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Article

Dimeric Benzodiazepines as Peptide Mimetics to Overcome p53-Dependent Drug Resistance of Tumors

1
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland
2
Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
*
Author to whom correspondence should be addressed.
Biomolecules 2023, 13(2), 291; https://doi.org/10.3390/biom13020291
Submission received: 15 December 2022 / Revised: 26 January 2023 / Accepted: 31 January 2023 / Published: 3 February 2023
(This article belongs to the Special Issue Nature Inspired Peptides in Medical Sciences)

Abstract

Benzodiazepines that consist of one α- and one β-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—human normal skin fibroblasts and MRC-5—human normal lung cell line). When tested on two isogenic cell lines, HCT116 and HCT116p53−/− (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.
Keywords: p53 protein; drug resistance; cytotoxicity; benzodiazepines; selectivity p53 protein; drug resistance; cytotoxicity; benzodiazepines; selectivity

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MDPI and ACS Style

Speina, E.; Wilczek, M.; Mieczkowski, A. Dimeric Benzodiazepines as Peptide Mimetics to Overcome p53-Dependent Drug Resistance of Tumors. Biomolecules 2023, 13, 291. https://doi.org/10.3390/biom13020291

AMA Style

Speina E, Wilczek M, Mieczkowski A. Dimeric Benzodiazepines as Peptide Mimetics to Overcome p53-Dependent Drug Resistance of Tumors. Biomolecules. 2023; 13(2):291. https://doi.org/10.3390/biom13020291

Chicago/Turabian Style

Speina, Elżbieta, Marcin Wilczek, and Adam Mieczkowski. 2023. "Dimeric Benzodiazepines as Peptide Mimetics to Overcome p53-Dependent Drug Resistance of Tumors" Biomolecules 13, no. 2: 291. https://doi.org/10.3390/biom13020291

APA Style

Speina, E., Wilczek, M., & Mieczkowski, A. (2023). Dimeric Benzodiazepines as Peptide Mimetics to Overcome p53-Dependent Drug Resistance of Tumors. Biomolecules, 13(2), 291. https://doi.org/10.3390/biom13020291

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