025 May 27]. https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK9896\/"},{"key":"pone.0344602.ref052","author":"GM Cooper","year":"2000","journal-title":"Mitochondria"},{"issue":"1","key":"pone.0344602.ref053","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/s41467-019-13668-3","article-title":"Mitochondrial TCA cycle metabolites control physiology and disease","volume":"11","author":"I Mart\u00ednez-Reyes","year":"2020","journal-title":"Nat Commun"},{"key":"pone.0344602.ref054","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.ab.2017.07.009","article-title":"Mitochondrial membrane potential","volume":"552","author":"LD Zorova","year":"2018","journal-title":"Anal Biochem"},{"key":"pone.0344602.ref055","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.3389\/fphys.2018.01661","article-title":"Emerging Roles of the Membrane Potential: Action Beyond the Action Potential","volume":"9","author":"L Abdul Kadir","year":"2018","journal-title":"Front Physiol"},{"issue":"1","key":"pone.0344602.ref056","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/S0014-5793(97)00669-8","article-title":"JC-1, but not DiOC6(3) or rhodamine 123, is a reliable fluorescent probe to assess delta psi changes in intact cells: implications for studies on mitochondrial functionality during apoptosis","volume":"411","author":"S Salvioli","year":"1997","journal-title":"FEBS Lett"},{"issue":"1","key":"pone.0344602.ref057","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/s41420-025-02391-2","article-title":"Comprehensive analysis of cellular metrics: From proliferation to mitochondrial membrane potential and cell death in a single sample","volume":"11","author":"S Sabirova","year":"2025","journal-title":"Cell Death Discov"},{"key":"pone.0344602.ref058","first-page":"301","article-title":"Analysis of cell cycle by flow cytometry","volume":"281","author":"P Pozarowski","year":"2004","journal-title":"Methods Mol Biol"},{"key":"pone.0344602.ref059","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/B978-0-12-816548-5.00008-3","article-title":"Principles and applications of flow cytometry","author":"MC Bajgelman","year":"2019","journal-title":"Data Processing Handbook for Complex Biological Data Sources. Elsevier"},{"issue":"5","key":"pone.0344602.ref060","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.3892\/mmr.2014.2008","article-title":"Colon cancer cells treated with 5\u2011fluorouracil exhibit changes in polylactosamine\u2011type N\u2011glycans","volume":"9","author":"L Gao","year":"2014","journal-title":"Mol Med Rep"},{"key":"pone.0344602.ref061","doi-asserted-by":"crossref","first-page":"640972","DOI":"10.3389\/fcell.2021.640972","article-title":"The frequent sampling of wound scratch assay reveals the \u201copportunity\u201d window for quantitative evaluation of cell motility-impeding drugs","volume":"9","author":"S Kauanova","year":"2021","journal-title":"Front Cell Dev Biol"},{"issue":"5","key":"pone.0344602.ref062","doi-asserted-by":"crossref","first-page":"440","DOI":"10.4161\/cam.36224","article-title":"An introduction to the wound healing assay using live-cell microscopy","volume":"8","author":"JEN Jonkman","year":"2014","journal-title":"Cell Adh Migr"},{"key":"pone.0344602.ref063","doi-asserted-by":"crossref","first-page":"993","DOI":"10.2147\/DDDT.S402824","article-title":"5-Fluorouracil combined with rutaecarpine synergistically suppresses the growth of colon cancer cells by inhibiting STAT3","volume":"17","author":"Z Yu","year":"2023","journal-title":"Drug Des Devel Ther"},{"issue":"7","key":"pone.0344602.ref064","doi-asserted-by":"crossref","first-page":"6197","DOI":"10.3390\/curroncol30070460","article-title":"In Vitro assessment of the synergistic effect of aspirin and 5-fluorouracil in colorectal adenocarcinoma cells","volume":"30","author":"M Susan","year":"2023","journal-title":"Curr Oncol"},{"issue":"2","key":"pone.0344602.ref065","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1002\/cbin.11493","article-title":"5-FU inhibits migration and invasion of CRC cells through PI3K\/AKT pathway regulated by MARCH1","volume":"45","author":"N Wang","year":"2021","journal-title":"Cell Biol