{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T10:52:38Z","timestamp":1780570358354,"version":"3.54.1"},"reference-count":83,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T00:00:00Z","timestamp":1770940800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Cancer remains the second leading cause of death worldwide, highlighting the urgent need for novel therapeutic agents. In this work, twenty derivatives of N-benzyl-6-chloro-4-hydroxy-2-quinolone-3-carboxamides were synthesized and spectroscopically analyzed using FT-IR, NMR (1H and 13C), and elemental analysis. Substitution of benzyl moiety with o-CH3 (8), p-OCH3 (10), m-CH3 (18), p-CH3 (19), and p-CF3 (21) demonstrated three-fold distinct cytotoxicity against human colon cancer (HCT-116) cells with IC50s of 72.0, 100.0\u2013112.0 \u00b5M. The cheminformatics calculations disclosed that the analogues possess diverse physicochemical properties and invariable predictions across six drug-likeness scoring models, supporting their potential cytotoxicity profile against colorectal cancer cell lines (Caco-2 and HCT-116). The docking studies against both wild-type and mutant PI3K\u03b1 clarified binding interactions, implying that particular functionalities improve efficacy and selectivity. This study provides further evidence for the therapeutic promise of quinolones in targeting cancer-specific pathways and expedites the process for developing potent anticancer agents.<\/jats:p>","DOI":"10.3390\/molecules31040655","type":"journal-article","created":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T17:51:32Z","timestamp":1771005092000},"page":"655","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["N-Benzyl-6-Chloro-4-Hydroxy-2-Quinolone-3-Carboxamides: Synthesis, Computational Studies, and Biological Investigation as Anticancer Agents"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-1140-1307","authenticated-orcid":false,"given":"Sara Jamal","family":"Meknas","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman 11733, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eveen","family":"Al-Shalabi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman 11733, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7090-5425","authenticated-orcid":false,"given":"Rima","family":"Hajjo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman 11733, Jordan"},{"name":"Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"},{"name":"National Center for Epidemics and Communicable Disease Control (JCDC), Amman 11183, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4823-0708","authenticated-orcid":false,"given":"Sanaa K.","family":"Bardaweel","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6654-4658","authenticated-orcid":false,"given":"Ghassan","family":"Abushaikha","sequence":"additional","affiliation":[{"name":"Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43606, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamal","family":"Sweidan","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The University of Jordan, Amman 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swapnaa","family":"Balaji","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit K.","family":"Tiwari","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5945-749X","authenticated-orcid":false,"given":"Haizhen A.","family":"Zhong","sequence":"additional","affiliation":[{"name":"DSC 309, Department of Chemistry, The University of Nebraska at Omaha, Omaha, NE 68182, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1428-5097","authenticated-orcid":false,"given":"Dima A.","family":"Sabbah","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman 11733, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1002\/1878-0261.12772","article-title":"Physical activity, obesity and sedentary behavior in cancer etiology: Epidemiologic evidence and biologic mechanisms","volume":"15","author":"Friedenreich","year":"2021","journal-title":"Mol. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1080\/13543776.2024.2338100","article-title":"Targeting the PI3K\/AKT signaling pathway in anticancer research: A recent update on inhibitor design and clinical trials (2020\u20132023)","volume":"34","author":"Sabbah","year":"2024","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1080\/13543776.2021.1924150","article-title":"Phosphatidylinositol 3-kinase (PI3K) inhibitors: A recent update on inhibitor design and clinical trials (2016\u20132020)","volume":"31","author":"Sabbah","year":"2021","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Pothongsrisit, S., and Pongrakhananon, V. (2021). Targeting the PI3K\/AKT\/mTOR Signaling Pathway in Lung Cancer: An Update Regarding Potential Drugs and Natural Products. Molecules, 26.","DOI":"10.3390\/molecules26134100"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"114971","DOI":"10.1016\/j.ejmech.2022.114971","article-title":"Recent advances in PI3K\/PKB\/mTOR inhibitors as new anticancer agents","volume":"246","author":"Occhiuzzi","year":"2022","journal-title":"Eur. J. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e39402","DOI":"10.1016\/j.heliyon.2024.e39402","article-title":"Downregulation of aquaporins and PI3K\/AKT and upregulation of PTEN expression induced by the flavone scutellarein in human colon cancer cell lines","volume":"10","author":"Tarawneh","year":"2024","journal-title":"Heliyon"},{"key":"ref_7","first-page":"2966","article-title":"Interfering with ITGB1-DT expression delays cancer progression and promotes cell sensitivity of NSCLC to cisplatin by inhibiting the MAPK\/ERK pathway","volume":"12","author":"Li","year":"2022","journal-title":"Am. J. Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1158\/1535-7163.MCT-22-0101","article-title":"Genotype-tailored ERK\/MAPK pathway and HDAC inhibition rewires the apoptotic rheostat to trigger colorectal cancer cell death","volume":"22","author":"Jenkins","year":"2023","journal-title":"Mol. Cancer Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1080\/13543776.2024.2327307","article-title":"Targeting the EGFR\/RAS\/RAF signaling pathway in anticancer research: A recent update on inhibitor design and clinical trials (2020\u20132023)","volume":"34","author":"Hajjo","year":"2024","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Guti\u00e9rrez-Hoya, A., and Soto-Cruz, I. (2020). Role of the JAK\/STAT Pathway in Cervical Cancer: Its Relationship with HPV E6\/E7 Oncoproteins. Cells, 9.","DOI":"10.3390\/cells9102297"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2170","DOI":"10.3390\/cimb45030139","article-title":"In Vitro Evaluation of ALDH1A3-Affinic Compounds on Breast and Prostate Cancer Cell Lines as Single Treatments and in Combination with Doxorubicin","volume":"45","author":"Abusara","year":"2023","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Hajjo, R., Sabbah, D.A., and Al Bawab, A.Q. (2022). Unlocking the Potential of the Human Microbiome for Identifying Disease Diagnostic Biomarkers. Diagnostics, 12.","DOI":"10.3390\/diagnostics12071742"},{"key":"ref_13","first-page":"269","article-title":"Compositional changes in human gut microbiota reveal a putative role of intestinal mycobiota in metabolic and biological decline during aging","volume":"6","author":"Alzaatreh","year":"2021","journal-title":"J. Nutr. Health Aging"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"50055","DOI":"10.1021\/acsomega.5c06528","article-title":"Identification and Biological Validation of MMP-12 Inhibitors Guided by Pharmacophore-Based Virtual Screening and Docking Studies","volume":"10","author":"Almutairi","year":"2025","journal-title":"ACS Omega"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1016\/j.bmcl.2011.12.044","article-title":"Biological evaluation and docking studies of recently identified inhibitors of phosphoinositide-3-kinases","volume":"22","author":"Sabbah","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"7175","DOI":"10.1016\/j.bmc.2012.09.059","article-title":"N-Phenyl-4-hydroxy-2-quinolone-3-carboxamides as selective inhibitors of mutant H1047R phosphoinositide-3-kinase (PI3K\u03b1)","volume":"20","author":"Sabbah","year":"2012","journal-title":"Bioorg. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00280-013-2321-8","article-title":"Mechanisms of action of tasquinimod on the tumour microenvironment","volume":"73","author":"Raymond","year":"2014","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1517\/13543784.2010.514262","article-title":"The long and winding road for the development of tasquinimod as an oral second-generation quinoline-3-carboxamide antiangiogenic drug for the treatment of prostate cancer","volume":"19","author":"Isaacs","year":"2010","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1016\/j.biopha.2018.12.119","article-title":"Repositioning of fluoroquinolones from antibiotic to anti-cancer agents: An underestimated truth","volume":"111","author":"Yadav","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Kloskowski, T., Fr\u0105ckowiak, S., Adamowicz, J., Szeliski, K., Rasmus, M., Drewa, T., and Pokrywczy\u0144ska, M. (2022). Quinolones as a Potential Drug in Genitourinary Cancer Treatment-A Literature Review. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.890337"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"104168","DOI":"10.1016\/j.arabjc.2022.104168","article-title":"Review on recent development of quinoline for anticancer activities","volume":"15","author":"Ilakiyalakshmi","year":"2022","journal-title":"Arab. J. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Ferrario, N., Marras, E., Vivona, V., Randisi, F., Fallica, A.N., Marrazzo, A., Perletti, G., and Gariboldi, M.B. (2024). Mechanisms of the Antineoplastic Effects of New Fluoroquinolones in 2D and 3D Human Breast and Bladder Cancer Cell Lines. Cancers, 16.","DOI":"10.3390\/cancers16122227"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"263","DOI":"10.2174\/1871520617666170911171152","article-title":"Structure-Based Design: Synthesis, X-ray Crystallography, and Biological Evaluation of N-Substituted-4-Hydroxy-2-Quinolone-3-Carboxamides as Potential Cytotoxic Agents","volume":"18","author":"Sabbah","year":"2018","journal-title":"Anticancer Agents Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Sabbah, D.A., Hasan, S.E., Abu Khalaf, R., Bardaweel, S.K., Hajjo, R., Alqaisi, K.M., Sweidan, K.A., and Al-Zuheiri, A.M. (2020). Molecular modeling, synthesis and biological evaluation of N-phenyl-4-hydroxy-6-methyl-2-quinolone-3-carboxamides as anticancer agents. Molecules, 25.","DOI":"10.3390\/molecules25225348"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Sabbah, D.A., Haroon, R.A., Bardaweel, S.K., Hajjo, R., and Sweidan, K. (2021). N-Phenyl-6-Chloro-4-Hydroxy-2-Quinolone-3-CarboxAmides: Molecular Docking, Synthesis, and Biological Investigation as Anticancer Agents. Molecules, 26.","DOI":"10.3390\/molecules26010073"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Liew, S.K., Malagobadan, S., Arshad, N.M., and Nagoor, N.H. (2020). A Review of the Structure\u2013Activity Relationship of Natural and Synthetic Antimetastatic Compounds. Biomolecules, 10.","DOI":"10.3390\/biom10010138"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5305","DOI":"10.1021\/acs.jmedchem.2c02015","article-title":"\u201cMagic chloro\u201d: Profound effects of the chlorine atom in drug discovery","volume":"66","author":"Chiodi","year":"2023","journal-title":"J. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1080\/07391102.2019.1604266","article-title":"4-Bromo-4\u2019-chloro pyrazoline analog of curcumin augmented anticancer activity against human cervical cancer, HeLa cells: In silico-guided analysis, synthesis, and in vitro cytotoxicity","volume":"38","author":"Chaudhary","year":"2020","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/BF00048384","article-title":"Heterogeneity of human colon carcinoma","volume":"3","author":"Brattain","year":"1984","journal-title":"Cancer Metastasis Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/s40246-024-00635-3","article-title":"Growth characteristics of HCT116 xenografts lacking asparagine synthetase vary according to sex","volume":"18","author":"Aladelokun","year":"2024","journal-title":"Hum. Genomics"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3904","DOI":"10.1021\/acs.jproteome.4c00252","article-title":"FAS Inhibited Proteomics and Phosphoproteomics Profiling of Colorectal Cancer Spheroids Shows Activation of Ferroptotic Death Mechanism","volume":"23","author":"Fries","year":"2024","journal-title":"J. Proteome Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1097\/CAD.0000000000001136","article-title":"Atractylenolide III induces apoptosis by regulating the Bax\/Bcl-2 signaling pathway in human colorectal cancer HCT-116 Cells in vitro and in vivo","volume":"33","author":"Zhang","year":"2022","journal-title":"Anticancer Drugs"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Kolawole, O.R., and Kashfi, K. (2022). NSAIDs and Cancer Resolution: New Paradigms beyond Cyclooxygenase. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031432"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"102591","DOI":"10.1016\/j.ceca.2022.102591","article-title":"p53 alters intracellular Ca(2+) signaling through regulation of TRPM4","volume":"104","author":"Kappel","year":"2022","journal-title":"Cell Calcium"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Huang, E.-Y., Chang, J.-C., Chen, H.-H., Hsu, C.-Y., Hsu, H.-C., and Wu, K.-L. (2018). Carcinoembryonic antigen as a marker of radioresistance in colorectal cancer: A potential role of macrophages. BMC Cancer, 18.","DOI":"10.1186\/s12885-018-4254-4"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Phang, C.W., Karsani, S.A., Sethi, G., and Abd Malek, S.N. (2016). Flavokawain C Inhibits Cell Cycle and Promotes Apoptosis, Associated with Endoplasmic Reticulum Stress and Regulation of MAPKs and Akt Signaling Pathways in HCT 116 Human Colon Carcinoma Cells. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0148775"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Huang, W.S., Hsieh, M.C., Huang, C.Y., Kuo, Y.H., Tung, S.Y., Shen, C.H., Hsieh, Y.Y., Teng, C.C., Lee, K.F., and Chen, T.C. (2016). The Association of CXC Receptor 4 Mediated Signaling Pathway with Oxaliplatin-Resistant Human Colorectal Cancer Cells. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0159927"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"21933","DOI":"10.1038\/s41598-020-78833-x","article-title":"Upregulation of PI3K\/AKT\/PTEN pathway is correlated with glucose and glutamine metabolic dysfunction during tamoxifen resistance development in MCF-7 cells","volume":"10","author":"Hamadneh","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Chen, C.Y., Yang, S.H., Chang, P.Y., Chen, S.F., Nieh, S., Huang, W.Y., Lin, Y.C., and Lee, O.K. (2024). Cancer-Associated-Fibroblast-Mediated Paracrine and Autocrine SDF-1\/CXCR4 Signaling Promotes Stemness and Aggressiveness of Colorectal Cancers. Cells, 13.","DOI":"10.3390\/cells13161334"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"110807","DOI":"10.1016\/j.biopha.2020.110807","article-title":"The response of PIK3CA\/KRAS-mutant colorectal cancer stem-like cells to RGD-peptide FraC produced by the strawberry anemone: A promising water-soluble peptide-based inhibitor of metastasis-driver gene CXCR4, stem cell regulatory genes and self-renewal","volume":"132","author":"Imani","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/s11010-020-03893-6","article-title":"Targeting STAT proteins via computational analysis in colorectal cancer","volume":"476","author":"Dariya","year":"2021","journal-title":"Mol. Cell Biochem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1007\/s13577-022-00815-0","article-title":"Genomic distribution of signal transducer and activator of transcription (STAT) family in colorectal cancer","volume":"36","author":"Hu","year":"2023","journal-title":"Hum. Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"795","DOI":"10.31557\/APJCP.2022.23.3.795","article-title":"Effect of Sodium Butyrate on p16INK4a, p14ARF, p15INK4b, Class I HDACs (HDACs 1, 2, 3) Class II HDACs (HDACs 4, 5, 6), Cell Growth Inhibition and Apoptosis Induction in Pancreatic Cancer AsPC-1 and Colon Cancer HCT-116 Cell Lines","volume":"23","author":"Sanaei","year":"2022","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Laranjeira, A.B.A., Nguyen, D., Pelosof, L.C., Doroshow, J.H., and Yang, S.X. (2024). Upregulation of TET2 and Resistance to DNA Methyltransferase (DNMT) Inhibitors in DNMT1-Deleted Cancer Cells. Diseases, 12.","DOI":"10.3390\/diseases12070163"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Pisheh, L., Matis, S., Taglieri, M., Di Gregorio, L., Benelli, R., and Poggi, A. (2024). EGFR-Targeted Antibody\u2013Drug Conjugate to Different Aminobisphosphonates: Direct and Indirect Antitumor Effects on Colorectal Carcinoma Cells. Cancers, 16.","DOI":"10.3390\/cancers16071256"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Abdelaal, M.R., Ibrahim, E., Elnagar, M.R., Soror, S.H., and Haffez, H. (2022). Augmented Therapeutic Potential of EC-Synthetic Retinoids in Caco-2 Cancer Cells Using an In Vitro Approach. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23169442"},{"key":"ref_47","first-page":"905","article-title":"Gallic acid attenuates LPS-induced inflammation in Caco-2 cells by suppressing the activation of the NF-\u03baB\/MAPK signaling pathway","volume":"56","author":"Chu","year":"2024","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.bbrc.2021.01.070","article-title":"mTORC1 silencing during intestinal epithelial Caco-2 cell differentiation is mediated by the activation of the AMPK\/TSC2 pathway","volume":"545","author":"Kaur","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Korsten, S., Vromans, H., Garssen, J., and Willemsen, L.E.M. (2023). Butyrate Protects Barrier Integrity and Suppresses Immune Activation in a Caco-2\/PBMC Co-Culture Model While HDAC Inhibition Mimics Butyrate in Restoring Cytokine-Induced Barrier Disruption. Nutrients, 15.","DOI":"10.3390\/nu15122760"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10565-005-0085-6","article-title":"The Caco-2 cell line as a model of the intestinal barrier: Influence of cell and culture-related factors on Caco-2 cell functional characteristics","volume":"21","author":"Sambuy","year":"2005","journal-title":"Cell Biol. Toxicol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1472","DOI":"10.1136\/gut.52.10.1472","article-title":"Phosphatidylinositol 3-kinase mediates proliferative signals in intestinal epithelial cells","volume":"52","author":"Sheng","year":"2003","journal-title":"Gut"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"100220","DOI":"10.1074\/jbc.RA120.016645","article-title":"The STAT3 inhibitor Stattic acts independently of STAT3 to decrease histone acetylation and modulate gene expression","volume":"296","author":"Poria","year":"2021","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Lombardi, A.P.G., Cavalheiro, R.P., Porto, C.S., and Vicente, C.M. (2021). Estrogen Receptor Signaling Pathways Involved in Invasion and Colony Formation of Androgen-Independent Prostate Cancer Cells PC-3. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22031153"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"7130","DOI":"10.1021\/acs.jmedchem.3c02433","article-title":"Discovery of a Potent Dual Son of Sevenless 1 (SOS1) and Epidermal Growth Factor Receptor (EGFR) Inhibitor for the Treatment of Prostate Cancer","volume":"67","author":"Zheng","year":"2024","journal-title":"J. Med. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"116097","DOI":"10.1016\/j.bcp.2024.116097","article-title":"Proliferation and migration of PC-3 prostate cancer cells is counteracted by PPAR\u03b3-cladosporol binding-mediated apoptosis and a decreased lipid biosynthesis and accumulation","volume":"222","author":"Rapuano","year":"2024","journal-title":"Biochem. Pharmacol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Sabbatino, F., Liguori, L., Polcaro, G., Salvato, I., Caramori, G., Salzano, F.A., Casolaro, V., Stellato, C., Dal Col, J., and Pepe, S. (2020). Role of Human Leukocyte Antigen System as A Predictive Biomarker for Checkpoint-Based Immunotherapy in Cancer Patients. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21197295"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s10585-012-9494-0","article-title":"Expression of TGF\u03b23 and its effects on migratory and invasive behavior of prostate cancer cells: Involvement of PI3-kinase\/AKT signaling pathway","volume":"30","author":"Walker","year":"2013","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1158\/0008-5472.CAN-21-4425","article-title":"BCA101 Is a Tumor-Targeted Bifunctional Fusion Antibody That Simultaneously Inhibits EGFR and TGF\u03b2 Signaling to Durably Suppress Tumor Growth","volume":"83","author":"Boreddy","year":"2023","journal-title":"Cancer Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.32604\/or.2024.048007","article-title":"Caffeic acid hinders the proliferation and migration through inhibition of IL-6 mediated JAK-STAT-3 signaling axis in human prostate cancer","volume":"32","author":"Yin","year":"2024","journal-title":"Oncol. Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"50","DOI":"10.21873\/cgp.20303","article-title":"SIRT5 Directly Inhibits the PI3K\/AKT Pathway in Prostate Cancer Cell Lines","volume":"19","author":"Choi","year":"2022","journal-title":"Cancer Genom. Proteom."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Chang, K.S., Chen, S.T., Sung, H.C., Hsu, S.Y., Lin, W.Y., Hou, C.P., Lin, Y.H., Feng, T.H., Tsui, K.H., and Juang, H.H. (2023). Androgen Receptor Upregulates Mucosa-Associated Lymphoid Tissue 1 to Induce NF-\u03baB Activity via Androgen-Dependent and -Independent Pathways in Prostate Carcinoma Cells. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24076245"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Su, P., Zhang, M., and Kang, X. (2023). Targeting c-Met in the treatment of urologic neoplasms: Current status and challenges. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1071030"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Hajjo, R., Sabbah, D.A., Alhaded, R., Alquabe\u2019h, A., and Bardaweel, S.K. (2025). Computational Insights into the Polypharmacological Landscape of BCR-ABL Inhibitors: Emphasis on Imatinib and Nilotinib. Pharmaceuticals, 18.","DOI":"10.3390\/ph18070936"},{"key":"ref_64","unstructured":"(2022). Molecular Operating Environment (MOE), Chemical Computing Group ULC. 2022.02."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1021\/ml400378e","article-title":"Crystal structures of PI3Kalpha complexed with PI103 and Its derivatives: New directions for inhibitors design","volume":"5","author":"Zhao","year":"2013","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"16996","DOI":"10.1073\/pnas.0908444106","article-title":"A frequent kinase domain mutation that changes the interaction between PI3K alpha and the membrane","volume":"106","author":"Mandelker","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1021\/jm0306430","article-title":"Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy","volume":"47","author":"Friesner","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"6177","DOI":"10.1021\/jm051256o","article-title":"Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes","volume":"49","author":"Friesner","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_69","unstructured":"(2022). Protein Preparation Wizard, Maestro, Macromodel, QPLD-Dock, and Pymol, Schr\u00f6dinger, LLC."