{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T19:23:38Z","timestamp":1790191418189,"version":"4.1.0"},"reference-count":81,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T00:00:00Z","timestamp":1763596800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007446","name":"King Khalid University","doi-asserted-by":"crossref","award":["RGP2\/500\/46"],"award-info":[{"award-number":["RGP2\/500\/46"]}],"id":[{"id":"10.13039\/501100007446","id-type":"DOI","asserted-by":"crossref"}]},{"name":"European Union\u2014Next Generation EU","award":["LX22NPO5102"],"award-info":[{"award-number":["LX22NPO5102"]}]},{"name":"Palacky University","award":["IGA_PrF_2025_011"],"award-info":[{"award-number":["IGA_PrF_2025_011"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: In the current medical era, Topoisomerase II is recognized as an essential enzyme that regulates DNA topology during critical biological processes such as DNA replication, transcription, and repair. This study aimed to design, synthesize, and biologically evaluate a new series of pyrazolo[3,4-b]pyridines (8a\u2013g, 10a\u2013g, and 12) as potential anticancer agents and Topoisomerase II inhibitors. Methods: The synthesized compounds were subjected to in vitro anticancer screening at the National Cancer Institute (NCI, USA). Active derivatives were further evaluated through a five-dose screening to determine their antiproliferative potency. Selected compounds were examined for their effects on leukemia cell lines (K562 and MV4-11), and mechanistic studies were performed to assess DNA damage, cell cycle distribution, and apoptosis-related protein modulation. Additionally, enzyme inhibition assays were conducted to determine Topoisomerase II\u03b1 (TOPII\u03b1) inhibition. Results: Initial single-dose screening identified several active compounds, notably 8b, 8c, 8e, 8f, 10b, 10c, 10e, and 10f. Among these, compound 8c exhibited potent and broad-spectrum antiproliferative activity across the NCI cancer cell line panel, with a GI50 MG-MID value of 1.33 \u00b5M (range: 0.54\u20132.08 \u00b5M). The synthesized molecules showed moderate to good anti-leukemic efficacy against K562 and MV4-11 cells. Mechanistic investigations revealed that compound 8c induced DNA damage and S-phase cell cycle arrest, leading to apoptosis as evidenced by the modulation of PARP-1, Bax, XIAP, and Caspases. Furthermore, target-based assays confirmed that compound 8c significantly inhibited the DNA relaxation activity of TOPII\u03b1 in a dose-dependent manner, comparable to etoposide. Conclusions: The study highlights compound 8c as a promising pyrazolo[3,4-b]pyridine derivative with potent antiproliferative activity and effective inhibition of Topoisomerase II\u03b1. These findings suggest its potential as a lead scaffold for further optimization in anticancer drug development..<\/jats:p>","DOI":"10.3390\/ph18111770","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T08:59:46Z","timestamp":1763715586000},"page":"1770","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Development of New Pyrazolo [3,4-b]Pyridine Derivatives as Potent Anti-Leukemic Agents and Topoisomerase II\u03b1 Inhibitors with Broad-Spectrum Cytotoxicity"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6996-4017","authenticated-orcid":false,"given":"Wagdy M.","family":"Eldehna","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6455-5716","authenticated-orcid":false,"given":"Haytham O.","family":"Tawfik","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denisa","family":"Vesel\u00e1","sequence":"additional","affiliation":[{"name":"Department of Experimental Biology, Faculty of Science, Palack\u00fd University Olomouc, \u0160lechtitel\u016f 27, 77900 Olomouc, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika","family":"Voj\u00e1\u010dkov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Experimental Biology, Faculty of Science, Palack\u00fd University Olomouc, \u0160lechtitel\u016f 27, 77900 Olomouc, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3399-3435","authenticated-orcid":false,"given":"Ahmed T.","family":"Negmeldin","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy and Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman 4184, United Arab Emirates"},{"name":"Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo 12613, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zainab M.","family":"Elsayed","sequence":"additional","affiliation":[{"name":"Scientific Research and Innovation Support Unit, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 6860404, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taghreed A.","family":"Majrashi","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, College of Pharmacy, King Khalid University, Asir 62521, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3578-6386","authenticated-orcid":false,"given":"Petra","family":"Kr\u0148\u00e1vkov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Experimental Biology, Faculty of Science, Palack\u00fd University Olomouc, \u0160lechtitel\u016f 27, 77900 Olomouc, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9073-4176","authenticated-orcid":false,"given":"Mostafa M.","family":"Elbadawi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0420-4364","authenticated-orcid":false,"given":"Moataz A.","family":"Shaldam","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghada H.","family":"Al-Ansary","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5838-2118","authenticated-orcid":false,"given":"Vladim\u00edr","family":"Kry\u0161tof","sequence":"additional","affiliation":[{"name":"Department of Experimental Biology, Faculty of Science, Palack\u00fd University Olomouc, \u0160lechtitel\u016f 27, 77900 Olomouc, Czech Republic"},{"name":"Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palack\u00fd University Olomouc, Hn\u011bvot\u00ednsk\u00e1 5, 77900 Olomouc, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2606-2504","authenticated-orcid":false,"given":"Hatem A.","family":"Abdel-Aziz","sequence":"additional","affiliation":[{"name":"Applied Organic Chemistry Department, National Research Center, Dokki, Cairo 12622, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,20]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","first-page":"10","article-title":"Cancer statistics, 2025","volume":"75","author":"Siegel","year":"2025","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3708","DOI":"10.1002\/cncr.35458","article-title":"Burden of 30 cancers among men: Global statistics in 2022 and projections for 2050 using population-based estimates","volume":"130","author":"Bizuayehu","year":"2024","journal-title":"Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.chest.2022.02.004","article-title":"Hematology Emergencies in Adults With Critical Illness: Malignant Hematology","volume":"162","author":"Spring","year":"2022","journal-title":"Chest"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1038\/s41375-024-02452-y","article-title":"Global patterns of leukemia by subtype, age, and sex in 185 countries in 2022","volume":"39","author":"Daltveit","year":"2025","journal-title":"Leukemia"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1038\/nrc.2016.3","article-title":"Leukaemia \u2018firsts\u2019 in cancer research and treatment","volume":"16","author":"Greaves","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Donaire-Arias, A., Montagut, A.M., Puig de la Bellacasa, R., Estrada-Tejedor, R., Teixid\u00f3, J., and Borrell, J.I. (2022). 1H-Pyrazolo [3,4-b]pyridines: Synthesis and Biomedical Applications. Molecules, 27.","DOI":"10.3390\/molecules27072237"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4297","DOI":"10.1016\/j.bmcl.2007.05.029","article-title":"Synthesis and evaluation of pyrazolo[3,4-b]pyridine CDK1 inhibitors as anti-tumor agents","volume":"17","author":"Lin","year":"2007","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Almansour, B.S., Binjubair, F.A., Abdel-Aziz, A.A.