{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T16:15:47Z","timestamp":1790957747599,"version":"4.1.0"},"reference-count":36,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T00:00:00Z","timestamp":1675382400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Benzodiazepines that consist of one \u03b1- and one \u03b2-amino acid residues linked together in a seven-membered heterocyclic ring could be treated as small, rigid, cyclic dipeptides capable of exhibiting a wide range of biological activities. During our research on novel analogues of anthramycin, a tricyclic antibiotic benzodiazepine, we developed the synthesis of two benzodiazepine dimers, obtained through the cyclization of appropriate linear tripeptides. The synthesized compounds were tested on a panel of seven cancer and normal cell lines. The developed molecules exhibited promising cytotoxic activity against the lung cancer cell lines A549 and NCI-H1299 and the epidermoid carcinoma cell line A-431. Moreover, they showed significant selectivity compared to the reference cell lines (BJ\u2014human normal skin fibroblasts and MRC-5\u2014human normal lung cell line). When tested on two isogenic cell lines, HCT116 and HCT116p53\u2212\/\u2212 (colon cancer), contrary to cisplatin being used as a positive control, the obtained compounds showed a cytotoxic effect independent of the p53 protein status. For the above reasons, the obtained compounds can be considered a new group of promising anticancer agents, useful in the fight against p53-dependent drug resistance in cancers. They can also be treated as convenient, leading structures suitable for further optimization and searching for more active and selective molecules.<\/jats:p>","DOI":"10.3390\/biom13020291","type":"journal-article","created":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T02:57:32Z","timestamp":1675652252000},"page":"291","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Dimeric Benzodiazepines as Peptide Mimetics to Overcome p53-Dependent Drug Resistance of Tumors"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0734-9390","authenticated-orcid":false,"given":"El\u017cbieta","family":"Speina","sequence":"first","affiliation":[{"name":"Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcin","family":"Wilczek","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5104-2564","authenticated-orcid":false,"given":"Adam","family":"Mieczkowski","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"195","DOI":"10.2165\/00003495-198019030-00004","article-title":"Benzodiazepines: Clinical pharmacology and therapeutic use","volume":"19","author":"Bellantuono","year":"1980","journal-title":"Drugs"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"229","DOI":"10.2174\/13895575113139990081","article-title":"Recent development in [1,4]benzodiazepines as potent anticancer agents: A review","volume":"14","author":"Gill","year":"2014","journal-title":"Mini-Rev. Med. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1517\/13543784.2011.573477","article-title":"The development of pyrrolobenzodiazepines as antitumour agents","volume":"20","author":"Hartley","year":"2011","journal-title":"Expert Opin. Investig. Drugs."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.4155\/fmc.10.226","article-title":"1,4-Benzodiazepin-2-ones in medicinal chemistry","volume":"2","author":"Spencer","year":"2010","journal-title":"Future Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"453","DOI":"10.2174\/1570193X14666170511121927","article-title":"A Mini Review on Synthetic Approaches and Biological Activities of Benzodiazepines","volume":"14","author":"Verma","year":"2017","journal-title":"Mini-Rev. Org. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1016\/j.cclet.2009.12.002","article-title":"Evodiagenine and dievodiamine, two new indole alkaloids from Evodia rutaecarpa","volume":"21","author":"Wang","year":"2010","journal-title":"Chin. Chem. Lett."},{"key":"ref_7","unstructured":"Wang, Q.Z., Feng, X., Wang, M., Chen, Y., Shan, Y., Yin, M., Guan, F., Zhao, X.-Z., and Zhao, Y. (2013). Preparation Method and Activity of a New Indolequinazoline Alkaloid. (CN103288827B), China Patent."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1038\/s41467-019-09515-0","article-title":"A New Terminal Cyano Group-containing Benzodiazepine Alkaloid from the Mangrove Endophytic Fungus Penicillium sp","volume":"10","author":"Li","year":"2015","journal-title":"Nat. Prod. