{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T20:02:16Z","timestamp":1780084936147,"version":"3.54.0"},"reference-count":70,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Fraunhofer-Institut f\u00fcr Toxikologie und Experimentelle Medizin ITEM"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arch Toxicol"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    \u03b2-Nitrostyrene, an important intermediate in chemical industry, shows relevant anti-proliferative and pro-apoptotic potential and has thus been suggested for potential use in tumor chemotherapy. If not derivatized, \u03b2-nitrostyrene is however, highly reactive and possess (geno)toxic potential. To decipher structural elements relevant for biological activity, crucial for both, chemical risk assessment and potential drug development, a panel of nine structural derivatives of \u03b2-nitrostyrene, was put together. It included structures with and without nitrovinyl moiety and was based on fingerprint similarity, QSAR-based mutagenicity alerts, and literature reports. It comprised simple structures like styrene and more complex structures such as 2-methoxy-5-[(E)-2-nitroethenyl]phenol. In\u00a0vitro experiments in human WS1 and mouse L5178\/TK\n                    <jats:sup>\u00b1<\/jats:sup>\n                    cells demonstrated that the nitrovinyl moiety of \u03b2-nitrostyrene seems vital for its cytotoxic (membrane damage, metabolic competence) and genotoxic (clastogenicity, mutagenicity) properties. The extent of adversity varied with modification of structural elements. For example 1-nitro-2-[(E)-2-nitroethenyl]benzene led to 2.3-fold higher mean tail intensities in the alkaline comet assay than \u03b2-nitrostyrene. Notably, all derivatives with a nitrovinyl moiety, except 5-[(E)-2-nitroethenyl]-1,3-benzodioxole, induced DNA double-strand breaks, as judged by \u03b3H2A.X induction. In conclusion, our study identified structural elements responsible for the cyto- and genotoxic potential of \u03b2-nitrostyrene, demonstrating that minor structural changes can significantly alter its adverse biological activity.\n                  <\/jats:p>","DOI":"10.1007\/s00204-026-04349-4","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T09:44:33Z","timestamp":1774950273000},"page":"2647-2664","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The nitrovinyl moiety determines the cyto- and genotoxic profiles of \u03b2-nitrostyrene derivatives: evidence from in silico and in vitro evaluation"],"prefix":"10.1007","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8288-932X","authenticated-orcid":false,"given":"Jan","family":"S\u00fcndermann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9872-5613","authenticated-orcid":false,"given":"Stella Marie","family":"Reamon-Buettner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Wilde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1539-2871","authenticated-orcid":false,"given":"Annette","family":"Bitsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3238-5385","authenticated-orcid":false,"given":"Christina","family":"Ziemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,31]]},"reference":[{"issue":"9","key":"4349_CR1","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1007\/s10822-009-9285-0","volume":"23","author":"SM Arif","year":"2009","unstructured":"Arif SM, Holliday JD, Willett P (2009) Analysis and use of fragment-occurrence data in similarity-based virtual screening. J Comput Aided Mol des 23(9):655\u2013668. https:\/\/doi.org\/10.1007\/s10822-009-9285-0","journal-title":"J Comput Aided Mol des"},{"issue":"2\u20133","key":"4349_CR2","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/S1383-5718(97)00158-7","volume":"395","author":"N A\u00dfmann","year":"1997","unstructured":"A\u00dfmann N, Emmrich M, Kampf G, Kaiser M (1997) Genotoxic activity of important nitrobenzenes and nitroanilines in the Ames test and their structure-activity relationship. Mutat Res\/genet Toxicol Environ Mutagenesis 395(2\u20133):139\u2013144. https:\/\/doi.org\/10.1016\/S1383-5718(97)00158-7","journal-title":"Mutat Res\/genet Toxicol Environ Mutagenesis"},{"issue":"2","key":"4349_CR3","doi-asserted-by":"publisher","first-page":"149","DOI":"10.14573\/altex.1601251","volume":"33","author":"N Ball","year":"2016","unstructured":"Ball N, Cronin MTD, Shen J, Blackburn K, Booth ED, Bouhifd M, Donley E, Egnash L, Hastings C, Juberg DR, Kleensang A, Kleinstreuer N, Kroese ED, Lee AC, Luechtefeld T, Maertens A, Marty S, Naciff JM, Palmer J, Pamies D, Penman M, Richarz A-N, Russo