Int"},{"issue":"2","key":"pone.0344602.ref066","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/s12272-016-0878-6","article-title":"5-Fluorouracil inhibits cell migration by induction of Sestrin2 in colon cancer cells","volume":"40","author":"K Seo","year":"2017","journal-title":"Arch Pharm Res"},{"issue":"1","key":"pone.0344602.ref067","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1080\/14756366.2022.2062337","article-title":"Identification of 3-(piperazinylmethyl)benzofuran derivatives as novel type II CDK2 inhibitors: design, synthesis, biological evaluation, and in silico insights","volume":"37","author":"WM Eldehna","year":"2022","journal-title":"J Enzyme Inhib Med Chem"},{"key":"pone.0344602.ref068","doi-asserted-by":"crossref","first-page":"37417","DOI":"10.1038\/srep37417","article-title":"Pterostilbene induces apoptosis and cell cycle arrest in diffuse large B-cell lymphoma cells","volume":"6","author":"Y Kong","year":"2016","journal-title":"Sci Rep"},{"issue":"29","key":"pone.0344602.ref069","doi-asserted-by":"crossref","first-page":"22318","DOI":"10.1074\/jbc.M110.131797","article-title":"Novel derivative of benzofuran induces cell death mostly by G2\/M cell cycle arrest through p53-dependent pathway but partially by inhibition of NF-kappaB","volume":"285","author":"SK Manna","year":"2010","journal-title":"J Biol Chem"},{"key":"pone.0344602.ref070","doi-asserted-by":"crossref","first-page":"10893","DOI":"10.1038\/srep10893","article-title":"A new arylbenzofuran derivative functions as an anti-tumour agent by inducing DNA damage and inhibiting PARP activity","volume":"5","author":"H Chen","year":"2015","journal-title":"Sci Rep"},{"issue":"19","key":"pone.0344602.ref071","doi-asserted-by":"crossref","first-page":"7777","DOI":"10.1021\/jf071520h","article-title":"Pterostilbene induces apoptosis and cell cycle arrest in human gastric carcinoma cells","volume":"55","author":"M-H Pan","year":"2007","journal-title":"J Agric Food Chem"},{"issue":"1","key":"pone.0344602.ref072","doi-asserted-by":"crossref","first-page":"228","DOI":"10.3390\/molecules25010228","article-title":"Pterostilbene suppresses both cancer cells and cancer stem-like cells in cervical cancer with superior bioavailability to resveratrol","volume":"25","author":"HJ Shin","year":"2020","journal-title":"Molecules"},{"issue":"10","key":"pone.0344602.ref073","doi-asserted-by":"crossref","first-page":"1976","DOI":"10.1080\/01635581.2020.1817513","article-title":"Pterostilbene as a phytochemical compound induces signaling pathways involved in the apoptosis and death of mutant p53-breast cancer cell lines","volume":"73","author":"AM Elsherbini","year":"2021","journal-title":"Nutr Cancer"},{"issue":"4","key":"pone.0344602.ref074","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1111\/jphp.12984","article-title":"Lipophilicity and hydrophobicity considerations in bio-enabling oral formulations approaches - a PEARRL review","volume":"71","author":"F Ditzinger","year":"2019","journal-title":"J Pharm Pharmacol"},{"key":"pone.0344602.ref075","doi-asserted-by":"crossref","first-page":"2209","DOI":"10.2174\/1568026619666181130140350","article-title":"In silico assessment of ADME properties: Advances in Caco-2 cell monolayer permeability modeling","volume":"18","author":"H Pham-The","year":"2019","journal-title":"Current Topics in Medicinal Chemistry"},{"key":"pone.0344602.ref076","doi-asserted-by":"crossref","first-page":"4199","DOI":"10.1021\/acs.molpharmaceut.6b00836","article-title":"Predicting passive permeability of drug-like molecules from chemical structure: where are we?","volume":"13","author":"F Broccatelli","year":"2016","journal-title":"Molecular Pharmaceutics"},{"issue":"9","key":"pone.0344602.ref077","doi-asserted-by":"crossref","first-page":"893","DOI":"10.2174\/138920008786485119","article-title":"Permeability for intestinal absorption: Caco-2 assay and related issues","volume":"9","author":"B Press","year":"2008","journal-title":"Curr Drug Metab"},{"issue":"20","key":"pone.0344602.ref078","doi-asserted-by":"crossref","first-page":"3714","DOI":"10.1021\/jm000942e","article-title":"Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties","volume":"43","author":"P Ertl","year":"2000","journal-title":"J Med