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/s13205-020-2081-1","article-title":"Endophytic Penicillium species and their agricultural, biotechnological, and pharmaceutical applications","volume":"10","author":"Toghueo","year":"2020","journal-title":"3 Biotech"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1042\/bj0570587","article-title":"Studies in the biochemistry of microorganisms. 93. Cyclopenin, a nitrogen-containing metabolic product of Penicillium cyclopium Westling","volume":"57","author":"Bracken","year":"1954","journal-title":"Biochem. J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1042\/bj0890196","article-title":"Studies in the Biochemistry of Micro-Organisms. 114. Viridicatol and Cyclopenol, Metabolites of Penicillium Viridicatum Westling and Penicillium Cyclopium Westling","volume":"89","author":"Birkinshaw","year":"1963","journal-title":"Biochem. J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1080\/14786419.2015.1033623","article-title":"A novel cyclic dipeptide from deep marine-derived fungus Aspergillus sp. SCSIOW2","volume":"30","author":"Zhou","year":"2016","journal-title":"Nat. Prod. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1016\/S0031-9422(00)83095-2","article-title":"Enzymatic synthesis of cyclopeptine intermediates in Penicillium cyclopium","volume":"24","author":"Gerlach","year":"1985","journal-title":"Phytochemistry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1002\/med.21803","article-title":"Isolation, chemistry, and biology of pyrrolo[1,4]benzodiazepine natural products","volume":"42","author":"Sakaine","year":"2022","journal-title":"Med. Res. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1055\/s-2006-957604","article-title":"Chemical constituents of Isatis indigotica","volume":"63","author":"Wu","year":"1997","journal-title":"Planta Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"602","DOI":"10.25135\/rnp.203.20.08.1766","article-title":"Benzodiazepine Derivatives from Marine-Derived Streptomyces cacaoi 14CM034","volume":"15","author":"Aksoy","year":"2021","journal-title":"Rec. Nat. Prod."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1248\/cpb.52.368","article-title":"Cycloanthranilylproline-derived constituents from a myxomycete Fuligo candida","volume":"52","author":"Nakatani","year":"2004","journal-title":"Chem. Pharm. Bull."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1159\/000220459","article-title":"Chemotherapeutic properities of anthramycin","volume":"11","author":"Grunberg","year":"1966","journal-title":"Chemotherapy"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2815","DOI":"10.1021\/cr100120f","article-title":"Synthesis of DNA-interactive pyrrolo[2,1-c][1,4]benzodiazepines (PBDs)","volume":"111","author":"Antonow","year":"2011","journal-title":"Chem. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6693","DOI":"10.1158\/0008-5472.CAN-03-2941","article-title":"SJG-136 (NSC 694501), a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumor activity: Part 1: Cellular pharmacology, in vitro and initial in vivo antitumor activity","volume":"64","author":"Hartley","year":"2004","journal-title":"Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6700","DOI":"10.1158\/0008-5472.CAN-03-2942","article-title":"SJG-136 (NSC 694501), a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumor activity: Part 2: Efficacy evaluations","volume":"64","author":"Alley","year":"2004","journal-title":"Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1002\/anie.201510610","article-title":"From Anthramycin to Pyrrolobenzodiazepine (PBD)-Containing Antibody-Drug Conjugates (ADCs)","volume":"56","author":"Mantaj","year":"2017","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Mieczkowski, A., Trzybi\u0144ski, D., Wilczek, M., Psurski, M., Bagi\u0144ski, M., Bieszczad, B., Mroczkowska, M., and Wo\u017aniak, K. (2017). (S)-2-(4-Chlorobenzoyl)-1,2,3,4-tetrahydrobenzo[e]pyrazino[1,2-a][1,4]diazepine-6,12(11H,12aH)-dione\u2014Synthesis and Crystallographic Studies. Molbank, 2017.","DOI":"10.3390\/M964"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1016\/j.bmcl.2018.01.034","article-title":"Novel (S)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4]benzodiazepine-6,12(2H,11H)-dione