{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T22:13:43Z","timestamp":1760220823808,"version":"build-2065373602"},"reference-count":32,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2013,12,31]],"date-time":"2013-12-31T00:00:00Z","timestamp":1388448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>In this work, a sensitive analytical method to study the stability of two new series of synthesized heterocyclic compounds, the benzimidazole-4,7-diones 5 and  N-oxide benzimidazole-4,7-dione derivatives 6 was established and validated. These derivatives were developed as potential anticancer substances to be activated under hypoxic conditions. At this point we were concerned with establishing their stability in some specific environments for further biological studies. For that, we developed and validated an RP-UPLC method. Next, selected compounds were tested in vitro for possible anticancer activity. Their effect on A549 tumour cell lines under normoxia and hypoxia conditions was determined by a WST-1 test. Four of the examined compounds (compounds 5a\u2013c and 6c) showed very good antiproliferative effects and three of them (compounds 6a, 6b and 6d) were specific for hypoxia conditions. The hypoxia\/normoxia cytotoxic coefficient of compound 6b is close to that of tirapazamine\u2014a reference compound in our experiments\u2014and this parameter locates it between mitomycin C and 2-nitroimidazole (misonidazole).<\/jats:p>","DOI":"10.3390\/molecules19010400","type":"journal-article","created":{"date-parts":[[2013,12,31]],"date-time":"2013-12-31T11:18:16Z","timestamp":1388488696000},"page":"400-413","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Synthesis, Anticancer Activity and UPLC Analysis of the Stability of Some New Benzimidazole-4,7-dione Derivatives"],"prefix":"10.3390","volume":"19","author":[{"given":"Katarzyna","family":"B\u0142aszczak-\u015awi\u0105tkiewicz","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry and Drug Analysis, Medical University, Muszy\u0144skiego 1, \u0141\u00f3d\u017a 90-151, Poland"}]},{"given":"Diogo","family":"Almeida","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry and Therapeutics, Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, Lisboa 1649-003, Portugal"}]},{"given":"Maria","family":"Perry","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry and Therapeutics, Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, Lisboa 1649-003, Portugal"}]},{"given":"El\u017cbieta","family":"Mikiciuk-Olasik","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry and Drug Analysis, Medical University, Muszy\u0144skiego 1, \u0141\u00f3d\u017a 90-151, Poland"}]}],"member":"1968","published-online":{"date-parts":[[2013,12,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1016\/j.ejmech.2008.06.022","article-title":"Towards an efficient prodrug of the alkylating metabolite monomethyltriazene: Synthesis and stability of N-acylamino acid derivatives of triazenes","volume":"44","author":"Perry","year":"2009","journal-title":"Eur. J. Med. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/nrc3064","article-title":"Targeting hypoxia in cancer therapy","volume":"1","author":"Wilson","year":"2011","journal-title":"Nat. Rev. Can."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S1470-2045(00)00006-1","article-title":"The role of hypoxia-activated prodrugs in cancer therapy","volume":"1","author":"Denny","year":"2000","journal-title":"Lancet Oncol."},{"key":"ref_4","first-page":"2662","article-title":"Virus-directed, enzyme prodrug therapy with nitroimidazole reductase: A phase I and pharmacokinetic study of its prodrug, CB1954","volume":"7","author":"Palmer","year":"2001","journal-title":"Clin. Cancer. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/1074-5521(95)90120-5","article-title":"Mitomycin C: Small, fast and deadly (but very selective)","volume":"2","author":"Tomasz","year":"1995","journal-title":"Chem. Biol."},{"key":"ref_6","first-page":"5863","article-title":"The hypoxic cell: A target for selective cancer therapy\u2014Eighteenth Bruce F. Cain memorial award lecture","volume":"59","author":"Brown","year":"1999","journal-title":"Cancer Res."},{"key":"ref_7","first-page":"3992","article-title":"Unusual oxygen concentration dependence of toxicity of SR-4233, a hypoxic cell toxin","volume":"53","author":"Koch","year":"1993","journal-title":"Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1158\/0008-5472.CAN-03-2488","article-title":"Selective potentiation of the hypoxic cytotoxicity of Tirapazamine by its 1-N-oxide metabolite SR 4317","volume":"64","author":"Siim","year":"2004","journal-title":"Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/S0167-8140(97)00224-7","article-title":"Potentiation of cisplatin activity by the bioreductive agent tirapazamine","volume":"47","author":"Siemann","year":"1998","journal-title":"Radiother. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1016\/j.jinorgbio.2006.05.001","article-title":"Comparative studies on the mechanism of cytotoxic action of novel platinum II complexes with pyrazole ligands","volume":"100","author":"Ciesielska","year":"2006","journal-title":"J. Inorg. Biochem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1016\/j.ejmech.2008.05.014","article-title":"Cytotoxic activity and chemical reactivity of cis-platinum(II) and trans-palladium(II) complexes with diethyl (pyridinylmethyl)phosphates","volume":"44","author":"Szmigiero","year":"2009","journal-title":"Eur. J. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1016\/j.jinorgbio.2010.12.013","article-title":"Proapoptotic activity in vitro of two novel ruthenium(II) complexes with flavanone-based ligands that overcome cisplatin resistance in human bladder carcinoma cells","volume":"105","author":"Kasprzak","year":"2011","journal-title":"J. Inorg. Biochem."