-M., and Al-Rashood, S.T. (2023). Synthesis and In Vitro Anticancer Activity of Novel 4-Aryl-3-(4-methoxyphenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridines Arrest Cell Cycle and Induce Cell Apoptosis by Inhibiting CDK2 and\/or CDK9. Molecules, 28.","DOI":"10.3390\/molecules28176428"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2405","DOI":"10.1016\/S0960-894X(03)00381-0","article-title":"1H-Pyrazolo[3,4-b]pyridine inhibitors of cyclin-dependent kinases: Highly potent 2,6-Difluorophenacyl analogues","volume":"13","author":"Misra","year":"2003","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.ejmech.2018.12.053","article-title":"3,5-Diaryl-1H-pyrazolo[3,4-b]pyridines as potent tubulin polymerization inhibitors: Rational design, synthesis and biological evaluation","volume":"168","author":"Zhai","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3055","DOI":"10.1016\/S0960-894X(03)00645-0","article-title":"6-Aryl-pyrazolo[3,4-b]pyridines: Potent inhibitors of glycogen synthase kinase-3 (GSK-3)","volume":"13","author":"Witherington","year":"2003","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Verma, N., Tiwari, G., Khanna, A., Mishra, V.K., Yadav, Y., Malviya, M., and Sagar, R. (2025). Molecular Design, Synthesis and Anticancer Activity of Novel Pyrazolo[3,4-b]pyridine-based Glycohybrid Molecules. Bioorganic Chem., 156.","DOI":"10.1016\/j.bioorg.2025.108161"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1021\/acsmedchemlett.6b00066","article-title":"Discovery of Substituted 1H-Pyrazolo[3,4-b]pyridine Derivatives as Potent and Selective FGFR Kinase Inhibitors","volume":"7","author":"Zhao","year":"2016","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1039\/D2MD00334A","article-title":"Design, synthesis and biological evaluation of pyrazolo[3,4-b]pyridine derivatives as TRK inhibitors","volume":"14","author":"Liu","year":"2023","journal-title":"RSC Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"El-Gohary, N.S., Hawas, S.S., Gabr, M.T., Shaaban, M.I., and El-Ashmawy, M.B. (2019). New series of fused pyrazolopyridines: Synthesis, molecular modeling, antimicrobial, antiquorum-sensing and antitumor activities. Bioorganic Chem., 92.","DOI":"10.1016\/j.bioorg.2019.103109"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2466","DOI":"10.1080\/00397911.2019.1618873","article-title":"Synthesis, molecular docking, antimicrobial, antiquorum-sensing and antiproliferative activities of new series of pyrazolo[3,4-b]pyridine analogs","volume":"49","author":"Hawas","year":"2019","journal-title":"Synth. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Kazemi, Z., Rudbari, H.A., Moini, N., Momenbeik, F., Carnamucio, F., and Micale, N. (2024). Indole-Containing Metal Complexes and Their Medicinal Applications. Molecules, 29.","DOI":"10.3390\/molecules29020484"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"112245","DOI":"10.1016\/j.ejmech.2020.112245","article-title":"Indole-based derivatives as potential antibacterial activity against methicillin-resistance Staphylococcus aureus (MRSA)","volume":"194","author":"Qin","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Siddique, S., Ahmad, K.R., Nawaz, S.K., Raza, A.R., Ahmad, S.N., Ali, R., Inayat, I., Suleman, S., Kanwal, M.A., and Usman, M. (2023). Evaluation of the antiinflammatory, analgesic, anti-pyretic and anti-ulcerogenic potentials of synthetic indole derivatives. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-35640-4"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e202202361","DOI":"10.1002\/slct.202202361","article-title":"Indole Derived Anticancer Agents","volume":"7","author":"Mehra","year":"2022","journal-title":"ChemistrySelect"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Hassan, S.M., Farid, A., Panda, S.S., Bekheit, M.S., Dinkins, H., Fayad, W., and Girgis, A.S. (2024). Indole Compounds in Oncology: Therapeutic Potential and Mechanistic Insights. Pharmaceuticals, 17.","DOI":"10.3390\/ph17070922"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/j.ejmech.2014.04.043","article-title":"Anticonvulsant evaluation of clubbed indole-1,2,4-triazine derivatives: A synthetic approach","volume":"80","author":"Ahuja","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"117017","DOI":"10.1016\/j.ejmech.2024.117017","article-title":"Recent report on indoles as a privileged antiviral scaffold in drug discovery","volume":"281","author":"Singh","year":"2025","journal-title":"Eur. J. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"113665","DOI":"10.1016\/j.ejmech.2021.113665","article-title":"Research progress of indole compounds with potential antidiabetic activity","volume":"223","author":"Zhu","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_26","unstructured":"Khan, M.T.H. (2007). Antioxidant Activities of Synthetic Indole Derivatives and Possible Activity Mechanisms. Bioactive Heterocycles V, Springer."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6366","DOI":"10.1016\/j.bmcl.2011.08.105","article-title":"Discovery of novel 3,5-disubstituted indole derivatives as potent inhibitors of Pim-1, Pim-2, and Pim-3 protein kinases","volume":"21","author":"Nishiguchi","year":"2011","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Al-Warhi, T., El Kerdawy, A.M., Aljaeed, N., Ismael, O.E., Ayyad, R.R., Eldehna, W.M., Abdel-Aziz, H.A., and Al-Ansary, G.H. (2020). Synthesis, Biological Evaluation and In Silico Studies of Certain Oxindole-Indole Conjugates as Anticancer CDK Inhibitors. Molecules, 25.","DOI":"10.3390\/molecules25092031"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"101760","DOI":"10.1016\/j.rechem.2024.101760","article-title":"Appraisal and synthesis of novel indole-thiazole derivatives as epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors against resistance mutation for lung cancer treatment","volume":"11","author":"Tiwari","year":"2024","journal-title":"Results Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.ejmech.2012.09.001","article-title":"Synthesis and biological evaluation of new 5-benzylated 4-oxo-3,4-dihydro-5H-pyridazino[4,5-b]indoles as PI3K\u03b1 inhibitors","volume":"57","author":"Bruel","year":"2012","journal-title":"Eur. J. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/s00044-022-02991-y","article-title":"Design, synthesis and anticancer activity studies of novel indole derivatives as Bcl-2\/Mcl-1 dual inhibitors","volume":"32","author":"Liu","year":"2023","journal-title":"Med. Chem. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1021\/acsmedchemlett.9b00557","article-title":"Synthesis, Antiproliferative Effect, and Topoisomerase II Inhibitory Activity of 3-Methyl-2-phenyl-1H-indoles","volume":"11","author":"Zidar","year":"2020","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"404","DOI":"10.2174\/1871520622666220607143040","article-title":"Recent Updates on Indole Derivatives as Kinase Inhibitors in the Treatment of Cancer","volume":"23","author":"Asati","year":"2023","journal-title":"Anticancer Agents Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Swedan, H.K., Kassab, A.E., Gedawy, E.M., and Elmeligie, S.E. (2023). Topoisomerase II inhibitors design: Early studies and new perspectives. Bioorganic Chem., 136.","DOI":"10.1016\/j.bioorg.2023.106548"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"McKie, S.J., Neuman, K.C., and Maxwell, A. (2021). DNA topoisomerases: Advances in understanding of cellular roles and multi-protein complexes via structure-function analysis. BioEssays News Rev. Mol. Cell. Dev. Biol., 43.","DOI":"10.1002\/bies.202000286"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/s41580-022-00452-3","article-title":"Human topoisomerases and their roles in genome stability and organization","volume":"23","author":"Pommier","year":"2022","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1146\/annurev-biochem-091724-010717","article-title":"Topoisomerase Regulation of Cancer Gene Expression","volume":"94","author":"Baranello","year":"2025","journal-title":"Annu. Rev. Biochem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1080\/14756366.2020.1821676","article-title":"DNA topoisomerases as molecular targets for anticancer drugs","volume":"35","author":"Buzun","year":"2020","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Matias-Barrios, V.M., and Dong, X. (2023). The Implication of Topoisomerase II Inhibitors in Synthetic Lethality for Cancer Therapy. Pharmaceuticals, 16.","DOI":"10.3390\/ph16010094"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1042\/BCJ20160583","article-title":"Topoisomerases as anticancer targets","volume":"475","author":"Delgado","year":"2018","journal-title":"Biochem. J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"107431","DOI":"10.1016\/j.phrs.2024.107431","article-title":"Recent developments of topoisomerase inhibitors: Clinical trials, emerging indications, novel molecules and global sales","volume":"209","author":"Bondarev","year":"2024","journal-title":"Pharmacol. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.3109\/10428194.2010.483749","article-title":"High levels of topoisomerase II\u03b1 protein expression in diffuse large B-cell lymphoma are associated with high proliferation, germinal center immunophenotype, and response to treatment","volume":"51","author":"Pentheroudakis","year":"2010","journal-title":"Leuk. Lymphoma"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Jang, J.Y., Kim, D., Im, E., and Kim, N.D. (2025). Etoposide as a Key Therapeutic Agent in Lung Cancer: Mechanisms, Efficacy, and Emerging Strategies. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26020796"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1021\/acs.jmedchem.9b00726","article-title":"Dual Inhibitors of Human DNA Topoisomerase II and Other Cancer-Related Targets","volume":"63","author":"Skok","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Bhutani, V., Varzideh, F., Wilson, S., Kansakar, U., Jankauskas, S.S., and Santulli, G. (2025). Doxorubicin-Induced Cardiotoxicity: A Comprehensive Update. J. Cardiovasc. Dev. Dis., 12.","DOI":"10.3390\/jcdd12060207"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2466","DOI":"10.2174\/1871520621666201229115612","article-title":"The Synthesis of Nano-Doxorubicin and its Anticancer Effect","volume":"21","author":"Zhu","year":"2021","journal-title":"Anticancer Agents Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"S64","DOI":"10.1007\/BF00684866","article-title":"Pharmacodynamics and long-term toxicity of etoposide","volume":"34","author":"Kobayashi","year":"1994","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Sharma, N.K., Bahot, A., Sekar, G., Bansode, M., Khunteta, K., Sonar, P.V., Hebale, A., Salokhe, V., and Sinha, B.K. (2024). Understanding Cancer\u2019s Defense against Topoisomerase-Active Drugs: A Comprehensive Review. Cancers, 16.","DOI":"10.3390\/cancers16040680"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"8947","DOI":"10.1021\/acs.jmedchem.7b01202","article-title":"Discovery of Novel Topoisomerase II Inhibitors by Medicinal Chemistry Approaches","volume":"61","author":"Hu","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Shen, G., Li, S., Zhu, Y., Xu, Z., Liu, X., Lv, C., Xing, Z., Cui, L., and Li, W. (2025). Recent progress in topoisomerase inhibitors as anticancer agents: Research and design strategies for Topo I and II inhibitors via structural optimization. Bioorganic Chem., 165.","DOI":"10.1016\/j.bioorg.2025.109040"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"116348","DOI":"10.1016\/j.ejmech.2024.116348","article-title":"Design, synthesis and biological evaluation of matrine contains benzimidazole derivatives as dual TOPOI and PARP inhibitors for cancer therapy","volume":"270","author":"Qiu","year":"2024","journal-title":"Eur. J. Med. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1021\/acs.jmedchem.4c01859","article-title":"Indolo[3,2-c]isoquinoline Hydroxamic Acid Derivatives as Novel Orally Topoisomerase-Histone Deacetylase Dual Inhibitors for NSCLC Therapy","volume":"68","author":"Wang","year":"2025","journal-title":"J. Med. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1080\/14756366.2022.2072308","article-title":"New 1,2,3-triazole linked ciprofloxacin-chalcones induce DNA damage by inhibiting human topoisomerase I& II and tubulin polymerization","volume":"37","author":"Mohammed","year":"2022","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Eldehna, W.M., Tawfik, H.O., Abdulla, M.-H., Nafie, M.S., Aref, H., Shaldam, M.A., Alhassan, N.S., Al Obeed, O., Elsayed, Z.M., and Abdel-Aziz, H.A. (2024). Identification of indole-grafted pyrazolopyrimidine and pyrazolopyridine derivatives as new anticancer agents: Synthesis, biological assessments, and molecular modeling insights. Bioorganic Chem., 153.","DOI":"10.1016\/j.bioorg.2024.107804"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"113952","DOI":"10.1016\/j.ejmech.2021.113952","article-title":"One-pot three-component synthesis of novel pyrazolo[3,4-b]pyridines as potent antileukemic agents","volume":"227","author":"Barghash","year":"2022","journal-title":"Eur. J. Med. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Eldehna, W.M., Abdulla, M.-H., Nafie, M.S., Elsawi, A.E., Ayman, S., Shahin, M.I., Alhassan, N.S., Zubaidi, A.M., Ghabbour, H.A., and Elaasser, M. (2024). Unveiling the anticancer potential of novel spirooxindole-tethered pyrazolopyridine derivatives. Bioorganic Chem., 153.","DOI":"10.1016\/j.bioorg.2024.107778"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/00304940802711218","article-title":"Recent progress in three-component reactions. An update","volume":"41","author":"Syamala","year":"2009","journal-title":"Org. Prep. Proced. Int."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"7632","DOI":"10.1039\/C9OB00772E","article-title":"Consecutive multicomponent reactions for the synthesis of complex molecules","volume":"17","author":"Zhi","year":"2019","journal-title":"Org. Biomol. Chem."},{"key":"ref_59","first-page":"848","article-title":"Recent Advances in Three-Component Synthesis of Difluorinated Compounds","volume":"62","author":"Wang","year":"2025","journal-title":"Org. Biomol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"6525","DOI":"10.1002\/ejoc.202001157","article-title":"The Ugi three-component reaction; a valuable tool in modern organic synthesis","volume":"2020","author":"Tripolitsiotis","year":"2020","journal-title":"Eur. J. Org. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Katariya, K.D., Shah, S.R., and Reddy, D. (2020). Anticancer, antimicrobial activities of quinoline based hydrazone analogues: Synthesis, characterization and molecular docking. Bioorganic Chem., 94.","DOI":"10.1016\/j.bioorg.2019.103406"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"114190","DOI":"10.1016\/j.ejmech.2022.114190","article-title":"Discovery of new carbonic anhydrase IX inhibitors as anticancer agents by toning the hydrophobic and hydrophilic rims of the active site to encounter the dual-tail approach","volume":"232","author":"Tawfik","year":"2022","journal-title":"Eur. J. Med. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1002\/ddr.430340203","article-title":"Some practical considerations and applications of the National Cancer Institute in vitro anticancer drug discovery screen","volume":"34","author":"Boyd","year":"1995","journal-title":"Drug Dev. Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"3202","DOI":"10.1016\/j.arabjc.2015.08.019","article-title":"Design and synthesis of benzimidazoles containing substituted oxadiazole, thiadiazole and triazolo-thiadiazines as a source of new anticancer agents","volume":"12","author":"Rashid","year":"2019","journal-title":"Arab. J. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.ejmech.2016.03.088","article-title":"Synthesis and in vitro evaluation of novel triazine analogues as anticancer agents and their interaction studies with bovine serum albumin","volume":"117","author":"Singla","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/S0301-472X(03)00083-3","article-title":"PARP-1, a determinant of cell survival in response to DNA damage","volume":"31","author":"Bouchard","year":"2003","journal-title":"Exp. Hematol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.molcel.2006.05.023","article-title":"Cell apoptosis: Requirement of H2AX in DNA ladder formation, but not for the activation of caspase-3","volume":"23","author":"Lu","year":"2006","journal-title":"Mol. Cell"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3041","DOI":"10.1021\/acs.jnatprod.0c00599","article-title":"Piperlonguminine and Piperine Analogues as TrxR Inhibitors that Promote ROS and Autophagy and Regulate p38 and Akt\/mTOR Signaling","volume":"83","author":"Zhu","year":"2020","journal-title":"J. Nat. Prod."