derivatives: Selective inhibition of MV-4-11 biphenotypic B myelomonocytic leukemia cells\u2019 growth is accompanied by reactive oxygen species overproduction and apoptosis","volume":"28","author":"Mieczkowski","year":"2018","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Bieszczad, B., Garbicz, D., Trzybi\u0144ski, D., Mielecki, D., Wo\u017aniak, K., Grzesiuk, E., and Mieczkowski, A. (2020). Unsymmetrically Substituted Dibenzo[b,f][1,5]-diazocine-6,12(5H,11H)dione-A Convenient Scaffold for Bioactive Molecule Design. Molecules, 25.","DOI":"10.3390\/molecules25040906"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Bieszczad, B., Garbicz, D., Trzybi\u0144ski, D., Dudek, M.K., Wo\u017aniak, K., Grzesiuk, E., and Mieczkowski, A. (2020). Unsymmetrically-Substituted 5,12-dihydrodibenzo[b,f][1,4]diazocine-6,11-dione Scaffold-A Useful Tool for Bioactive Molecules Design. Molecules, 25.","DOI":"10.3390\/molecules25122855"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"127493","DOI":"10.1016\/j.bmcl.2020.127493","article-title":"Synthesis, crystal structure and biological activity of novel analogues of tricyclic drugs","volume":"30","author":"Bieszczad","year":"2020","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e2000733","DOI":"10.1002\/cbdv.202000733","article-title":"Design and in Vitro Characterization of Tricyclic Benzodiazepine Derivatives as Potent and Selective Antileukemic Agents","volume":"18","author":"Mieczkowski","year":"2021","journal-title":"Chem. Biodivers."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Mieczkowski, A., Speina, E., Trzybi\u0144ski, D., Winiewska-Szajewska, M., Wi\u0144ska, P., Borsuk, E.M., Podsiad\u0142a-Bia\u0142osk\u00f3rska, M., Przygodzki, T., Drabikowski, K., and Sta\u0144czyk, L. (2021). Diketopiperazine-Based, Flexible Tadalafil Analogues: Synthesis, Crystal Structures and Biological Activity Profile. Molecules, 26.","DOI":"10.3390\/molecules26040794"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Bieszczad, B., Garbicz, D., \u015awitalska, M., Dudek, M.K., Warszycki, D., Wietrzyk, J., Grzesiuk, E., and Mieczkowski, A. (2021). Improved HDAC Inhibition, Stronger Cytotoxic Effect and Higher Selectivity against Leukemias and Lymphomas of Novel, Tricyclic Vorinostat Analogues. Pharmaceuticals, 14.","DOI":"10.20944\/preprints202105.0251.v1"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Bojarska, J., Mieczkowski, A., Ziora, Z.M., Skwarczy\u0144ski, M., Toth, I., Shalash, A.O., Parang, K., El-Mowafi, S.A., Mohammed, E.H.M., and Elnagdy, S. (2021). Cyclic Dipeptides: The Biological and Structural Landscape with Special Focus on the Anti-Cancer Proline-Based Scaffold. Biomolecules, 11.","DOI":"10.3390\/biom11101515"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"6507","DOI":"10.1038\/onc.2008.315","article-title":"The p53 family and programmed cell death","volume":"27","author":"Pietsch","year":"2008","journal-title":"Oncogene"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"703","DOI":"10.4161\/rna.20481","article-title":"The hallmarks of cancer: A long non-coding RNA point of view","volume":"9","author":"Gutschner","year":"2012","journal-title":"RNA Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1093\/carcin\/bgv028","article-title":"Mechanisms of environmental chemicals that enable the cancer hallmark of evasion of growth suppression","volume":"36","author":"Nahta","year":"2015","journal-title":"Carcinogenesis"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"219","DOI":"10.2131\/jts.45.219","article-title":"Pro-apoptotic functions of TRAF2 in p53-mediated apoptosis induced by cisplatin","volume":"45","author":"Tsuchida","year":"2020","journal-title":"J. Toxicol. Sci."},{"key":"ref_36","first-page":"165","article-title":"p53 gene status and chemosensitivity in ovarian cancer","volume":"14","author":"Kigawa","year":"2001","journal-title":"Hum. Cell"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/2\/291\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:23:45Z","timestamp":1760120625000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/2\/291"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,3]]},"references-count":36,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["biom13020291"],"URL":"https:\/\/doi.org\/10.3390\/biom13020291","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,3]]}}}