{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T06:21:44Z","timestamp":1770272504573,"version":"3.49.0"},"reference-count":42,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T00:00:00Z","timestamp":1619049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Materials"],"abstract":"<jats:p>N-Heterocycles are considered as desirable scaffolds for the development of novel lead compounds for anticancer drug research. Among them, phosphorus-containing amino-derivatives play a crucial role. A series of imines and products of their further reactions with P-nucleophiles were obtained starting from vicinal bisamines. Reaction of ethylenediamine and \u03b1-carbonyl esters yielded in novel unexpected products, which structures were confirmed by crystallographic measurements. The cytotoxic activity evaluation was done on a variety of cell lines including HUH7, AKH12, DAOY, UW228-2, D283, D425, and U251. Human umbilical vein endothelial cells (HUVECs) were used as control. Two of the tested compounds, bearing TADDOL-derived, and trifluoromethyl substituents showed a significant effect on cell viability, though comparable to nonmalignant cells.<\/jats:p>","DOI":"10.3390\/ma14092138","type":"journal-article","created":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T13:59:14Z","timestamp":1619099954000},"page":"2138","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Cytotoxic Activity of Piperazin-2-One-Based Structures: Cyclic Imines, Lactams, Aminophosphonates, and Their Derivatives"],"prefix":"10.3390","volume":"14","author":[{"given":"Jakub","family":"Iwanejko","sequence":"first","affiliation":[{"name":"Faculty of Chemistry, Wroc\u0142aw University of Science and Technology, Wybrze\u017ce Wyspia\u0144skiego 27, 50-370 Wroc\u0142aw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0842-6578","authenticated-orcid":false,"given":"Mahzeiar","family":"Samadaei","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, AKH Vienna W\u00e4hringer G\u00fcrtel 18-20, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7260-532X","authenticated-orcid":false,"given":"Matthias","family":"Pinter","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, AKH Vienna W\u00e4hringer G\u00fcrtel 18-20, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Senfter","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Adolescent Medicine, Molecular Neuro-Oncology, Medical University of Vienna, AKH Vienna W\u00e4hringer G\u00fcrtel 18-20, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sibylle","family":"Madlener","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Adolescent Medicine, Molecular Neuro-Oncology, Medical University of Vienna, AKH Vienna W\u00e4hringer G\u00fcrtel 18-20, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrzej","family":"Kochel","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, University of Wroc\u0142aw, 14 F. 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Chem. Int. Ed."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1016\/j.tetasy.2006.04.023","article-title":"Enantioselective synthesis of (R)-(\u2212)-praziquantel (PZQ)","volume":"17","author":"Roszkowski","year":"2006","journal-title":"Tetrahedron Asymetry"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.5665\/sleep.3208","article-title":"Efficacy of vestipitant, a neurokinin-1 receptor antagonist, in primary insomnia","volume":"36","author":"Ratti","year":"2013","journal-title":"Sleep"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2293","DOI":"10.1021\/cr980440x","article-title":"Gadolinium(III) chelates as mri contrast agents: Structure, dynamics, and applications","volume":"99","author":"Caravan","year":"1999","journal-title":"Chem. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"751","DOI":"10.2174\/0929867053507379","article-title":"Gadolinium meets medicinal chemistry: MRI contrast agent development","volume":"12","author":"Zhang","year":"2005","journal-title":"Curr. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2252","DOI":"10.1016\/j.tetasy.2008.09.025","article-title":"Chelating 2-azanorbornyl derivatives as effective nitrogen\u2013nitrogen and nitrogen\u2013chalcogen donating ligands in palladium-catalyzed asymmetric allylic alkylation","volume":"19","year":"2008","journal-title":"Tetrahedron Asymmetry"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.tetasy.2010.12.011","article-title":"New 2-azanorbornyl derivatives: Chiral (N,N)-donating ligands for asymmetric catalysis","volume":"22","year":"2011","journal-title":"Tetrahedron Asymmetry"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.tetasy.2015.04.012","article-title":"\u03b1-Hydroxyphosphonic acid derivatives of 2-azanorbornane: Synthesis, DFT