{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T08:59:38Z","timestamp":1790758778270,"version":"4.1.0"},"reference-count":39,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Chalcones from medicinal plants are attractive starting points for anticancer lead discovery, and this study aimed to improve the anti-NSCLC potential of 2\u2032,4\u2032-dihydroxy-6\u2032-methoxy-3\u2032,5\u2032-dimethylchalcone (DMC) from Syzygium nervosum through targeted structural modification and mechanistic computational analysis. Air-dried seeds were extracted with CH2Cl2, DMC was purified by silica gel chromatography and crystallization, and its structure was confirmed by HRMS, FTIR and NMR; 4\u2032-O-derivatization with meta\u2013 or para\u2013[(bromomethyl)phenyl]methyl groups afforded derivatives 2a and 2b (89\u201392% yield). Antiproliferative activity and cytotoxicity were evaluated by MTT assay in NSCLC cell lines (A549, NCI-H460) and normal lung fibroblasts (MRC-5) with osimertinib as a reference. Derivatives 2a and 2b showed enhanced activity against NCI-H460 (IC50 = 7.97 \u00b1 0.62 \u00b5M and 7.91 \u00b1 2.77 \u00b5M) while remaining weak against A549, and they were less cytotoxic to MRC-5 (IC50 \u2265 50 \u00b5M and 16.08 \u00b1 0.45 \u00b5M) than osimertinib (IC50 = 3.43 \u00b1 0.35 \u00b5M). DFT\/MEP analyses, docking to wild-type EGFR (1M17; redocking RMSD 1.228 \u00c5), and 500 ns \u00d7 3 replica MD simulations supported improved EGFR binding stability for 2a\/2b, with MM\/GBSA indicating favorable binding free energies (\u221228.78 \u00b1 6.11 and \u221221.99 \u00b1 9.39 kcal\/mol). Overall, 4\u2032-O-functionalization of DMC generated lead derivatives with improved in vitro activity in NCI-H460 and computationally supported target\u2013ligand stabilization.<\/jats:p>","DOI":"10.3390\/ijms27146104","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T17:27:31Z","timestamp":1783531651000},"page":"6104","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["[(Bromomethyl)phenyl]methyl-Conjugated Chalcone Derivatives as Potential Lung Cancer Inhibitors: Structure Modification, Molecular Docking, Molecular Dynamics and In Vitro Validation"],"prefix":"10.3390","volume":"27","author":[{"given":"Nathaporn","family":"Cheechana","sequence":"first","affiliation":[{"name":"Office of Research Administration, Chiang Mai University, Chiang Mai 50200, Thailand"},{"name":"Department of Chemistry, Faculty of Science, Chiang Mai University, 239 Huay Kaew Road, Chiang Mai 50200, 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Thailand"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3458-9568","authenticated-orcid":false,"given":"Kraikrit","family":"Utama","sequence":"additional","affiliation":[{"name":"Office of Research Administration, Chiang Mai University, Chiang Mai 50200, Thailand"},{"name":"Department of Chemistry, Faculty of Science, Chiang Mai University, 239 Huay Kaew Road, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Chawanakorn","family":"Kongsak","sequence":"additional","affiliation":[{"name":"Office of Research Administration, Chiang Mai University, Chiang Mai 50200, Thailand"},{"name":"Department of Chemistry, Faculty of Science, Chiang Mai University, 239 Huay Kaew Road, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Puracheth","family":"Rithchumpon","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8399-3367","authenticated-orcid":false,"given":"Padchanee","family":"Sangthong","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, Chiang Mai University, 239 Huay Kaew Road, Chiang Mai 50200, Thailand"},{"name":"Center of Excellence in Materials Science and Technology, Chiang Mai University, 239 Huay Kaew Road, Chiang Mai 50200, Thailand"},{"name":"Division 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World Health Organ."},{"key":"ref_2","first-page":"007","article-title":"Public Attention Index of Air Pollution Exposure from PM2.5 in Thailand","volume":"47","author":"Suntigul","year":"2025","journal-title":"App. Environ. Res."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Inlaung, K., Chotamonsak, C., Macatangay, R., and Surapipith, V. (2024). Assessment of Transboundary PM2.5 from Biomass Burning in Northern Thailand Using the WRF-Chem Model. Toxics, 262.","DOI":"10.3390\/toxics12070462"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"101080","DOI":"10.1016\/j.redox.2018.101080","article-title":"Particulate matter induces inflammatory cytokine production via activation of NF\u03baB by TLR5-NOX4-ROS signaling in human skin keratinocyte and mouse skin","volume":"21","author":"Ryu","year":"2019","journal-title":"Redox Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1620\/tjem.239.117","article-title":"Airborne Fine Particulate Matter Induces Oxidative Stress and Inflammation in Human Nasal Epithelial Cells","volume":"239","author":"Hong","year":"2016","journal-title":"Tohoku J. Exp. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.ijcard.2014.07.012","article-title":"Oxidative stress and systemic inflammation as modifiers of cardiac autonomic responses to particulate air pollution","volume":"176","author":"Lee","year":"2014","journal-title":"Int. J. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/S0140-6736(21)00312-3","article-title":"Lung cancer","volume":"398","author":"Thai","year":"2021","journal-title":"Lancet"},{"key":"ref_8","first-page":"e139\u2212e146","article-title":"Global urban temporal trends in fine particulate matter (PM2.5) and attributable health burdens: Estimates from global datasets","volume":"6","author":"Southerland","year":"2022","journal-title":"Lancet Planet. Health"},{"key":"ref_9","first-page":"7506","article-title":"Function of PM2.5 in the pathogenesis of lung cancer and chronic airway inflammatory diseases (Review)","volume":"15","author":"Li","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1002\/1097-0142(19950101)75:1+<191::AID-CNCR2820751307>3.0.CO;2-Y","article-title":"Lung cancer","volume":"75","author":"Travis","year":"1995","journal-title":"Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Wu, X., Song, W., Cheng, C., Liu, Z., Li, X., Cui, Y., Gao, Y., and Li, D. (2023). Small molecular inhibitors for KRAS-mutant cancers. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1223433"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.lungcan.2022.11.017","article-title":"The impact of population-based EGFR testing in non-squamous metastatic non-small cell lung cancer in Alberta, Canada","volume":"175","author":"Brenner","year":"2023","journal-title":"Lung Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1634\/theoncologist.2017-0582","article-title":"Osimertinib: A Novel Dermatologic Adverse Event Profile in Patients with Lung Cancer","volume":"23","author":"Chu","year":"2018","journal-title":"Oncologist"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3318","DOI":"10.1158\/1078-0432.CCR-22-0383","article-title":"Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C Mutant Non\u2013Small Cell Lung Cancer","volume":"28","author":"Sabari","year":"2022","journal-title":"Clin. Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/s40265-013-0170-8","article-title":"Afatinib: A Review of Its Use in the Treatment of Advanced Non-Small Cell Lung Cancer","volume":"74","author":"Keating","year":"2014","journal-title":"Drugs"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"8263670","DOI":"10.1155\/2020\/8263670","article-title":"Ethnopharmacology, phytochemistry, and pharmacology of Syzygium nervosum","volume":"2020","author":"Pham","year":"2020","journal-title":"Evid.-Based Complement. Altern. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"8522","DOI":"10.1021\/acs.joc.8b01050","article-title":"Phloroglucinol Derivatives with Unusual Skeletons from Cleistocalyx operculatus and Their in Vitro Antiviral Activity","volume":"83","author":"Su","year":"2018","journal-title":"J. Org. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Swamy, M.K., and Akhtar, M.S. (2019). Natural Bio-Active Compounds, Volume 2; Chemistry, Pharmacology and Health Care Practices, Springer Nature.","DOI":"10.1007\/978-981-13-7205-6"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/j.metabol.2015.12.010","article-title":"DMC (2\u2032,4\u2032-dihydroxy-6\u2032-methoxy-3\u2032,5\u2032-dimethylchalcone) improves glucose tolerance as a potent AMPK activator","volume":"65","author":"Choi","year":"2016","journal-title":"Metabolism"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1021\/np1002753","article-title":"C-Methylated Flavonoids from Cleistocalyx operculatus and Their Inhibitory Effects on Novel Influenza A (H1N1) Neuraminidase","volume":"73","author":"Dao","year":"2010","journal-title":"J. Nat. Prod."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Yimsoo, T., Taychaworaditsakul, W., Chansakaow, S., Kongkiatpaiboon, S., Tayana, N., Chewonarin, T., Khonsung, P., and Sireeratawong, S. (2025). The Effect of the Ethanolic Extracts from Syzygium aromaticum and Syzygium nervosum on Antiproliferative Activity and Apoptosis in HCT116 and HT-29 Cells. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26146826"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1016\/j.leukres.2005.01.006","article-title":"Induction of apoptosis in K562 human leukemia cells by 2\u2032,4\u2032-dihydroxy-6\u2032-methoxy-3\u2032,5\u2032-dimethylchalcone","volume":"29","author":"Ye","year":"2005","journal-title":"Leuk. Res."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Tuan, H.N., Minh, B.H., Tran, P.T., Lee, J.H., Oanh, H.V., Ngo, Q.M.T., Nguyen, Y.N., Lien, P.T.K., and Tran, M.H. (2019). The Effects of 2\u2032,4\u2032-Dihydroxy-6\u2032-methoxy-3\u2032,5\u2032-dimethylchalcone from Cleistocalyx operculatus Buds on Human Pancreatic Cancer Cell Lines. Molecules, 24.","DOI":"10.3390\/molecules24142538"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.phrs.2004.05.004","article-title":"In vitro anti-tumor activity of 2\u2032,4\u2032-dihydroxy-6\u2032-methoxy-3\u2032,5\u2032-dimethylchalcone against six established human cancer cell lines","volume":"50","author":"Ye","year":"2004","journal-title":"Pharmacol. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2303","DOI":"10.3892\/ol.2015.2981","article-title":"Apoptosis induced in MCF-7 human breast cancer cells by 2\u2032,4\u2032-dihydroxy-6-methoxy-3,5-dimethylchalcone isolated from Eugenia aquea Burm f. leaves","volume":"9","author":"Subarnas","year":"2015","journal-title":"Oncol. Lett."},{"key":"ref_26","first-page":"3551","article-title":"Apoptosis-mediated antiproliferation of A549 lung cancer cells mediated by Eugenia aquea leaf compound 2\u2032,4\u2032-dihydroxy-6\u2032-methoxy-3\u2032,5\u2032-dimethylchalcone and its molecular interaction with caspase receptor in molecular docking simulation","volume":"19","author":"Hadisaputri","year":"2020","journal-title":"Oncol. Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"31433","DOI":"10.1039\/D1RA05445G","article-title":"Synthesis, cytotoxicity evaluation and molecular docking studies on 2\u2032,4\u2032-dihydroxy-6\u2032-methoxy-3\u2032,5\u2032-dimethylchalcone derivatives","volume":"11","author":"Khamto","year":"2021","journal-title":"RSC Adv."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"161","DOI":"10.4236\/cc.2021.93010","article-title":"Investigation of the Antioxidant and UV Absorption Properties of 2-(2\u2032-hydroxy-5\u2032-methylphenyl)-benzotriazole and Its Ortho-Substituted Derivatives via DFT\/TD-DFT","volume":"9","author":"Tasheh","year":"2021","journal-title":"Comput. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.1021\/jp065459f","article-title":"Electrodonating and Electroaccepting Powers","volume":"111","author":"Cedillo","year":"2007","journal-title":"J. Phys. Chem. A"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.saa.2013.12.037","article-title":"The spectroscopic (FT-IR, FT-Raman and NMR), NCA, Fukui function analysis first order hyperpolarizability, TGA of 6-chloro-3,4dihydro-2H-1,2,4-benzothiazine-7-sulphonamide1,1-dioxide by ab initio HF and Density Functional method","volume":"123","author":"Muthu","year":"2014","journal-title":"Spectrochim. Acta Part A"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Czele\u0144, P., and Szefler, B. (2026). Design and Evaluation of New 6-Trifluoromethoxy-Isatin Derivatives as Potential CDK2 Inhibitors. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27041802"},{"key":"ref_32","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M., Cheeseman, J.R., Scalmani, G., Barone, V.P., Petersson, G.A., and Nakatsuji, H.J. (GaussView, 2019). GaussView, version 6.0."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"46265","DOI":"10.1074\/jbc.M207135200","article-title":"Structure of the Epidermal Growth Factor Receptor Kinase Domain Alone and in Complex with a 4-Anilinoquinazoline Inhibitor","volume":"277","author":"Stamos","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_34","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":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1002\/pro.3280","article-title":"Improvements to the APBS biomolecular solvation software suite","volume":"27","author":"Jurrus","year":"2018","journal-title":"Protein Sci."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Sundaramoorthy, P., Sim, J.J., Jang, Y.S., Mishra, S.K., Jeong, K.Y., Mander, P., Chul, O.B., Shim, W.S., Oh, S.H., and Nam, K.Y. (2015). Modulation of Intracellular Calcium Levels by Calcium Lactate Affects Colon Cancer Cell Motility through Calcium-Dependent Calpain. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0116984"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1002\/wcms.1121","article-title":"An overview of the amber biomolecular simulation package","volume":"3","author":"Case","year":"2013","journal-title":"Wiley Interdiscip. Rev. Comput. Mol. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6281","DOI":"10.1021\/acs.jctc.1c00645","article-title":"gmx_MMPBSA: A new tool to perform end-state free energy calculations with GROMACS","volume":"17","author":"Valiente","year":"2021","journal-title":"J. Chem. Theor. Comput."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1002\/prot.20033","article-title":"Exploring protein native states and largescale conformational changes with a modified generalized born model","volume":"55","author":"Onufriev","year":"2004","journal-title":"Proteins"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6104\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T08:18:23Z","timestamp":1790756303000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6104"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,8]]},"references-count":39,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27146104"],"URL":"https:\/\/doi.org\/10.3390\/ijms27146104","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,8]]}}}