DP, Stuard SB, Patlewicz G, van Ravenzwaay B, Wu S, Zhu H, Hartung T (2016) Toward Good Read-Across Practice (GRAP) guidance. Altex 33(2):149\u2013166. https:\/\/doi.org\/10.14573\/altex.1601251","journal-title":"Altex"},{"issue":"3","key":"4349_CR4","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0090586","volume":"9","author":"M Bartels","year":"2014","unstructured":"Bartels M, Calgarotto AK, Martens AC, Maso V, Da Silva SL, Bierings MB, de Souza Queiroz ML, Coffer PJ (2014) Differential effects of nitrostyrene derivatives on myelopoiesis involve regulation of C\/EBP\u03b1 and p38MAPK activity. PLoS ONE 9(3):e90586. https:\/\/doi.org\/10.1371\/journal.pone.0090586","journal-title":"PLoS ONE"},{"issue":"1","key":"4349_CR5","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1186\/s13321-024-00830-3","volume":"16","author":"D Boldini","year":"2024","unstructured":"Boldini D, Ballabio D, Consonni V, Todeschini R, Grisoni F, Sieber SA (2024) Effectiveness of molecular fingerprints for exploring the chemical space of natural products. J Cheminform 16(1):35. https:\/\/doi.org\/10.1186\/s13321-024-00830-3","journal-title":"J Cheminform"},{"issue":"3","key":"4349_CR6","doi-asserted-by":"publisher","first-page":"227","DOI":"10.3109\/10408448909037472","volume":"19","author":"JA Bond","year":"1989","unstructured":"Bond JA (1989) Review of the toxicology of styrene. Crit Rev Toxicol 19(3):227\u2013249. https:\/\/doi.org\/10.3109\/10408448909037472","journal-title":"Crit Rev Toxicol"},{"issue":"4024","key":"4349_CR7","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1038\/158876a0","volume":"158","author":"PW Brain","year":"1946","unstructured":"Brain PW, Grove JF, Mcgowan JC (1946) Fungistatic activity of ethylenic and acetylenic compounds. Nature 158(4024):876. https:\/\/doi.org\/10.1038\/158876a0","journal-title":"Nature"},{"issue":"2","key":"4349_CR8","doi-asserted-by":"publisher","first-page":"181","DOI":"10.2174\/1573406413666171002123907","volume":"14","author":"AJ Byrne","year":"2018","unstructured":"Byrne AJ, Bright SA, Fayne D, McKeown JP, McCabe T, Twamley B, Williams C, Meegan MJ (2018) Synthesis, antiproliferative and pro-apoptotic effects of nitrostyrenes and related compounds in Burkitt\u2019s lymphoma. Med Chem 14(2):181\u2013199. https:\/\/doi.org\/10.2174\/1573406413666171002123907","journal-title":"Med Chem"},{"issue":"24","key":"4349_CR9","doi-asserted-by":"publisher","first-page":"8095","DOI":"10.3390\/molecules28248095","volume":"28","author":"AJ Byrne","year":"2023","unstructured":"Byrne AJ, Bright SA, McKeown JP, Bergin A, Twamley B, McElligott AM, Noorani S, Kandwal S, Fayne D, O\u2019Boyle NM, Williams DC, Meegan MJ (2023) Synthesis and pro-apoptotic effects of nitrovinylanthracenes and related compounds in chronic lymphocytic leukaemia (CLL) and Burkitt\u2019s lymphoma (BL). Molecules 28(24):8095. https:\/\/doi.org\/10.3390\/molecules28248095","journal-title":"Molecules"},{"issue":"11","key":"4349_CR10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0166453","volume":"11","author":"W-C Chiu","year":"2016","unstructured":"Chiu W-C, Lee Y-C, Su Y-H, Wang Y-Y, Tsai C-H, Hou Y-A, Wang C-H, Huang Y-F, Huang C-J, Chou S-H, Hsieh P-W, Yuan S-SF (2016) The synthetic \u03b2-nitrostyrene derivative CYT-Rx20 inhibits esophageal tumor growth and metastasis via PI3K\/AKT and STAT3 pathways. PLoS ONE 11(11):e0166453. https:\/\/doi.org\/10.1371\/journal.pone.0166453","journal-title":"PLoS ONE"},{"issue":"2\u20133","key":"4349_CR11","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.tox.2006.06.001","volume":"226","author":"J-K Chung","year":"2006","unstructured":"Chung J-K, Yuan W, Liu G, Zheng J (2006) Investigation of bioactivation and toxicity of styrene in CYP2E1 transgenic cells. Toxicology 226(2\u20133):99\u2013106. https:\/\/doi.org\/10.1016\/j.tox.2006.06.001","journal-title":"Toxicology"},{"key":"4349_CR12","volume-title":"Nitrobenzene","author":"L Davies","year":"2003","unstructured":"Davies L (2003) Nitrobenzene. World Health Organization, Geneva"},{"issue":"2","key":"4349_CR13","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/0027-5107(77)90202-0","volume":"56","author":"C de Meester","year":"1977","unstructured":"de Meester C, Poncelet F, Roberfroid M, Rondelet J, Mercier M (1977) Mutagenicity of styrene and styrene oxide. Mutat Res\/fundam Mol Mech Mutagenesis 56(2):147\u2013152. https:\/\/doi.org\/10.1016\/0027-5107(77)90202-0","journal-title":"Mutat Res\/fundam Mol Mech Mutagenesis"},{"issue":"2","key":"4349_CR14","first-page":"81","volume":"30","author":"JC