Chem"},{"issue":"14","key":"pone.0344602.ref079","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.2174\/1381612821666150302113710","article-title":"Studies on drug-human serum albumin binding: the current state of the matter","volume":"21","author":"ZD Zhivkova","year":"2015","journal-title":"Curr Pharm Des"},{"issue":"3","key":"pone.0344602.ref080","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1002\/med.10039","article-title":"In silico prediction of drug-binding strengths to human serum albumin","volume":"23","author":"G Colmenarejo","year":"2003","journal-title":"Med Res Rev"},{"issue":"9","key":"pone.0344602.ref081","doi-asserted-by":"crossref","first-page":"2484","DOI":"10.1016\/j.drudis.2022.05.021","article-title":"Escape from planarity in fragment-based drug discovery: A synthetic strategy analysis of synthetic 3D fragment libraries","volume":"27","author":"HF Klein","year":"2022","journal-title":"Drug Discov Today"},{"issue":"10","key":"pone.0344602.ref082","doi-asserted-by":"crossref","first-page":"1839","DOI":"10.1016\/j.drudis.2020.07.017","article-title":"Fsp3: A new parameter for drug-likeness","volume":"25","author":"W Wei","year":"2020","journal-title":"Drug Discov Today"},{"key":"pone.0344602.ref083","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.drudis.2010.11.014","article-title":"The impact of aromatic ring count on compound developability: further insights by examining carbo- and hetero-aromatic and -aliphatic ring types","volume":"16","author":"TJ Ritchie","year":"2011","journal-title":"Drug Discov Today"},{"key":"pone.0344602.ref084","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1517\/17460441.2014.932346","article-title":"What does the aromatic ring number mean for drug design?","volume":"9","author":"SE Ward","year":"2014","journal-title":"Expert Opin Drug Discov"},{"key":"pone.0344602.ref085","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.drudis.2010.11.002","article-title":"The graphical representation of ADME-related molecule properties for medicinal chemists","volume":"16","author":"TJ Ritchie","year":"2011","journal-title":"Drug Discov Today"},{"issue":"4","key":"pone.0344602.ref086","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/s41573-022-00633-x","article-title":"The evolving role of investigative toxicology in the pharmaceutical industry","volume":"22","author":"F Pognan","year":"2023","journal-title":"Nat Rev Drug Discov"},{"key":"pone.0344602.ref087","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.1021\/acs.jcim.3c00200","article-title":"Artificial intelligence in drug toxicity prediction: Recent advances, challenges, and future perspectives","volume":"63","author":"TTV Tran","year":"2023","journal-title":"J Chem Inf Model"},{"key":"pone.0344602.ref088","doi-asserted-by":"crossref","first-page":"135106","DOI":"10.1016\/j.ijbiomac.2024.135106","article-title":"Correlations between in vitro gastrointestinal digestion of \u03b2-galactosidase\/carboxymethylchitosan-silica dosage powder and its physicochemical properties","volume":"279","author":"YNF Tob\u00f3n","year":"2024","journal-title":"Int J Biol Macromol"},{"key":"pone.0344602.ref089","doi-asserted-by":"crossref","first-page":"1197569","DOI":"10.3389\/fphar.2023.1197569","article-title":"Dodonaea viscosa Jacq. induces cytotoxicity, antiproliferative activity, and cell death in colorectal cancer cells via regulation of caspase 3 and p53","volume":"14","author":"O Herrera-Calderon","year":"2023","journal-title":"Front Pharmacol"},{"issue":"3","key":"pone.0344602.ref090","first-page":"351","article-title":"Promising Hybrids Derived from S-Allylcysteine and NSAIDs Fragments against Colorectal Cancer: Synthesis, In-vitro Evaluation, Drug-Likeness and In-silico ADME\/tox Studies","volume":"20","author":"A Herrera-R","year":"2021","journal-title":"Iran J Pharm Res"},{"key":"pone.0344602.ref091","unstructured":"National Cancer Institute, Division of Cancer Treatment and Diagnosis. NCI-60 Screening Methodology. 2021."},{"key":"pone.0344602.ref092","unstructured":"National Cancer Institute. Screening Methodology (NCI-60 HTS384) | NCI-60 Human Tumor Cell Lines Screen | Discovery & Development Services | Developmental Therapeutics Program (DTP). 