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Elsebaie, H.A., El-Bastawissy, E.A., Elberembally, K.M., Khaleel, E.F., Badi, R.M., Shaldam, M.A., Eldehna, W.M., Tawfik, H.O., and El-Moselhy, T.F. (2023). Novel 4-(2-arylidenehydrazineyl)thienopyrimidine derivatives as anticancer EGFR inhibitors: Design, synthesis, biological evaluation, kinome selectivity and in silico insights. Bioorganic Chem., 140.","DOI":"10.1016\/j.bioorg.2023.106799"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Tawfik, H.O., Mousa, M.H.A., Zaky, M.Y., El-Dessouki, A.M., Sharaky, M., Abdullah, O., El-Hamamsy, M.H., and Al-Karmalawy, A.A. (2024). Rationale design of novel substituted 1,3,5-triazine candidates as dual IDH1(R132H)\/IDH2(R140Q) inhibitors with high selectivity against acute myeloid leukemia: In vitro and in vivo preclinical investigations. Bioorganic Chem., 149.","DOI":"10.1016\/j.bioorg.2024.107483"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2241674","DOI":"10.1080\/14756366.2023.2241674","article-title":"Recruitment of hexahydroquinoline as anticancer scaffold targeting inhibition of wild and mutants EGFR (EGFRWT, EGFRT790M, and EGFRL858R)","volume":"38","author":"Tawfik","year":"2023","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"7666","DOI":"10.1021\/acsomega.2c07285","article-title":"Terminators or Guardians? Design, Synthesis, and Cytotoxicity Profiling of Chalcone-Sulfonamide Hybrids","volume":"8","author":"Aboukhatwa","year":"2023","journal-title":"ACS Omega"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1080\/14756366.2022.2056734","article-title":"Novel 3-(6-methylpyridin-2-yl)coumarin-based chalcones as selective inhibitors of cancer-related carbonic anhydrases IX and XII endowed with antiproliferative activity","volume":"37","author":"Tawfik","year":"2022","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1423","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":"Eldehna","year":"2021","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"20438","DOI":"10.1021\/acs.jmedchem.4c01894","article-title":"4-(Pyrazolyl)benzenesulfonamide Ureas as Carbonic Anhydrases Inhibitors and Hypoxia-Mediated Chemo-Sensitizing Agents in Colorectal Cancer Cells","volume":"67","author":"Eldehna","year":"2024","journal-title":"J. Med. Chem."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"10558","DOI":"10.1021\/acs.jmedchem.3c00721","article-title":"1,5-Diaryl-1,2,4-triazole Ureas as New SLC-0111 Analogues Endowed with Dual Carbonic Anhydrase and VEGFR-2 Inhibitory Activities","volume":"66","author":"Elsawi","year":"2023","journal-title":"J. Med. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"113261","DOI":"10.1016\/j.ejmech.2021.113261","article-title":"Discovery of 4-alkoxy-2-aryl-6,7-dimethoxyquinolines as a new class of topoisomerase I inhibitors endowed with potent in vitro anticancer activity","volume":"215","author":"Elbadawi","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1126\/science.1204117","article-title":"Structural Basis of Type II Topoisomerase Inhibition by the Anticancer Drug Etoposide","volume":"333","author":"Wu","year":"2011","journal-title":"Science"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Eldehna, W.M., Mohamed, R., Elnagar, R.M., Giovannuzzi, S., Tayel, A., Abdulla, M.-H., Alhassan, N.S., Shaldam, M.A., Nocentini, A., and Supuran, C.T. (2025). Identification of isatin-triazole-benzenesulfonamide hybrids as dual hCA IX\/XII and c-met inhibitors with hypoxia-mediated chemo-sensitizing activity. Bioorganic Chem., 166.","DOI":"10.1016\/j.bioorg.2025.109071"},{"key":"ref_80","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_81","doi-asserted-by":"crossref","unstructured":"Abo-Kamar, A.M., Abdelaziz, A.A., Ashour, A.E., Shaldam, M.A., and Elekhnawy, E. (2025). Employing diclofenac sodium as a novel therapeutic frontier for Staphylococcus epidermidis infections. Sci. Rep., 15.","DOI":"10.1038\/s41598-025-14316-1"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/11\/1770\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T05:30:51Z","timestamp":1763789451000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/11\/1770"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,20]]},"references-count":81,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ph18111770"],"URL":"https:\/\/doi.org\/10.3390\/ph18111770","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,20]]}}}