Dor\u00e9","year":"1995","unstructured":"Dor\u00e9 JC, Viel C (1995) Recherches en chimiotherapie antitumorale. X. Activit\u00e9 cytotoxique et antitumorale de beta-nitrostyr\u00e8nes et de compos\u00e9s nitrovinyliques d\u00e9riv\u00e9s. Il Farmaco; Edizione Scientifica 30(2):81\u2013109","journal-title":"Il Farmaco; Edizione Scientifica"},{"issue":"5","key":"4349_CR15","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1002\/1521-3935(20010301)202:5<689:AID-MACP689>3.0.CO;2-1","volume":"202","author":"MV Encinas","year":"2001","unstructured":"Encinas MV, Lissi EA, Jimenez S, Norambuena E (2001) \u03b2-nitrostyrene derivatives as inhibitors of the free radical polymerization. Macromol Chem Phys 202(5):689\u2013693. https:\/\/doi.org\/10.1002\/1521-3935(20010301)202:5%3c689:AID-MACP689%3e3.0.CO;2-1","journal-title":"Macromol Chem Phys"},{"key":"4349_CR16","doi-asserted-by":"publisher","unstructured":"European Chemicals Agency ECHA (2017) Read-across Assessment Framework (RAAF). https:\/\/doi.org\/10.2823\/619212.","DOI":"10.2823\/619212"},{"issue":"3","key":"4349_CR17","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1093\/carcin\/2.3.165","volume":"2","author":"ES Fiala","year":"1981","unstructured":"Fiala ES, Kohl NE, Hecht SS, Yang JJ, Shimada T, Fiala ES, Kohl NE, Hecht SS, Yang JJ, Shimada T (1981) The formation of azoxy-2-phenylethane during the biological oxidation of phenylethylamine by rabbit liver microsomes. Carcinogenesis 2(3):165\u2013173. https:\/\/doi.org\/10.1093\/carcin\/2.3.165","journal-title":"Carcinogenesis"},{"issue":"2","key":"4349_CR18","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/j.drudis.2016.11.024","volume":"22","author":"P Franco","year":"2017","unstructured":"Franco P, Porta N, Holliday JD, Willett P (2017) Molecular similarity considerations in the licensing of orphan drugs. Drug Discov Today 22(2):377\u2013381. https:\/\/doi.org\/10.1016\/j.drudis.2016.11.024","journal-title":"Drug Discov Today"},{"issue":"3","key":"4349_CR19","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1177\/1087057103262836","volume":"9","author":"F Gasparri","year":"2004","unstructured":"Gasparri F, Mariani M, Sola F, Galvani A (2004) Quantification of the proliferation index of human dermal fibroblast cultures with the ArrayScan high-content screening reader. J Biomol Screen 9(3):232\u2013243. https:\/\/doi.org\/10.1177\/1087057103262836","journal-title":"J Biomol Screen"},{"issue":"1","key":"4349_CR20","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1021\/cc9800071","volume":"1","author":"AK Ghose","year":"1999","unstructured":"Ghose AK, Viswanadhan VN, Wendoloski JJ (1999) A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J Combin Chem 1(1):55\u201368. https:\/\/doi.org\/10.1021\/cc9800071","journal-title":"J Combin Chem"},{"issue":"1","key":"4349_CR21","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/0165-7992(84)90118-0","volume":"139","author":"T Gichner","year":"1984","unstructured":"Gichner T, Velem\u00ednsk\u00fd J (1984) Inhibition of dimethylnitrosamine-induced mutagenesis in Arabidopsis thaliana by diethyldithiocarbamate and carbon monoxide. Mutat Res Fundam Mol Mech Mutagen 139(1):29\u201333. https:\/\/doi.org\/10.1016\/0165-7992(84)90118-0","journal-title":"Mutat Res Fundam Mol Mech Mutagen"},{"issue":"8","key":"4349_CR22","doi-asserted-by":"publisher","first-page":"742","DOI":"10.1038\/s43587-022-00263-3","volume":"2","author":"I Heckenbach","year":"2022","unstructured":"Heckenbach I, Mkrtchyan GV, Ezra MB, Bakula D, Madsen JS, Nielsen MH, Or\u00f3 D, Osborne B, Covarrubias AJ, Idda ML, Gorospe M, Mortensen L, Verdin E, Westendorp R, Scheibye-Knudsen M (2022) Nuclear morphology is a deep learning biomarker of cellular senescence. Nat Aging 2(8):742\u2013755. https:\/\/doi.org\/10.1038\/s43587-022-00263-3","journal-title":"Nat Aging"},{"issue":"21","key":"4349_CR23","doi-asserted-by":"publisher","first-page":"7621","DOI":"10.1016\/j.bmc.2010.08.039","volume":"18","author":"P-W Hsieh","year":"2010","unstructured":"Hsieh P-W, Chang Y-T, Chuang WY, Shih H-C, Chiang S-Z, Wu C-C (2010) The synthesis and biologic evaluation of anti-platelet and cytotoxic \u03b2-nitrostyrenes. Bioorg Med Chem 18(21):7621\u20137627. https:\/\/doi.org\/10.1016\/j.bmc.2010.08.039","journal-title":"Bioorg Med Chem"},{"issue":"2","key":"4349_CR24","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1080\/10590500701399234","volume":"25","author":"C-H Hsu","year":"2007","unstructured":"Hsu C-H, Stedeford T, Okochi-Takada E, Ushijima T, Noguchi H, Muro-Cacho