2024. [Cited 2025 April 9]. https:\/\/dtp.cancer.gov\/discovery_development\/nci-60\/methodology_HTS384.htm"},{"issue":"18","key":"pone.0344602.ref093","doi-asserted-by":"crossref","DOI":"10.1002\/slct.202500902","article-title":"Development of a New Melatonin\/Coumarin Hybrid Scaffold Targeting Colorectal Cancer: Synthesis, Cytotoxic Activity, and ADME\/ Tox Modeling","volume":"10","author":"M Silva\u2010Garc\u00eda","year":"2025","journal-title":"ChemistrySelect"},{"issue":"3","key":"pone.0344602.ref094","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1007\/s00044-024-03358-1","article-title":"Development of novel triconjugates fusing melatonin\/isatin\/N-acylhydrazone targeting colorectal cancer: design, synthesis, biological, and in silico ADME\/Tox profiling","volume":"34","author":"SM Guti\u00e9rrez","year":"2025","journal-title":"Med Chem Res"},{"key":"pone.0344602.ref095","doi-asserted-by":"crossref","first-page":"40","DOI":"10.3390\/scipharm90030040","article-title":"Colorectal cancer chemoprevention by S-allyl cysteine\u2013caffeic acid hybrids: In vitro biological activity and in silico studies","volume":"90","author":"A Herrera-Ramirez","year":"2022","journal-title":"Sci Pharm"},{"issue":"14","key":"pone.0344602.ref096","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1002\/(SICI)1096-987X(19981115)19:14<1639::AID-JCC10>3.0.CO;2-B","article-title":"Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function","volume":"19","author":"GM Morris","year":"1998","journal-title":"J Comput Chem"},{"issue":"2","key":"pone.0344602.ref097","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"O Trott","year":"2010","journal-title":"J Comput Chem"},{"key":"pone.0344602.ref098","doi-asserted-by":"crossref","first-page":"42717","DOI":"10.1038\/srep42717","article-title":"SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules","volume":"7","author":"A Daina","year":"2017","journal-title":"Sci Rep"},{"key":"pone.0344602.ref099","author":"T Sander"},{"key":"pone.0344602.ref100","unstructured":"U.S. EPA. User\u2019s Guide for T.E.S.T. (version 5.1) (Toxicity Estimation Software Tool): A Program to Estimate Toxicity from Molecular Structure. 2020."},{"key":"pone.0344602.ref101","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gky318","article-title":"ProTox-II: a webserver for the prediction of toxicity of chemicals","volume":"46","author":"P Banerjee","year":"2018","journal-title":"Nucleic Acids Res"},{"issue":"10","key":"pone.0344602.ref102","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1002\/minf.201500040","article-title":"Pred-hERG: A Novel web-Accessible Computational Tool for Predicting Cardiac Toxicity","volume":"34","author":"RC Braga","year":"2015","journal-title":"Mol Inform"},{"issue":"9","key":"pone.0344602.ref103","doi-asserted-by":"crossref","first-page":"4066","DOI":"10.1021\/acs.jmedchem.5b00104","article-title":"pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures","volume":"58","author":"DEV Pires","year":"2015","journal-title":"J Med Chem"},{"key":"pone.0344602.ref104","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1080\/10629360802083871","article-title":"An evaluation of the implementation of the Cramer classification scheme in the Toxtree software","volume":"19","author":"G Patlewicz","year":"2008","journal-title":"SAR QSAR Environ Res"},{"issue":"11","key":"pone.0344602.ref105","doi-asserted-by":"crossref","first-page":"3099","DOI":"10.1021\/ci300367a","article-title":"admetSAR: a comprehensive source and free tool for assessment of chemical ADMET properties","volume":"52","author":"F Cheng","year":"2012","journal-title":"J Chem Inf Model"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0344602","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T17:27:00Z","timestamp":1776101220000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0344602"}},"subtitle":[],"editor":[{"given":"Wagdy M.","family":"Eldehna","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2026,4,13]]},"references-count":105,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4,13]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0344602","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,13]]}}}