calculations, and crystal structure analysis","volume":"26","author":"Olszewski","year":"2015","journal-title":"Tetrahedron Asymmetry"},{"key":"ref_9","first-page":"162","article-title":"Chiral pyrrolidine thioethers and 2-azanorbornane derivatives bearing additional nitrogen functions. Enantiopure ligands for palladium-catalyzed Tsuji-Trost reaction","volume":"ii","year":"2017","journal-title":"Arkivoc"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6116","DOI":"10.1039\/C5OB00173K","article-title":"2-Azanorbornane\u2014A versatile chiral aza-Diels\u2013Alder cycloadduct: Preparation, applications in stereoselective synthesis and biological activity","volume":"13","author":"Kleniewska","year":"2015","journal-title":"Org. Biomol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/j.tetasy.2016.06.009","article-title":"Synthesis, structure and antiproliferative activity of chiral polyamines based on a 2-azanorbornane skeleton","volume":"27","author":"Wietrzyk","year":"2016","journal-title":"Tetrahedron Asymmetry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6619","DOI":"10.1016\/j.tetlet.2014.10.081","article-title":"Stereoselective preparation of chiral compounds in Mannich-type reactions of a bicyclic imine and phenols or indole","volume":"55","author":"Iwanejko","year":"2014","journal-title":"Tetrahedron Lett."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2276","DOI":"10.1016\/j.tet.2017.03.017","article-title":"New chiral Mannich adducts of di-tert-butylphenols and a bicyclic imine\u2014Synthesis and antiproliferative activity","volume":"73","author":"Iwanejko","year":"2017","journal-title":"Tetrahedron"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1016\/j.tet.2019.01.062","article-title":"Hydrophosphonylation of chiral hexahydroquinoxalin-2(1H)-one derivatives as an effective route to new bicyclic compounds: Aminophosphonates, enamines and imines","volume":"75","author":"Iwanejko","year":"2019","journal-title":"Tetrahedron"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7352","DOI":"10.1039\/C9OB01346F","article-title":"Aminophosphonates and aminophosphonic acids with tetrasubstituted stereogenic center: Diastereoselective synthesis from cyclic ketimines","volume":"17","author":"Iwanejko","year":"2019","journal-title":"Org. Biomol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1080\/10426509108029443","article-title":"Biological activity of aminophosphonic acids","volume":"63","author":"Kafarski","year":"1991","journal-title":"Phosphorus Sulfur Silicon Relat. Elem."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Iwanejko, J., Wojaczy\u0144ska, E., Turlej, E., Maciejewska, M., and Wietrzyk, J. (2020). Octahydroquinoxalin-2(1H)-one-based aminophosphonic acids and their derivatives\u2014biological activity towards cancer cells. Materials, 13.","DOI":"10.3390\/ma13102393"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1021\/acsmedchemlett.8b00473","article-title":"Identification of portimine B, a new cell permeable spiroimine that induces apoptosis in oral squamous cell carcinoma","volume":"10","author":"Fribley","year":"2019","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7098","DOI":"10.1039\/c2ob25875g","article-title":"Synthesis and antitumor activity of \u03b1-aminophosphonates containing thiazole[5,4-b]pyridine moiety","volume":"10","author":"Gu","year":"2012","journal-title":"Org. Biomol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"El Newahie, A.M.S., Nissan, Y.M., Ismail, N.S.M., El Ella, D.A.A., Khojah, S.M., and Abouzid, K.A.M. (2019). Design and synthesis of new quinoxaline derivatives as anticancer agents and apoptotic inducers. Molecules, 24.","DOI":"10.3390\/molecules24061175"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"112067","DOI":"10.1016\/j.ejmech.2020.112067","article-title":"Synthesis, mechanisms of action, and toxicity of novel aminophosphonates derivatives conjugated irinotecan in vitro and in vivo as potent antitumor agents","volume":"189","author":"Huang","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"10077","DOI":"10.1021\/acs.joc.7b01548","article-title":"Rationalization of benzazole-2-carboxylate versus benzazine-3-one\/benzazine-2,3-dione selectivity switch during cyclocondensation of 2-aminothiophenols\/phenols\/anilines with 1,2-biselectrophiles in aqueous medium","volume":"82","author":"Dhameliya","year":"2017","journal-title":"J. Org. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2312","DOI":"10.1007\/BF00954715","article-title":"Reaction of methyl esters of fluorine-containing \u03b1-keto acids with amines","volume":"32","author":"Saloutin","year":"1983","journal-title":"Bull. Acad. Sci. USSR Div. Chem. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3598","DOI":"10.1021\/acs.orglett.6b01609","article-title":"Solid phase synthesis of (benzannelated) six-membered heterocycles via cyclative cleavage of resin-bound pseudo-oxazolones","volume":"18","author":"Vanderheiden","year":"2016","journal-title":"Org. Lett."},{"key":"ref_25","unstructured":"Hayoz, P., and Ilg, S. (2013). Process for the Production of Strongly Adherent Coatings. (No. 8414982), U.S. Patent."},{"key":"ref_26","unstructured":"(2021, March 21). CrysAlis Pro. Available online: https:\/\/www.rigaku.com\/products\/crystallography\/crysalis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1107\/S0108767307043930","article-title":"A short history of SHELX","volume":"A64","author":"Sheldrick","year":"2008","journal-title":"Acta Cryst."},{"key":"ref_28","first-page":"3","article-title":"Crystal structure refinement with SHELXL","volume":"C71","author":"Sheldrick","year":"2008","journal-title":"Acta Cryst."},{"key":"ref_29","unstructured":"(2021, March 21). Diamond-Crystal and Molecular Structure Visualization. Available online: http:\/\/www.crystalimpact.com\/diamond."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/sj.bjc.6604440","article-title":"New cellular tools reveal complex epithelial-mesenchymal interactions in hepatocarcinogenesis","volume":"99","author":"Sagmeister","year":"2008","journal-title":"Br. J. Cancer."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1002\/mnfr.200700149","article-title":"Lipid hydroperoxides from processed dietary oils enhance growth of hepatocarcinoma cells","volume":"52","author":"Stolze","year":"2008","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1002\/jhet.2616","article-title":"Transition metal acetate promoted syntheses of some new n-heterocycles by multicomponent reactions","volume":"54","author":"Li","year":"2017","journal-title":"J. Heterocycl. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Samadaei, M., Pinter, M., Senfter, D., Madlener, S., Rohr-Udilova, N., Iwan, D., Kami\u0144ska, K., Wojaczy\u0144ska, E., Wojaczy\u0144ski, J., and Kochel, A. (2020). Synthesis and cytotoxic activity of chiral sulfonamides based on the 2-azanorbornane skeleton. Molecules, 25.","DOI":"10.3390\/molecules25102355"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1002\/ijc.29210","article-title":"Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012","volume":"136","author":"Ferlay","year":"2015","journal-title":"Int. J. Cancer."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/s41572-019-0063-6","article-title":"Medulloblastoma","volume":"5","author":"Northcott","year":"2019","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.jbiotec.2016.07.028","article-title":"In vitro models of medulloblastoma: Choosing the right tool for the job","volume":"236","author":"Ivanov","year":"2016","journal-title":"J. Biotechnol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3423","DOI":"10.21873\/anticanres.13487","article-title":"Pleiotropic chemotherapy to abrogate glioblastoma multiforme migration\/invasion","volume":"39","author":"Helson","year":"2019","journal-title":"Anticancer Res."},{"key":"ref_39","unstructured":"Wojaczy\u0144ska, E., Iwanejko, J., Olszewski, T.K., Grzywa, R., Sie\u0144czyk, M., Pyr\u0107, K., and Pachota, M. (2019). Zastosowanie Chiralnej Pochodnej (1R, 2R)-diaminocykloheksanu z Podstawnikiem Taddolowym. (PL P.429779), Patent No., submitted."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1021\/jm50003a001","article-title":"The Trifluoromethyl group in medical chemistry","volume":"1","author":"Yale","year":"1958","journal-title":"J. Med. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1039\/B610213C","article-title":"Fluorine in medicinal chemistry","volume":"37","author":"Purser","year":"2008","journal-title":"Chem. Soc. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2432","DOI":"10.1021\/cr4002879","article-title":"Fluorine in pharmaceutical industry: Fluorine-containing drugs introduced to the market in the last decade (2001\u20132011)","volume":"114","author":"Wang","year":"2014","journal-title":"Chem. Rev."}],"container-title":["Materials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1996-1944\/14\/9\/2138\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:51:33Z","timestamp":1760161893000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1996-1944\/14\/9\/2138"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,22]]},"references-count":42,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["ma14092138"],"URL":"https:\/\/doi.org\/10.3390\/ma14092138","relation":{},"ISSN":["1996-1944"],"issn-type":[{"value":"1996-1944","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,22]]}}}