C, Holder JW, Banasik M (2007) Framework analysis for the carcinogenic mode of action of nitrobenzene. J Environ Sci Health Part C Environ Carcinogenesis Ecotoxicol Rev 25(2):155\u2013184. https:\/\/doi.org\/10.1080\/10590500701399234","journal-title":"J Environ Sci Health Part C Environ Carcinogenesis Ecotoxicol Rev"},{"issue":"2","key":"4349_CR25","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/j.canlet.2015.11.035","volume":"371","author":"AC Hung","year":"2016","unstructured":"Hung AC, Tsai C-H, Hou M-F, Chang W-L, Wang C-H, Lee Y-C, Ko A, Hu SC-S, Chang F-R, Hsieh P-W, Yuan S-SF (2016) The synthetic \u03b2-nitrostyrene derivative CYT-Rx20 induces breast cancer cell death and autophagy via ROS-mediated MEK\/ERK pathway. Cancer Lett 371(2):251\u2013261. https:\/\/doi.org\/10.1016\/j.canlet.2015.11.035","journal-title":"Cancer Lett"},{"issue":"1","key":"4349_CR26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.2174\/1568011023354290","volume":"2","author":"MA Jordan","year":"2002","unstructured":"Jordan MA (2002) Mechanism of action of antitumor drugs that interact with microtubules and tubulin. Curr Med Chem Anti-Cancer Agents 2(1):1\u201317. https:\/\/doi.org\/10.2174\/1568011023354290","journal-title":"Curr Med Chem Anti-Cancer Agents"},{"issue":"4","key":"4349_CR27","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1016\/S0006-2952(02)01618-0","volume":"65","author":"S Kaap","year":"2003","unstructured":"Kaap S, Quentin I, Tamiru D, Shaheen M, Eger K, Steinfelder HJ (2003) Structure activity analysis of the pro-apoptotic, antitumor effect of nitrostyrene adducts and related compounds. Biochem Pharmacol 65(4):603\u2013610. https:\/\/doi.org\/10.1016\/S0006-2952(02)01618-0","journal-title":"Biochem Pharmacol"},{"issue":"8","key":"4349_CR28","doi-asserted-by":"publisher","first-page":"1983","DOI":"10.1007\/s00204-015-1599-1","volume":"90","author":"L Khoury","year":"2016","unstructured":"Khoury L, Zalko D, Audebert M (2016) Complementarity of phosphorylated histones H2AX and H3 quantification in different cell lines for genotoxicity screening. Arch Toxicol 90(8):1983\u20131995. https:\/\/doi.org\/10.1007\/s00204-015-1599-1","journal-title":"Arch Toxicol"},{"issue":"12","key":"4349_CR29","doi-asserted-by":"publisher","first-page":"989","DOI":"10.1016\/0278-6915(93)90008-M","volume":"31","author":"A Laires","year":"1993","unstructured":"Laires A, Gaspar J, Borba H, Proen\u00e7a M, Monteiro M, Rueff J (1993) Genotoxicity of nitrosated red wine and of the nitrosatable phenolic compounds present in wine: tyramine, quercetin and malvidine-3-glucoside. Food Chem Toxicol 31(12):989\u2013994. https:\/\/doi.org\/10.1016\/0278-6915(93)90008-M","journal-title":"Food Chem Toxicol"},{"key":"4349_CR30","first-page":"1176","volume":"6","author":"H-S Lee","year":"2004","unstructured":"Lee H-S, Kim S-Y, Lee C-H, Ahn Y-J (2004) Cytotoxic and mutagenic effects of cinnamomum cassia bark-derived materials. J Microbiol Biotechnol 6:1176\u20131181","journal-title":"J Microbiol Biotechnol"},{"issue":"1\u20133","key":"4349_CR31","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/S0169-409X(96)00423-1","volume":"23","author":"CA Lipinski","year":"1997","unstructured":"Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 23(1\u20133):3\u201325. https:\/\/doi.org\/10.1016\/S0169-409X(96)00423-1","journal-title":"Adv Drug Deliv Rev"},{"key":"4349_CR32","doi-asserted-by":"publisher","first-page":"1378","DOI":"10.3389\/fonc.2020.01378","volume":"10","author":"H Liu","year":"2020","unstructured":"Liu H, Xu Y, Liang K, Liu R (2020) Immune cells combined with NLRP3 inflammasome inhibitor exert better antitumor effect on pancreatic ductal adenocarcinoma. Front Oncol 10:1378. https:\/\/doi.org\/10.3389\/fonc.2020.01378","journal-title":"Front Oncol"},{"key":"4349_CR33","doi-asserted-by":"publisher","unstructured":"Mac\u016frek L, Lindqvist A, Voets O, Kool J, Vos HR, Medema RH (2010) Wip1 phosphatase is associated with chromatin and dephosphorylates gammaH2AX to promote checkpoint inhibition. Oncogene 29(15):2281\u20132291. https:\/\/doi.org\/10.1038\/onc.2009.501","DOI":"10.1038\/onc.2009.501"},{"issue":"8","key":"4349_CR34","doi-asserted-by":"publisher","first-page":"3186","DOI":"10.1021\/jm401411z","volume":"57","author":"G Maggiora","year":"2014","unstructured":"Maggiora G, Vogt M, Stumpfe D, Bajorath J (2014) Molecular similarity in medicinal chemistry. J Med Chem 57(8):3186\u20133204. https:\/\/doi.org\/10.1021\/jm401411z","journal-title":"J Med