{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T20:30:07Z","timestamp":1772742607448,"version":"3.50.1"},"reference-count":33,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,4,21]],"date-time":"2021-04-21T00:00:00Z","timestamp":1618963200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["UMO-2014\/15\/B\/NZ7\/00966"],"award-info":[{"award-number":["UMO-2014\/15\/B\/NZ7\/00966"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Based on previously identified dicarboximides with significant anticancer and immunomodulatory activities, a series of 26 new derivatives were designed and synthesized by the Diels\u2013Alder reaction between appropriate diene and maleimide or hydroxymaleimide moieties. The resulting imides were functionalized with alkanolamine or alkylamine side chains and subsequently converted to their hydrochlorides. The structures of the obtained compounds were confirmed by 1H and 13C NMR and by ESI MS spectral analysis. Their cytotoxicity was evaluated in human leukemia (K562, MOLT4), cervical cancer (HeLa), and normal endothelial cells (HUVEC). The majority of derivatives exhibited high to moderate cytotoxicity and induced apoptosis in K562 cells. Microarray gene profiling demonstrated upregulation of proapoptotic genes involved in receptor-mediated and mitochondrial cell death pathways as well as antiapoptotic genes involved in NF-kB signaling. Selected dicarboximides activated JNK and p38 kinases in leukemia cells, suggesting that MAPKs may be involved in the regulation of apoptosis. The tested dicarboximides bind to DNA as assessed by a plasmid DNA cleavage protection assay. The selected dicarboximides offer new scaffolds for further development as anticancer drugs.<\/jats:p>","DOI":"10.3390\/ijms22094318","type":"journal-article","created":{"date-parts":[[2021,4,21]],"date-time":"2021-04-21T12:47:07Z","timestamp":1619009227000},"page":"4318","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["New Succinimides with Potent Anticancer Activity: Synthesis, Activation of Stress Signaling Pathways and Characterization of Apoptosis in Leukemia and Cervical Cancer Cells"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9628-214X","authenticated-orcid":false,"given":"Marcin","family":"Cie\u015blak","sequence":"first","affiliation":[{"name":"Centre of Molecular and Macromolecular Studies, Department of Bioorganic Chemistry, Polish Academy of Sciences, 112 Sienkiewicza, 90-363 Lodz, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1174-2208","authenticated-orcid":false,"given":"Mariola","family":"Napi\u00f3rkowska","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Medical University of Warsaw, 1 Banacha, 02-097 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8560-5727","authenticated-orcid":false,"given":"Julia","family":"Ka\u017amierczak-Bara\u0144ska","sequence":"additional","affiliation":[{"name":"Centre of Molecular and Macromolecular Studies, Department of Bioorganic Chemistry, Polish Academy of Sciences, 112 Sienkiewicza, 90-363 Lodz, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karolina","family":"Kr\u00f3lewska-Goli\u0144ska","sequence":"additional","affiliation":[{"name":"Centre of Molecular and Macromolecular Studies, Department of Bioorganic Chemistry, Polish Academy of Sciences, 112 Sienkiewicza, 90-363 Lodz, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8924-169X","authenticated-orcid":false,"given":"Anna","family":"Hawry\u0142","sequence":"additional","affiliation":[{"name":"Department of Inorganic Chemistry, Faculty of Pharmacy, Medical University of Lublin, Chod\u017aki 4a, 20-093 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iwona","family":"Wybra\u0144ska","sequence":"additional","affiliation":[{"name":"Clinical Biochemistry, Department of Genetics and Nutrigenomics, Faculty of Medicine, Jagiellonian University Medical College, 15a Kopernika, 31-501 Krak\u00f3w, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4084-4334","authenticated-orcid":false,"given":"Barbara","family":"Nawrot","sequence":"additional","affiliation":[{"name":"Centre of Molecular and Macromolecular Studies, Department of Bioorganic Chemistry, Polish Academy of Sciences, 112 Sienkiewicza, 90-363 Lodz, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,21]]},"reference":[{"key":"ref_1","unstructured":"Didkowska, J., Wojciechowska, U., and Zato\u0144ski, W. (2021, April 20). Prediction of Cancer Incidence and Mortality in Poland Up to the Year 2025. Warszawa 2009, ISSN 0867-8251. Available online: http:\/\/onkologia.org.pl\/wp-content\/uploads\/Prognozy_2025.pdf."