{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:04:10Z","timestamp":1777334650085,"version":"3.51.4"},"reference-count":48,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,2,28]],"date-time":"2023-02-28T00:00:00Z","timestamp":1677542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Symmetry"],"abstract":"<jats:p>The structural symmetry or asymmetry of organic compounds is one of the most fundamental characteristics. Z-geometrical isomers are promiscuous and kinetically preferred structures with a plethora of biological activities. A new series of hybrid molecules containing Schiff base and 3,4,5-trimethoxybenzamide moieties were synthesized from the starting material ethyl acrylate ester derivative (Z)-1 and structurally confirmed by elemental microanalysis, 1H-NMR, and 13C-NMR spectroscopic studies. The in vitro cytotoxic activity of the target hybrids was tested against the MCF-7 breast cancer line compared with colchicine as the reference compound. Most of the newly synthesized hybrids showed good growth inhibition activity against the MCF-7 cells compared to the reference substance. The results of the \u03b2-tubulin polymerization inhibition activity assay showed that the p-vanillin Schiff base 4g displayed good inhibition activity. In addition, p-vanillin Schiff base 4g exhibited antiproliferative activity over the MCF-7 cells by cellular cycle blockade at the G2\/M phase and it is a potent apoptotic agent. qRT-PCR analysis showed that Schiff base 4g boosted the mRNA expression of the p53 and Bax levels while lowering the expression of the Bcl-2 level.<\/jats:p>","DOI":"10.3390\/sym15030609","type":"journal-article","created":{"date-parts":[[2023,2,28]],"date-time":"2023-02-28T03:00:38Z","timestamp":1677553238000},"page":"609","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["New Schiff Base\u2013TMB Hybrids: Design, Synthesis and Antiproliferative Investigation as Potential Anticancer Agents"],"prefix":"10.3390","volume":"15","author":[{"given":"Najiah M.","family":"Alyamani","sequence":"first","affiliation":[{"name":"Department of Biology, College of Science, University of Jeddah, Jeddah 21493, Saudi Arabia"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"\u0141ukasiewicz, S., Czeczelewski, M., Forma, A., Baj, J., Sitarz, R., and Stanis\u0142awek, A. (2021). Breast Cancer\u2014Epidemiology, Risk Factors, Classification, Prognostic Markers, and Current Treatment Strategies\u2014An Updated Review. Cancers, 13.","DOI":"10.3390\/cancers13174287"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"775","DOI":"10.2174\/1871520621666211201150818","article-title":"Is it time to consider the Androgen receptor as a therapeutic target in breast cancer?","volume":"22","author":"Forooshani","year":"2022","journal-title":"Anti-Cancer Agents Med. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4036","DOI":"10.1007\/s00330-022-08617-6","article-title":"Breast cancer screening in women with extremely dense breasts recommendations of the European Society of Breast Imaging (EUSOBI)","volume":"32","author":"Mann","year":"2022","journal-title":"Eur. Radiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/s41556-022-00862-7","article-title":"Defining cancer growth beyond the mitotic index","volume":"24","author":"Chinnaiyan","year":"2022","journal-title":"Nat. Cell Biol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Novais, P., Silva, P., Amorim, I., and Bousbaa, H. (2021). Second-generation antimitotics in cancer clinical trials. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13071011"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7963","DOI":"10.1021\/acs.jmedchem.1c00100","article-title":"Recent Progress on Tubulin Inhibitors with Dual Targeting Capabilities for Cancer Therapy","volume":"64","author":"Shuai","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Ebenezer, O., Shapi, M., and Tuszynski, J.A. (2022). A Review of the Recent Developments of Molecular Hybrids Targeting Tubulin Polymerization. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23074001"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"23665","DOI":"10.1038\/s41598-021-03076-3","article-title":"Characterization of a recently synthesized microtubule-targeting compound that disrupts mitotic spindle poles in human cells","volume":"11","author":"Jaunky","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_9","first-page":"1623181","article-title":"Microtubule Organization Is Essential for Maintaining Cellular Morphology and Function","volume":"2022","author":"Huang","year":"2022","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"R651","DOI":"10.1016\/j.cub.2021.03.064","article-title":"Cellular functions of actin- and microtubule-associated septins","volume":"31","author":"Spiliotis","year":"2021","journal-title":"Curr. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"105320","DOI":"10.1016\/j.bioorg.2021.105320","article-title":"Microtubule associated proteins as targets for anticancer drug development","volume":"116","author":"Khwaja","year":"2021","journal-title":"Bioorg. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"115534","DOI":"10.1016\/j.taap.2021.115534","article-title":"Microtubule and tubulin binding and regulation of microtubule dynamics by the antibody drug conjugate (ADC) payload, monomethyl auristatin E (MMAE): Mechanistic insights into MMAE ADC peripheral neuropathy","volume":"421","author":"Best","year":"2021","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"113229","DOI":"10.1016\/j.ejmech.2021.113229","article-title":"A facile synthesis of diaryl pyrroles led to the discovery of potent colchicine site antimitotic agents","volume":"214","author":"Romagnoli","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3266","DOI":"10.1016\/j.bmcl.2008.04.053","article-title":"Synthesis and antitumor activity of benzils related to combretastatin A-4","volume":"18","author":"Mousset","year":"2008","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.ejmech.2013.04.057","article-title":"Elaboration of thorough simplified vinca alkaloids as antimitotic agents based on pharmacophore similarity","volume":"65","author":"Zheng","year":"2013","journal-title":"Eur. J. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Pieku\u015b-S\u0142omka, N., Mikstacka, R., Ronowicz, J., and Sobiak, S. (2019). Hybrid cis-stilbene molecules: Novel anticancer agents. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20061300"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Bukhari, S.N.A., Zakaria, M., Munir, M., Ahmad, N., Elsherif, M., Badr, R., Hassan, A., Almaaty, A., and Zaki, I. (2022). Design, Synthesis, In Vitro Biological Activity Evaluation and Stabilized Nanostructured Lipid Carrier Formulation of Newly Synthesized Schiff Bases-Based TMP Moieties. Pharmaceuticals, 15.","DOI":"10.3390\/ph15060679"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"McLoughlin, E.C., and O\u2019Boyle, N.M. (2020). Colchicine-Binding Site Inhibitors from Chemistry to Clinic: A Review. Pharmaceuticals, 13.","DOI":"10.3390\/ph13010008"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1038\/s41423-020-00630-3","article-title":"Necroptosis, pyroptosis and apoptosis: An intricate game of cell death","volume":"18","author":"Bertheloot","year":"2021","journal-title":"Cell. Mol. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"118939","DOI":"10.1016\/j.lfs.2020.118939","article-title":"MicroRNA-383-5p restrains the proliferation and migration of breast cancer cells and promotes apoptosis via inhibition of PD-L1","volume":"267","author":"Azarbarzin","year":"2021","journal-title":"Life Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"154015","DOI":"10.1016\/j.phymed.2022.154015","article-title":"Activation of mitochondrial-associated apoptosis signaling pathway and inhibition of PI3K\/Akt\/mTOR signaling pathway by voacamine suppress breast cancer progression","volume":"99","author":"Zuo","year":"2022","journal-title":"Phytomedicine"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e40","DOI":"10.1038\/cddis.2010.18","article-title":"A survey of the anti-apoptotic Bcl-2 subfamily expression in cancer types provides a platform to predict the efficacy of Bcl-2 antagonists in cancer therapy","volume":"1","author":"Placzek","year":"2010","journal-title":"Cell Death Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2679","DOI":"10.1080\/14756366.2022.2116016","article-title":"Design and synthesis of new trimethoxylphenyl-linked combretastatin analogues loaded on diamond nanoparticles as a panel for ameliorated solubility and antiproliferative activity","volume":"37","author":"Zaki","year":"2022","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"114184","DOI":"10.1016\/j.ejmech.2022.114184","article-title":"Trends in targeting Bcl-2 anti-apoptotic proteins for cancer treatment","volume":"232","author":"Zhang","year":"2022","journal-title":"Eur. J. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Al-Warhi, T., Aldhahrani, A., Althobaiti, F., Fayad, E., Ali, O.A., Albogami, S., Almaaty, A.A., Khedr, A., Bukhari, S., and Zaki, I. (2022). Design, Synthesis and Cytotoxic Activity Evaluation of Newly Synthesized Amides-Based TMP Moiety as Potential Anticancer Agents over HepG2 Cells. Molecules, 27.","DOI":"10.3390\/molecules27123960"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1786","DOI":"10.2174\/1871520619666190227171716","article-title":"Schiff Bases and their metal complexes as potential anticancer candidates: A review of recent works","volume":"19","author":"Tadele","year":"2019","journal-title":"Anti-Cancer Agents Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Howsaui, H.B., Basaleh, A., Abdellattif, M., Hassan, W., and Hussien, M.A. (2021). Synthesis, Structural Investigations, Molecular Docking, and Anticancer Activity of Some Novel Schiff Bases and Their Uranyl Complexes. Biomolecules, 11.","DOI":"10.3390\/biom11081138"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/s42247-021-00234-1","article-title":"Schiff base metallodrugs in antimicrobial and anticancer chemotherapy applications: A comprehensive review","volume":"5","author":"Shekhar","year":"2022","journal-title":"Emergent Mater."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3246","DOI":"10.1080\/07391102.2019.1654924","article-title":"Synthesis, characterization, and anticancer activity of Schiff bases","volume":"38","author":"Uddin","year":"2020","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1080\/14756360412331280473","article-title":"Naphthalene Combretastatin Analogues: Synthesis, Cytotoxicity and Antitubulin Activity","volume":"19","author":"Medarde","year":"2004","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.ejps.2016.09.039","article-title":"Multifaceted properties of 1,4-dimethylcarbazoles: Focus on trimethoxybenzamide and trimethoxyphenylurea derivatives as novel human topoisomerase II inhibitors","volume":"96","author":"Iacopetta","year":"2017","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.1080\/07391102.2017.1336943","article-title":"N-(4-Hydroxyphenyl)-3,4,5-trimethoxybenzamide derivatives as potential memory enhancers: Synthesis, biological evaluation and molecular simulation studies","volume":"36","author":"Piplani","year":"2018","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"E294","DOI":"10.1002\/jhet.1951","article-title":"New Trimethoxybenzamides and Trimethoxyphenylureas Derived from Dimethylcarbazole as Cytotoxic Agents. Part I","volume":"51","author":"Panno","year":"2014","journal-title":"J. Heterocycl. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"104076","DOI":"10.1016\/j.bioorg.2020.104076","article-title":"Synthesis and biological evaluation of benzofuran-based 3,4,5-trimethoxybenzamide derivatives as novel tubulin polymerization inhibitors","volume":"102","author":"Li","year":"2020","journal-title":"Bioorg. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.ejmech.2015.05.047","article-title":"Exploring the size adaptability of the B ring binding zone of the colchicine site of tubulin with para-nitrogen substituted isocombretastatins","volume":"100","author":"Ellahioui","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"15757","DOI":"10.1002\/chem.202102737","article-title":"Investigation on Optical and Biological Properties of 2-(4-Dimethylaminophenyl)benzothiazole Based Cycloplatinated Complexes","volume":"27","author":"Lara","year":"2021","journal-title":"Chem. Eur. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"132749","DOI":"10.1016\/j.molstruc.2022.132749","article-title":"Design, synthesis and cytotoxicity screening of new synthesized pyrimidine-5-carbonitrile derivatives showing marked apoptotic effect","volume":"1259","author":"Zaki","year":"2022","journal-title":"J. Mol. Struct."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Al-Warhi, T., Abualnaja, M., Ali, O.A., Althobaiti, F., Alharthi, F., Elsaid, F., Shati, A., Fayad, E., Elghareeb, D., and Almaaty, A.A. (2022). Synthesis and Biological Activity Screening of Newly Synthesized Trimethoxyphenyl-Based Analogues as Potential Anticancer Agents. Molecules, 27.","DOI":"10.3390\/molecules27144621"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Al-Warhi, T., Alqahtani, L., Abualnaja, M., Beigh, S., Ali, O.A., Elsaid, F., Shati, A., Saleem, R., Maghrabi, A., and Alharthi, A. (2022). Design, Synthesis, and In Vitro Antiproliferative Screening of New Hydrazone Derivatives Containing cis-(4-Chlorostyryl) Amide Moiety. Symmetry, 14.","DOI":"10.3390\/sym14112457"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Boichuk, S., Galembikova, A., Syuzov, K., Dunaev, P., Bikinieva, F., Aukhadieva, A., Zykova, S., Igidov, N., Gankova, K., and Novikova, M. (2021). The Design, Synthesis, and Biological Activities of Pyrrole-Based Carboxamides: The Novel Tubulin Inhibitors Targeting the Colchicine-Binding Site. Molecules, 26.","DOI":"10.3390\/molecules26195780"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1080\/13543776.2019.1648433","article-title":"Tubulin inhibitors as novel anticancer agents: An overview on patents (2013\u20132018)","volume":"29","author":"Haider","year":"2019","journal-title":"Expert Opin. Ther. Patents"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"114660","DOI":"10.1016\/j.ejmech.2022.114660","article-title":"Recent advances in combretastatin A-4 codrugs for cancer therapy","volume":"241","author":"Guo","year":"2022","journal-title":"Eur. J. Med. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Borys, F., Joachimiak, E., Krawczyk, H., and Fabczak, H. (2020). Intrinsic and Extrinsic Factors Affecting Microtubule Dynamics in Normal and Cancer Cells. Molecules, 25.","DOI":"10.3390\/molecules25163705"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"105513","DOI":"10.1016\/j.ejps.2020.105513","article-title":"Fluorinated benzylidene indanone exhibits antiproliferative activity through modulation of microtubule dynamics and antiangiogenic activity","volume":"154","author":"Srivastava","year":"2020","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.it.2006.03.005","article-title":"Apoptotic cell removal in development and tissue homeostasis","volume":"27","author":"Henson","year":"2006","journal-title":"Trends Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Piskorz, W.M., and Cechowska-Pasko, M. (2022). Senescence of Tumor Cells in Anticancer Therapy\u2014Beneficial and Detrimental Effects. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911082"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/cdd.2017.161","article-title":"The BCL-2 arbiters of apoptosis and their growing role as cancer targets","volume":"25","author":"Adams","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"183716","DOI":"10.1016\/j.bbamem.2021.183716","article-title":"Apoptosis regulation at the mitochondria membrane level","volume":"1863","author":"Dadsena","year":"2021","journal-title":"Biochim. Biophys. Acta Biomembr."}],"container-title":["Symmetry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-8994\/15\/3\/609\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:43:43Z","timestamp":1760121823000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-8994\/15\/3\/609"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,28]]},"references-count":48,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["sym15030609"],"URL":"https:\/\/doi.org\/10.3390\/sym15030609","relation":{},"ISSN":["2073-8994"],"issn-type":[{"value":"2073-8994","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,28]]}}}