Chem"},{"issue":"5470","key":"4349_CR35","doi-asserted-by":"publisher","first-page":"1425","DOI":"10.1126\/science.288.5470.1425","volume":"288","author":"N Mailand","year":"2000","unstructured":"Mailand N, Falck J, Lukas C, Sylju\u00e2sen RG, Welcker M, Bartek J, Lukas J (2000) Rapid destruction of human Cdc25A in response to DNA damage. Science 288(5470):1425\u20131429. https:\/\/doi.org\/10.1126\/science.288.5470.1425","journal-title":"Science"},{"issue":"3","key":"4349_CR36","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/S0300-483X(97)00151-0","volume":"124","author":"G Malich","year":"1997","unstructured":"Malich G, Markovic B, Winder C (1997) The sensitivity and specificity of the MTS tetrazolium assay for detecting the in vitro cytotoxicity of 20 chemicals using human cell lines. Toxicology 124(3):179\u2013192. https:\/\/doi.org\/10.1016\/S0300-483X(97)00151-0","journal-title":"Toxicology"},{"issue":"8","key":"4349_CR37","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.3390\/ph17081034","volume":"17","author":"JP McKeown","year":"2024","unstructured":"McKeown JP, Byrne AJ, Bright SA, Charleton CE, Kandwal S, \u010cmelo I, Twamley B, McElligott AM, Fayne D, O\u2019Boyle NM, Williams DC, Meegan MJ (2024) Synthesis and biochemical evaluation of ethanoanthracenes and related compounds: antiproliferative and pro-apoptotic effects in chronic lymphocytic leukemia (CLL). Pharmaceuticals (Basel, Switzerland) 17(8):1034. https:\/\/doi.org\/10.3390\/ph17081034","journal-title":"Pharmaceuticals (Basel, Switzerland)"},{"issue":"12","key":"4349_CR38","doi-asserted-by":"publisher","first-page":"4078","DOI":"10.1016\/j.bmc.2006.02.006","volume":"14","author":"N Milhazes","year":"2006","unstructured":"Milhazes N, Calheiros R, Marques MPM, Garrido J, Cordeiro MNDS, Rodrigues C, Quinteira S, Novais C, Peixe L, Borges F (2006) Beta-nitrostyrene derivatives as potential antibacterial agents: a structure-property-activity relationship study. Bioorg Med Chem 14(12):4078\u20134088. https:\/\/doi.org\/10.1016\/j.bmc.2006.02.006","journal-title":"Bioorg Med Chem"},{"issue":"23","key":"4349_CR39","doi-asserted-by":"publisher","first-page":"8073","DOI":"10.1016\/j.bmc.2006.07.035","volume":"14","author":"R Mohan","year":"2006","unstructured":"Mohan R, Rastogi N, Namboothiri INN, Mobin SM, Panda D (2006) Synthesis and evaluation of \u03b1-hydroxymethylated conjugated nitroalkenes for their anticancer activity: inhibition of cell proliferation by targeting microtubules. Bioorg Med Chem 14(23):8073\u20138085. https:\/\/doi.org\/10.1016\/j.bmc.2006.07.035","journal-title":"Bioorg Med Chem"},{"issue":"40","key":"4349_CR40","doi-asserted-by":"publisher","first-page":"14244","DOI":"10.1073\/pnas.0506252102","volume":"102","author":"L Monaco","year":"2005","unstructured":"Monaco L, Kolthur-Seetharam U, Loury R, Murcia JM, de Murcia G, Sassone-Corsi P (2005) Inhibition of Aurora-B kinase activity by poly(ADP-ribosyl)ation in response to DNA damage. Proc Natl Acad Sci USA 102(40):14244\u201314248. https:\/\/doi.org\/10.1073\/pnas.0506252102","journal-title":"Proc Natl Acad Sci USA"},{"issue":"17","key":"4349_CR41","doi-asserted-by":"publisher","first-page":"12935","DOI":"10.1074\/jbc.M109.071696","volume":"285","author":"S-H Moon","year":"2010","unstructured":"Moon S-H, Lin L, Zhang X, Nguyen T-A, Darlington Y, Waldman AS, Lu X, Donehower LA (2010) Wild-type p53-induced phosphatase 1 dephosphorylates histone variant gamma-H2AX and suppresses DNA double strand break repair. J Biol Chem 285(17):12935\u201312947. https:\/\/doi.org\/10.1074\/jbc.M109.071696","journal-title":"J Biol Chem"},{"issue":"1","key":"4349_CR42","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/em.20159","volume":"47","author":"MM Moore","year":"2006","unstructured":"Moore MM, Honma M, Clements J, Bolcsfoldi G, Burlinson B, Cifone M, Clarke J, Delongchamp R, Durward R, Fellows M, Gollapudi B, Hou S, Jenkinson P, Lloyd M, Majeska J, Myhr B, O\u2019Donovan M, Omori T, Riach C, San R, Stankowski LF, Thakur AK, van Goethem F, Wakuri S, Yoshimura I (2006) Mouse lymphoma thymidine kinase gene mutation assay: follow-up meeting of the International Workshop on Genotoxicity Testing--Aberdeen, Scotland, 2003--assay acceptance criteria, positive controls, and data evaluation. Environ Mol Mutagen 47(1):1\u20135. https:\/\/doi.org\/10.1002\/em.20159","journal-title":"Environ Mol Mutagen"},{"key":"4349_CR43","doi-asserted-by":"publisher","first-page":"bav087","DOI":"10.1093\/database\/bav087","volume":"205","author":"G Nicola","year":"2015","unstructured":"Nicola G, Berthold MR, Hedrick MP, Gilson MK (2015) Connecting