},{"key":"ref_2","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_3","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/0753-3322(96)82631-X","article-title":"The cytotoxicity of N-pyridinyl and N-quinolinyl substituted derivatives of phthalimide and succinimide","volume":"49","author":"Hall","year":"1995","journal-title":"Biomed. Pharmacother."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.jfluchem.2014.09.019","article-title":"Synthesis and anticancer activity evaluation of 3,4-mono- and bicyclosubstituted N-(het)aryl trifluoromethyl succinimides","volume":"168","author":"Luzina","year":"2014","journal-title":"J. Fluor. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.bbrc.2014.04.035","article-title":"A novel cantharidin analog N-Benzylcantharidinamide reduces the expression of MMP-9 and invasive potentials of Hep3B via inhibiting cytosolic translocation of HuR","volume":"447","author":"Lee","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3626","DOI":"10.1016\/j.bmc.2008.02.005","article-title":"Synthesis and anti-cancer activity of benzothiazole containing phthalimide on human carcinoma cell lines","volume":"16","author":"Kok","year":"2008","journal-title":"Bioorg. Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.ejmech.2015.04.041","article-title":"Design, synthesis and structure\u2013activity relationship of phthalimides endowed with dual antiproliferative and immunomodulatory activities","volume":"96","author":"Cardoso","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.molmed.2017.02.006","article-title":"A Brighter Side to Thalidomide: Its Potential Use in Immunological Disorders","volume":"23","author":"Millrine","year":"2017","journal-title":"Trends Mol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"852","DOI":"10.2174\/1871520616666160223114318","article-title":"New, Substituted Derivatives of Dicarboximides and their Cytotoxic Properties","volume":"16","author":"Kuran","year":"2016","journal-title":"Anti-Cancer Agents Med. Chem."},{"key":"ref_10","unstructured":"Kuran, B., Krawiecka, M., Kossakowski, J., Cieslak, M., Kazmierczak-Baranska, J., Kr\u00f3lewska, K., and Nawrot, B. (2013). Dicarboximides Derivatives for Use in the Treatment of Cancer. (EP13176421), European Patent Application."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Cie\u015blak, M., Ka\u017amierczak-Bara\u0144ska, J., Kr\u00f3lewska-Goli\u0144ska, K., Napi\u00f3rkowska, M., Stukan, I., Wojda, U., and Nawrot, B. (2019). New Thalidomide-Resembling Dicarboximides Target ABC50 Protein and Show Antileukemic and Immunomodulatory Activities. Biomolecules, 9.","DOI":"10.3390\/biom9090446"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.ejphar.2004.08.053","article-title":"Biological evaluation of novel Pt(II) and Pd(II) complexes with pyrazole-containing ligands","volume":"502","author":"Budzisz","year":"2004","journal-title":"Eur. J. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"51","DOI":"10.2174\/157018009787158490","article-title":"Synthesis and Antitumor Activity of Novel 4-Chloro-3-Arylmaleimide Derivatives","volume":"6","author":"Xu","year":"2009","journal-title":"Lett. Drug Des. Discov."},{"key":"ref_14","unstructured":"Hsiang, Y.H., Jiang, J.B., and Liu, L.F. (1989). Topoisomerase II-mediated DNA cleavage by amonafide and its structural analogs. Mol. Pharmacol., 36."},{"key":"ref_15","unstructured":"Lipinski, C.A., Lombardo, F., Dominy, B.W., and Feeney, P.J. (2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 46."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1038\/nrd2445","article-title":"The influence of drug-like concepts on decision-making in medicinal chemistry","volume":"6","author":"Leeson","year":"2007","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"205","DOI":"10.15171\/apb.2019.024","article-title":"Understanding Apoptosis and Apoptotic Pathways Targeted Cancer Therapeutics","volume":"9","author":"Jan","year":"2019","journal-title":"Adv. Pharm. Bull."