{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T10:16:18Z","timestamp":1771236978548,"version":"3.50.1"},"reference-count":40,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T00:00:00Z","timestamp":1769990400000},"content-version":"vor","delay-in-days":1,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Biochem &amp;amp; Molecular Tox"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The anticancer activity of a series of newly synthesized pyrrole derivatives was systematically evaluated in HeLa cervical cancer cells, focusing on their potential as tyrosine kinase inhibitors and modulators of the mTOR signaling pathway. This study builds on our previous synthetic work by investigating the biological effects of seven structurally characterized compounds (d1\u2013d7). Among them, compounds d1 and d3 exhibited the most potent cytotoxicity, with IC\u2085\u2080 values of 140.6\u2009\u03bcM and 366.4\u2009\u03bcM, respectively, after 48\u2009h of treatment. Both compounds significantly impaired cell cycle progression\u2014d1 induced S\u2010phase arrest, while d3 caused G1\u2010phase arrest\u2014and markedly suppressed cell migration in wound healing assays. Mechanistically, these effects were accompanied by reduced phosphorylation of p70S6K (Thr389, Ser421\/424) and increased p\u20104EBP1, indicating inhibition of mTORC1 signaling. These findings suggest that d1 and d3 are promising lead compounds with dual antiproliferative and anti\u2010migratory activity in cervical cancer, mediated through modulation of the PI3K\/Akt\/mTOR axis.<\/jats:p>","DOI":"10.1002\/jbt.70665","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T07:02:56Z","timestamp":1770102176000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Anticancer Properties of Newly Synthesized Pyrrole Derivatives as Potential Tyrosine Kinase Inhibitors"],"prefix":"10.1002","volume":"40","author":[{"given":"Meltem","family":"Kaya","sequence":"first","affiliation":[{"name":"Department of Chemistry \u0130zmir Institute of Technology \u0130zmir T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunus","family":"Kara","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Sciences Ataturk University Erzurum T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0282-4428","authenticated-orcid":false,"given":"G\u00fcl\u015fah","family":"\u015eanl\u0131\u2010Mohamed","sequence":"additional","affiliation":[{"name":"Department of Chemistry \u0130zmir Institute of Technology \u0130zmir T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,2,2]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/AOG.0b013e3181e4629f"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1042\/CS20050369"},{"issue":"1","key":"e_1_2_8_5_1","first-page":"A6","article-title":"HPV Vaccination: The Global Progress and Challenges","volume":"40","author":"Bruni L.","year":"2022","journal-title":"Vaccine"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1309748"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.18.01265"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)32470-X"},{"issue":"3","key":"e_1_2_8_9_1","first-page":"115","article-title":"Viruses and Human Cancer","volume":"79","author":"Liao J. B.","year":"2006","journal-title":"The Yale Journal of Biology and Medicine"},{"key":"e_1_2_8_10_1","article-title":"The PI3K\/AKT\/mTOR Pathway in Cervical Cancer: A Potential Therapeutic Target","volume":"2020","author":"Wang X.","year":"2020","journal-title":"BioMed Research International"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.02.004"},{"issue":"2","key":"e_1_2_8_12_1","first-page":"209","article-title":"Deadly Liaisons: mTOR Signaling and Human Disease","volume":"21","author":"Chen C. C.","year":"2009","journal-title":"Current Opinion in Cell Biology"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbapap.2009.12.001"},{"issue":"3","key":"e_1_2_8_14_1","first-page":"581","article-title":"Increased Phosphorylation of mTORC1 Targets 4EBP1 and p70S6K in Human Cervical Cancer Tissues","volume":"18","author":"Lu Y.","year":"2012","journal-title":"Pathology & Oncology Research"},{"issue":"5","key":"e_1_2_8_15_1","first-page":"453","article-title":"Pyrrole: A Biologically Active Heterocycle","volume":"23","author":"Alam M. M.","year":"2015","journal-title":"Saudi Pharmaceutical Journal: SPJ"},{"key":"e_1_2_8_16_1","first-page":"163","article-title":"Medicinal Chemistry of Pyrrole Derivatives: Current Developments","volume":"173","author":"Srivastava V. K.","year":"2019","journal-title":"European Journal of Medicinal Chemistry"},{"key":"e_1_2_8_17_1","article-title":"Recent Advances in Pyrrole\u2010Based Anticancer Agents","volume":"94","author":"Jain S.","year":"2020","journal-title":"Bioorganic Chemistry"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.25864"},{"issue":"11","key":"e_1_2_8_19_1","first-page":"2606","article-title":"Design and SAR of Isoindole\u2010Fused Pyrrole Derivatives as Kinase Inhibitors","volume":"27","author":"Pal M.","year":"2018","journal-title":"Medicinal Chemistry Research"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2022.03.021"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seminoncol.2025.152374"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.2174\/9789815040043122020004"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2019.103421"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1759(83)90303-4"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1759(95)00072-I"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.990130802"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2007.30"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.4103\/1947-2714.100998"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-016-1787-7"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10495-016-1221-x"},{"issue":"3","key":"e_1_2_8_31_1","first-page":"482","article-title":"Novel Pyrrole\u2010Containing Histone Deacetylase Inhibitors Endowed With Cytodifferentiating Activity on Murine Erythroleukemia Cells","volume":"46","author":"Mai A.","year":"2004","journal-title":"Medicinal Chemistry (Sh\u0101riqah (United Arab Emirates))"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2019.103421"},{"issue":"10","key":"e_1_2_8_33_1","first-page":"712","article-title":"Tyrosine Kinase Inhibitors and Autophagy Resistance Mechanisms","volume":"11","author":"Kung H. J.","year":"2011","journal-title":"Nature Reviews Cancer"},{"issue":"23","key":"e_1_2_8_34_1","first-page":"37382","article-title":"Stellettin B Induces Autophagy and G1 Arrest via mTOR Inhibition in Cancer Cells","volume":"7","author":"Wang Y.","year":"2016","journal-title":"Oncotarget"},{"key":"e_1_2_8_35_1","first-page":"79","article-title":"Synthesis and Evaluation of Diindolylmethane Derivatives as Anticancer Agents","volume":"51","author":"Sharma R.","year":"2012","journal-title":"European Journal of Medicinal Chemistry"},{"issue":"2","key":"e_1_2_8_36_1","first-page":"242","article-title":"Monocrotaline Pyrrole Induces S Phase Arrest in Endothelial Cells","volume":"138","author":"Thomas D. A.","year":"1996","journal-title":"Toxicology and Applied Pharmacology"},{"issue":"1","key":"e_1_2_8_37_1","first-page":"24","article-title":"Pyrrole\u2010Imidazole Polyamides Inhibit Metastasis in HeLa Cells","volume":"295","author":"Wang C.","year":"2010","journal-title":"Cancer Letters"},{"issue":"1","key":"e_1_2_8_38_1","first-page":"7","article-title":"PI3K\/mTOR Pathway in Cervical Cancer: Implications for Targeted Therapy","volume":"33","author":"Vici P.","year":"2014","journal-title":"Journal of Experimental & Clinical Cancer Research"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.017"},{"issue":"5","key":"e_1_2_8_40_1","first-page":"533","article-title":"mTOR as a Central Hub of Nutrient Signalling and Cell Fate","volume":"17","author":"Kim J.","year":"2015","journal-title":"Nature Cell Biology"},{"key":"e_1_2_8_41_1","first-page":"62","article-title":"mTOR Signaling in Cancer Metastasis: Mechanisms and Inhibitors","volume":"4","author":"Xie J.","year":"2019","journal-title":"Signal Transduction and Targeted Therapy"}],"container-title":["Journal of Biochemical and Molecular Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jbt.70665","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jbt.70665","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jbt.70665","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T09:33:45Z","timestamp":1771234425000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jbt.70665"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2]]},"references-count":40,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,2]]}},"alternative-id":["10.1002\/jbt.70665"],"URL":"https:\/\/doi.org\/10.1002\/jbt.70665","archive":["Portico"],"relation":{},"ISSN":["1095-6670","1099-0461"],"issn-type":[{"value":"1095-6670","type":"print"},{"value":"1099-0461","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2]]},"assertion":[{"value":"2025-06-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-19","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-02","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70665"}}