proteins with drug-like compounds: Open source drug discovery workflows with BindingDB and KNIME. Database J Biol Databases Curation 205:bav087. https:\/\/doi.org\/10.1093\/database\/bav087","journal-title":"Database J Biol Databases Curation"},{"key":"4349_CR44","doi-asserted-by":"publisher","unstructured":"OECD (2016a) Test No. 489: in vivo Mammalian alkaline comet assay. https:\/\/doi.org\/10.1787\/20745788.","DOI":"10.1787\/20745788"},{"key":"4349_CR45","doi-asserted-by":"publisher","unstructured":"OECD (2016b) Test No. 490: in vitro mammalian cell gene mutation tests using the thymidine kinase gene. https:\/\/doi.org\/10.1787\/9789264264908-en.","DOI":"10.1787\/9789264264908-en"},{"key":"4349_CR46","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2022.113189","volume":"165","author":"EA Oyeniyi","year":"2022","unstructured":"Oyeniyi EA, Sorgi CA, Gardinassi LG, Azevedo LF, Adeyemi JA, Omotoso OT, Faccioli LH, Greggi Antunes LM, Barbosa F (2022) Phospholipids modifications, genotoxic and anticholinesterase effects of pepper fruit (Dennettia tripetala G. Baker) extract in Swiss mice. Food Chem Toxicol 165:113189. https:\/\/doi.org\/10.1016\/j.fct.2022.113189","journal-title":"Food Chem Toxicol"},{"issue":"4","key":"4349_CR47","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1602\/neurorx.2.4.541","volume":"2","author":"H Pajouhesh","year":"2005","unstructured":"Pajouhesh H, Lenz GR (2005) Medicinal chemical properties of successful central nervous system drugs. NeuroRx 2(4):541\u2013553. https:\/\/doi.org\/10.1602\/neurorx.2.4.541","journal-title":"NeuroRx"},{"issue":"8","key":"4349_CR48","doi-asserted-by":"publisher","first-page":"2009","DOI":"10.1038\/s41375-022-01614-0","volume":"36","author":"SB Panina","year":"2022","unstructured":"Panina SB, Pei J, Baran N, Tjahjono E, Patel S, Alatrash G, Konoplev S, Stolbov LA, Poroikov VV, Konopleva M, Kirienko NV (2022) Novel mitochondria-targeting compounds selectively kill human leukemia cells. Leukemia 36(8):2009\u20132021. https:\/\/doi.org\/10.1038\/s41375-022-01614-0","journal-title":"Leukemia"},{"issue":"2","key":"4349_CR49","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1002\/wcms.1240","volume":"6","author":"AB Raies","year":"2016","unstructured":"Raies AB, Bajic VB (2016) In silico toxicology: computational methods for the prediction of chemical toxicity. Wires Comput Mol Sci 6(2):147\u2013172. https:\/\/doi.org\/10.1002\/wcms.1240","journal-title":"Wires Comput Mol Sci"},{"key":"4349_CR50","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2022.114609","volume":"240","author":"A Ramzan","year":"2022","unstructured":"Ramzan A, Padder SA, Masoodi KZ, Shafi S, Tahir I, Rehman RU, Prasad R, Shah AH (2022) \u03b2-Nitrostyrene derivatives as broad range potential antifungal agents targeting fungal cell wall. Eur J Med Chem 240:114609. https:\/\/doi.org\/10.1016\/j.ejmech.2022.114609","journal-title":"Eur J Med Chem"},{"key":"4349_CR51","doi-asserted-by":"publisher","DOI":"10.1016\/j.mad.2020.111412","volume":"193","author":"SM Reamon-Buettner","year":"2021","unstructured":"Reamon-Buettner SM, Hackbarth A, Leonhardt A, Braun A, Ziemann C (2021) Cellular senescence as a response to multiwalled carbon nanotube (MWCNT) exposure in human mesothelial cells. Mech Ageing Dev 193:111412. https:\/\/doi.org\/10.1016\/j.mad.2020.111412","journal-title":"Mech Ageing Dev"},{"issue":"13","key":"4349_CR52","doi-asserted-by":"publisher","first-page":"6102","DOI":"10.1021\/acs.jmedchem.9b00355","volume":"62","author":"S Salillas","year":"2019","unstructured":"Salillas S, Al\u00edas M, Michel V, Mah\u00eda A, Luc\u00eda A, Rodrigues L, Bueno J, Galano-Frutos JJ, de Reuse H, Vel\u00e1zquez-Campoy A, Carrodeguas JA, Sostres C, Castillo J, A\u00ednsa JA, D\u00edaz-de-Villegas MD, Lanas \u00c1, Touati E, Sancho J (2019) Design, synthesis, and efficacy testing of Nitroethylene- and 7-Nitrobenzoxadiazol-based flavodoxin inhibitors against Helicobacter pylori drug-resistant clinical strains and in Helicobacter pylori-infected mice. J Med Chem 62(13):6102\u20136115. https:\/\/doi.org\/10.1021\/acs.jmedchem.9b00355","journal-title":"J Med Chem"},{"issue":"2","key":"4349_CR53","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1016\/S0027-5107(96)00227-8","volume":"373","author":"RD Storer","year":"1997","unstructured":"Storer RD, Kraynak AR, McKelvey TW, Elia MC, Goodrow TL, DeLuca JG (1997) The mouse lymphoma L5178Y Tk+\/\u2212 cell line is heterozygous for a codon 170 mutation in the p53 tumor suppressor gene. Mutat Res Fundam Mol Mech Mutagen 