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3250","DOI":"10.1096\/fj.10-177527","article-title":"Triggering of a novel intrinsic apoptosis pathway by the kinase inhibitor staurosporine: Activation of caspase-9 in the absence of Apaf","volume":"25","author":"Manns","year":"2011","journal-title":"FASEB J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.coph.2004.02.006","article-title":"Targeting death receptors in cancer with Apo2L\/TRAIL","volume":"4","author":"Kelley","year":"2004","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.1016\/j.ejca.2011.06.003","article-title":"Death Receptor 5 and cellular FLICE-inhibitory protein regulate pemetrexed-induced apoptosis in human lung cancer cells","volume":"47","author":"Su","year":"2011","journal-title":"Eur. J. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"E5944","DOI":"10.1073\/pnas.1806973115","article-title":"Regulation of a distinct activated RIPK1 intermediate bridging complex I and complex II in TNF\u03b1-mediated apoptosis","volume":"115","author":"Amin","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.tibs.2018.11.002","article-title":"The Structural Basis of Necroptotic Cell Death Signaling","volume":"44","author":"Petrie","year":"2019","journal-title":"Trends Biochem. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.bbamcr.2010.12.019","article-title":"Molecular biology of Bax and Bak activation and action","volume":"1813","author":"Westphal","year":"2011","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Cell Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"11318","DOI":"10.1073\/pnas.201208798","article-title":"Expression of bbc3, a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signals","volume":"98","author":"Han","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1839","DOI":"10.1084\/jem.189.11.1839","article-title":"The IKK\u03b2 Subunit of I\u03baB Kinase (IKK) is Essential for Nuclear Factor \u03baB Activation and Prevention of Apoptosis","volume":"189","author":"Li","year":"1999","journal-title":"J. Exp. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1016\/S1097-2765(00)80262-2","article-title":"Female Mice Heterozygous for IKK\u03b3\/NEMO Deficiencies Develop a Dermatopathy Similar to the Human X-Linked Disorder Incontinentia Pigmenti","volume":"5","author":"Makris","year":"2000","journal-title":"Mol. Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3227","DOI":"10.1038\/sj.onc.1210414","article-title":"The ERK1\/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition","volume":"26","author":"Meloche","year":"2007","journal-title":"Oncogene"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6245","DOI":"10.1038\/onc.2008.301","article-title":"JNK signaling in apoptosis","volume":"27","author":"Dhanasekaran","year":"2008","journal-title":"Oncogene"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"44","DOI":"10.7150\/ijbs.5.44","article-title":"Non-Classical P38 Map Kinase Functions: Cell Cycle Checkpoints and Survival","volume":"5","author":"Thornton","year":"2009","journal-title":"Int. J. Biol. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1016\/j.bbamcr.2007.03.010","article-title":"p38 MAP-Kinases pathway regulation, function and role in human diseases","volume":"1773","author":"Cuenda","year":"2007","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Cell Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1002\/jcc.20309","article-title":"Accurate prediction of basicity in aqueous solution with COSMO-RS","volume":"27","author":"Eckert","year":"2005","journal-title":"J. Comput. Chem."},{"key":"ref_32","first-page":"459","article-title":"Proapoptotic activity of heterocyclic compounds containing succinimide moiety in the promyelocytic leukemia cell line HL-60","volume":"70","author":"Kuran","year":"2013","journal-title":"Acta Pol. Pharm. Drug Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S0021-9673(00)85726-X","article-title":"Gradient Elution in High performance Liquid Chromatography: II. Practical Application to Reversed-phase Systems","volume":"165","author":"Snyder","year":"1979","journal-title":"J. Chromatogr. 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