},{"key":"ref_13","first-page":"5714","article-title":"NLCQ-1 (NSC 709257): Exploiting hypoxia with a weak DNA-intercalating bioreductive drug","volume":"9","author":"Papadopoulou","year":"2003","journal-title":"Clin. Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1054\/bjoc.2000.1564","article-title":"AQ4N: A new approach to hypoxia-activated cancer chemotherapy","volume":"83","author":"Patterson","year":"2000","journal-title":"Br. J. Cancer"},{"key":"ref_15","first-page":"279","article-title":"New benzimidazole derivatives with potential cytotoxic activity\u2014Study of their stability by RP-HPLC","volume":"59","author":"Mirowski","year":"2012","journal-title":"Acta Biochim. Pol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/S0960-894X(00)00087-1","article-title":"Heterocyclic bibenzimidazole derivatives as topoisomerase I inhibitors","volume":"10","author":"Jin","year":"2000","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"561","DOI":"10.18388\/abp.2007_3229","article-title":"1H-Benzimidazole derivatives as mammalian DNA topoisomerase I inhibitors","volume":"54","author":"Alpan","year":"2007","journal-title":"Acta Biochim. Pol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2193","DOI":"10.1016\/S0960-894X(00)00429-7","article-title":"Synthesis and antiproliferative activity of some benzimidazole-4,7-dione derivatives","volume":"10","author":"Garuti","year":"2000","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1021\/jm00396a041","article-title":"Heterocyclic quinones with potential antitumor activity. Synthesis, antitumor activity of some benzimidazole-4,7-dione derivatives","volume":"31","author":"Antonini","year":"1988","journal-title":"J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.farmac.2004.04.001","article-title":"Differential antiproliferative activity of new benzimidazole-4,7-diones","volume":"59","author":"Garuti","year":"2004","journal-title":"Il Farmaco"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"9131","DOI":"10.1016\/j.tet.2004.07.070","article-title":"Efficient microwave-assisted synthesis of new sulfonylbenzimidazole-4,7-diones: Heterocyclic quinones with potential antitumor activity","volume":"60","author":"Boufatah","year":"2004","journal-title":"Tetrahedron"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2280","DOI":"10.1016\/j.ejmech.2008.06.018","article-title":"Synthesis and biological activity evaluation of 1H-benzimidazoles via mammalian DNA topoisomerase I and cytostaticity assays","volume":"44","author":"Coban","year":"2009","journal-title":"Eur. J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1080\/14756360701342516","article-title":"Some benzoxazoles and benzimidazoles as DNA topoisomerase I and II inhibitors","volume":"23","author":"Oksuzoglu","year":"2008","journal-title":"J. Enz. Inh. Med. Chem."},{"key":"ref_24","first-page":"45","article-title":"Inhibitory topoizomerazy I\u2014Unikalna grupa lek\u00f3w przeciwnowotworowych","volume":"7","year":"2003","journal-title":"Wsp\u00f3\u0142. Onko."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/j.ejmech.2010.11.046","article-title":"Synthesis and biological activity of novel inhibitors of topoisomerase I: 2-Aryl-substituted 2-bis-1H-benzimidazoles","volume":"46","author":"Singh","year":"2011","journal-title":"Eur. J. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"10131","DOI":"10.1021\/bi1009419","article-title":"A novel DNA topoisomerase I inhibitor with different mechanism from camptothecin induces G2\/M phase cell cycle arrest to K562 cells","volume":"49","author":"Wu","year":"2010","journal-title":"Biochemistry"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0014-827X(03)00042-9","article-title":"Some new bi- and ter-benzimidazole derivatives as topoisomerase Inhibitors","volume":"58","author":"Alper","year":"2003","journal-title":"II Farmaco"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1080\/14756360802420831","article-title":"Biological activity of bis-benzimidazole derivatives on DNA topoisomerase I and HeLa, MCF7 and A431 cells","volume":"24","author":"Alpan","year":"2009","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1080\/10826076.2011.582211","article-title":"Application of HPLC method for investigation of stability of new benzimidazole derivatives","volume":"34","year":"2011","journal-title":"J. Liq. Chrom. Rel. Tech."},{"key":"ref_30","first-page":"427","article-title":"Biological evaluation of activity of new benzimidazole derivatives","volume":"60","author":"Olszewska","year":"2013","journal-title":"Acta Biochim. Pol."},{"key":"ref_31","first-page":"239","article-title":"New derivatives of quinazoline and 1,2-dihydroquinazoline N3 \u2013oxide with expected antitumour acivity","volume":"5","author":"Krajewska","year":"2004","journal-title":"Arch. Pharm. Pharm. Med. Chem."},{"key":"ref_32","unstructured":"Vogel, A.I., and Furniss, B.S. (1978). Vogel\u2019s Textbook of Practical Chemistry Including Qualitative Organic, The English Language Book Society Analysis."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/19\/1\/400\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:51:45Z","timestamp":1760219505000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/19\/1\/400"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,12,31]]},"references-count":32,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2014,1]]}},"alternative-id":["molecules19010400"],"URL":"https:\/\/doi.org\/10.3390\/molecules19010400","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2013,12,31]]}}}