373(2):157\u2013165. https:\/\/doi.org\/10.1016\/S0027-5107(96)00227-8","journal-title":"Mutat Res Fundam Mol Mech Mutagen"},{"key":"4349_CR54","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2024.105622","author":"J S\u00fcndermann","year":"2024","unstructured":"S\u00fcndermann J, Bitsch A, Kellner R, Doll T (2024) Is read-across for chemicals comparable to medical device equivalence and where to use it for conformity assessment? Regul Toxicol Pharmacol. https:\/\/doi.org\/10.1016\/j.yrtph.2024.105622","journal-title":"Regul Toxicol Pharmacol"},{"issue":"2","key":"4349_CR55","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1080\/01480545.2016.1190740","volume":"40","author":"G Taner","year":"2017","unstructured":"Taner G, \u00d6zkan Vardar D, Aydin S, Ayta\u00e7 Z, Ba\u015faran A, Ba\u015faran N (2017) Use of in vitro assays to assess the potential cytotoxic, genotoxic and antigenotoxic effects of vanillic and cinnamic acid. Drug Chem Toxicol 40(2):183\u2013190. https:\/\/doi.org\/10.1080\/01480545.2016.1190740","journal-title":"Drug Chem Toxicol"},{"key":"#cr-split#-4349_CR56.1","unstructured":"The European Parliament and the Council of the European Union (2006) Regulation"},{"key":"#cr-split#-4349_CR56.2","unstructured":"(EC) No 1907\/2006 of the European Parliament and of the Council: concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), establishing a European Chemicals Agency, amending Directive 1999\/45\/EC and repealing Council Regulation (EEC) No 793\/93 and Commission Regulation"},{"key":"#cr-split#-4349_CR56.3","unstructured":"(EC) No 1488\/94 as well as Council Directive 76\/769\/EEC and Commission Directives 91\/155\/EEC, 93\/67\/EEC, 93\/105\/EC and 2000\/21\/EC"},{"key":"4349_CR57","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.lfs.2016.12.009","volume":"172","author":"C-H Tsai","year":"2017","unstructured":"Tsai C-H, Hsieh P-W, Lee Y-C, Wang C-H, Chiu W-C, Lu C-W, Wang Y-Y, Hu SC-S, Cheng T-L, Yuan S-SF (2017a) 3\u2019-Hydroxy-4\u2019-methoxy-\u03b2-methyl-\u03b2-nitrostyrene inhibits tumor growth through ROS generation and GSH depletion in lung cancer cells. Life Sci 172:19\u201326. https:\/\/doi.org\/10.1016\/j.lfs.2016.12.009","journal-title":"Life Sci"},{"issue":"11","key":"4349_CR58","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.14996","volume":"8","author":"C-H Tsai","year":"2017","unstructured":"Tsai C-H, Hung AC, Chen Y-Y, Chiu Y-W, Hsieh P-W, Lee Y-C, Su Y-H, Chang P-C, Chu-Sung HS, Yuan S-SF, Hu SC-S (2017b) 3\u2019-hydroxy-4\u2019-methoxy-\u03b2-methyl-\u03b2-nitrostyrene inhibits tumorigenesis in colorectal cancer cells through ROS-mediated DNA damage and mitochondrial dysfunction \/\/ 3\u2019-hydroxy-4\u2019-methoxy-\u03b2-methyl-\u03b2-nitrostyrene inhibits tumorigenesis in colorectal cancer cells through ROS-mediated DNA damage and mitochondrial dysfunction. Oncotarget 8(11):18106. https:\/\/doi.org\/10.18632\/oncotarget.14996","journal-title":"Oncotarget"},{"issue":"10","key":"4349_CR59","doi-asserted-by":"publisher","first-page":"1874","DOI":"10.1007\/s00044-020-02607-3","volume":"29","author":"SE Ugheighele","year":"2020","unstructured":"Ugheighele SE, Imafidon KE, Choudhary MI, Shakil A, Khan M, Sherwani ZA, Ul-Haq Z (2020) Anti-urease and cytotoxic activity of 1-Nitro-2-phenylethane and Nerolidol; Two major compounds isolated from the seeds of Dennettia tripetala. Med Chem Res 29(10):1874\u20131881. https:\/\/doi.org\/10.1007\/s00044-020-02607-3","journal-title":"Med Chem Res"},{"issue":"19","key":"4349_CR60","doi-asserted-by":"publisher","first-page":"1526","DOI":"10.1093\/jnci\/80.19.1526","volume":"80","author":"JM van Maanen","year":"1988","unstructured":"van Maanen JM, Ret\u00e8l J, de Vries J, Pinedo HM (1988) Mechanism of action of antitumor drug etoposide: A review. J Natl Cancer Inst 80(19):1526\u20131533. https:\/\/doi.org\/10.1093\/jnci\/80.19.1526","journal-title":"J Natl Cancer Inst"},{"issue":"1","key":"4349_CR61","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/S1383-5718(98)00019-9","volume":"413","author":"E Vock","year":"1998","unstructured":"Vock E, Lutz W, Hormes P, Hoffmann H, Vamvakasa S (1998) Discrimination between genotoxicity and cytotoxicity in the induction of DNA double-strand breaks in cells treated with etoposide, melphalan, cisplatin, potassium cyanide, Triton X-100, and \u03b3-irradiation. Mutat Res Genet Toxicol Environ Mutagen 413(1):83\u201394. https:\/\/doi.org\/10.1016\/S1383-5718(98)00019-9","journal-title":"Mutat Res Genet Toxicol Environ Mutagen"},{"issue":"3","key":"4349_CR62","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1016\/j.dental.2017.12.013","volume":"34","author":"J Volk","year":"2018","unstructured":"Volk J, Ziemann C, Leyhausen G, Geurtsen W (2018) Genotoxic and mutagenic potential of camphorquinone in L5178\/TK+\/- mouse lymphoma cells. Dent Mater 34(3):519\u2013530. https:\/\/doi.org\/10.1016\/j.dental.2017.12.013","journal-title":"Dent Mater"},{"issue":"6","key":"4349_CR63","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1002\/hed.24664","volume":"39","author":"Y-Y Wang","year":"2017","unstructured":"Wang Y-Y, Chen Y-K, Hsu Y-L, Chiu W-C, Tsai C-H, Hu SC-S, Hsieh P-W, Yuan S-SF (2017a) Synthetic \u03b2-nitrostyrene derivative CYT-Rx20 as inhibitor of oral cancer cell proliferation and tumor growth through glutathione suppression and reactive oxygen species induction. Head Neck 39(6):1055\u20131064. https:\/\/doi.org\/10.1002\/hed.24664","journal-title":"Head Neck"},{"issue":"6","key":"4349_CR64","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1007\/s00280-017-3330-9","volume":"79","author":"Y-Y Wang","year":"2017","unstructured":"Wang Y-Y, Chen Y-K, Hu SC-S, Hsu Y-L, Tsai C-H, Chi T-C, Huang W-L, Hsieh P-W, Yuan S-SF (2017b) CYT-Rx20 inhibits ovarian cancer cells in vitro and in vivo through oxidative stress-induced DNA damage and cell apoptosis. Cancer Chemother Pharmacol 79(6):1129\u20131140. https:\/\/doi.org\/10.1007\/s00280-017-3330-9","journal-title":"Cancer Chemother Pharmacol"},{"issue":"3","key":"4349_CR65","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1002\/mlf2.12135","volume":"3","author":"J Wang","year":"2024","unstructured":"Wang J, Yang J, Durairaj P, Wang W, Wei D, Tang S, Liu H, Wang D, Jia A-Q (2024) Discovery of \u03b2-nitrostyrene derivatives as potential quorum sensing inhibitors for biofilm inhibition and antivirulence factor therapeutics against Serratia marcescens. mLife 3(3):445\u2013458. https:\/\/doi.org\/10.1002\/mlf2.12135","journal-title":"mLife"},{"issue":"1","key":"4349_CR66","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1007\/s10495-006-0530-x","volume":"12","author":"JM Werner","year":"2007","unstructured":"Werner JM, Eger K, J\u00fcrgen Steinfelder H (2007) Comparison of the rapid pro-apoptotic effect of trans-beta-nitrostyrenes with delayed apoptosis induced by the standard agent 5-fluorouracil in colon cancer cells. Apoptosis 12(1):235\u2013246. https:\/\/doi.org\/10.1007\/s10495-006-0530-x","journal-title":"Apoptosis"},{"issue":"Suppl 21","key":"4349_CR67","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1002\/em.2850190603","volume":"19","author":"E Zeiger","year":"1992","unstructured":"Zeiger E, Anderson B, Haworth S, Lawlor T, Mortelmans K (1992) Salmonella mutagenicity tests: V. results from the testing of 311 chemicals. Environ Mol Mutagen 19(Suppl 21):2\u2013141. https:\/\/doi.org\/10.1002\/em.2850190603","journal-title":"Environ Mol Mutagen"},{"key":"4349_CR68","doi-asserted-by":"publisher","unstructured":"Ziemann C, Krau\u00df S, Brockmeyer H, Leonhardt U, Steinfelder HJ (2006) Abstracts of the 47th Spring Meeting, Deutsche Gesellschaft f\u00fcr experimentelle und klinische Pharmakologie und Toxikologie, 4-6 April 2006, Mainz, Germany: Involvement of Topoisomerase II inhibition in clastogenic activity of trans-\u03b2-nitrostyrene. Naunyn-Schmiedeberg\u2019s Arch Pharmacol 372(Suppl 1):13\u2013149. https:\/\/doi.org\/10.1007\/s00210-006-0059-0","DOI":"10.1007\/s00210-006-0059-0"}],"container-title":["Archives of Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00204-026-04349-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00204-026-04349-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00204-026-04349-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T19:32:22Z","timestamp":1780083142000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00204-026-04349-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,31]]},"references-count":70,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["4349"],"URL":"https:\/\/doi.org\/10.1007\/s00204-026-04349-4","relation":{},"ISSN":["0340-5761","1432-0738"],"issn-type":[{"value":"0340-5761","type":"print"},{"value":"1432-0738","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,31]]},"assertion":[{"value":"2 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 February 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 March 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors have no financial or proprietary interests in any material discussed in this article.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}