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"15815","DOI":"10.1021\/acsomega.9b01439","article-title":"Structural Perturbations due to Mutation (H1047R) in Phosphoinositide-3-kinase (PI3K\u03b1) and Its Involvement in Oncogenesis: An in Silico Insight","volume":"4","author":"Sharma","year":"2019","journal-title":"ACS Omega"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1021\/ci900175n","article-title":"Class I phospho-inositide-3-kinases (PI3Ks) isoform-specific inhibition study by the combination of docking and molecular dynamics simulation","volume":"50","author":"Han","year":"2010","journal-title":"J. Chem. Inf. Model."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.1021\/ci1002679","article-title":"Docking studies on isoform-specific inhibition of phosphoinositide-3-kinases","volume":"50","author":"Sabbah","year":"2010","journal-title":"J. Chem. Inf. Model."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Islim, R.A., Hamadeh, N.S., Khalaf, R.A., Hajjo, R., Bardaweel, S.K., Sweidan, K., Al-Zuheiri, A.M., Balaji, S., Tiwari, A.K., and Abushaikha, G. (2025). Exploring the anticancer potential of nitrated N-substituted-4-hydroxy-2-quinolone-3-carboxamides: Synthesis, biological assessment, and computational analysis. BMC Chem., 19.","DOI":"10.1186\/s13065-025-01616-w"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"e202200662","DOI":"10.1002\/slct.202200662","article-title":"Design, Synthesis, and Biological Examination of N-Phenyl-6-fluoro-4-hydroxy-2-quinolone-3-carboxamides as Anticancer Agents","volume":"7","author":"Sabbah","year":"2022","journal-title":"ChemistrySelect"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1744","DOI":"10.1126\/science.1150799","article-title":"The structure of a human p110 alpha\/p85 alpha complex elucidates the effects of oncogenic PI3K alpha mutations","volume":"318","author":"Huang","year":"2007","journal-title":"Science"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Balaji, S., Neupane, R., Malla, S., Khupse, R., Amawi, H., Kumari, S., Tukaramrao, D.B., Chattopadhyay, S., Ashby, C.R., and Boddu, S.H. (2022). IND-2, a Quinoline Derivative, Inhibits the Proliferation of Prostate Cancer Cells by Inducing Oxidative Stress, Apoptosis and Inhibiting Topoisomerase II. Life, 12.","DOI":"10.3390\/life12111879"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Neupane, R., Malla, S., Abou-Dahech, M.S., Balaji, S., Kumari, S., Waiker, D.K., Moorthy, N.H.N., Trivedi, P., Ashby, C.R., and Karthikeyan, C. (2021). Antiproliferative Efficacy of N-(3-chloro-4-fluorophenyl)-6, 7-dimethoxyquinazolin-4-amine, DW-8, in Colon Cancer Cells Is Mediated by Intrinsic Apoptosis. Molecules, 26.","DOI":"10.3390\/molecules26154417"},{"key":"ref_78","unstructured":"(2025, May 01). ChemDraw Professional 15.0, Revvity Signals Software, Inc. Available online: https:\/\/revvitysignals.com\/products\/research\/chemdraw."},{"key":"ref_79","unstructured":"National Library of Medicine (NLM) (2025, August 24). PubChem Explore Chemistry, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/."},{"key":"ref_80","unstructured":"(2025, August 25). alvaDesc version 1.0.22. Available online: https:\/\/www.alvascience.com\/alvadesc\/."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Roy, K. (2020). alvaDesc: A Tool to Calculate and Analyze Molecular Descriptors and Fingerprints. Ecotoxicological QSARs, Springer.","DOI":"10.1007\/978-1-0716-0150-1"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Mauri, A., and Bertola, M. (2022). Alvascience: A New Software Suite for the QSAR Workflow Applied to the Blood\u2013Brain Barrier Permeability. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232112882"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2136","DOI":"10.1021\/acs.jcim.3c00610","article-title":"AlvaBuilder: A Software for De Novo Molecular Design","volume":"64","author":"Mauri","year":"2024","journal-title":"J. Chem. Inf. Model."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/4\/655\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,15]],"date-time":"2026-02-15T05:20:02Z","timestamp":1771132802000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/4\/655"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,13]]},"references-count":83,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["molecules31040655"],"URL":"https:\/\/doi.org\/10.3390\/molecules31040655","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,13]]}}}