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

Sep 28, 2026

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Benzodiazepines built from one α- and one β-amino acid residue linked in a seven-membered heterocycle can act as small, rigid, cyclic dipeptide mimetics with diverse bioactivities. Using research on anthramycin-derived tricyclic benzodiazepines, two benzodiazepine dimers were synthesized by cyclizing suitable linear tripeptides and tested across seven cancer and normal cell lines. The compounds showed promising cytotoxicity in A549 and NCI-H1299 lung cancer cells and A-431 epidermoid carcinoma, with notable selectivity versus BJ and MRC-5 controls.

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Abstract

Background and natural benzodiazepine derivatives

Dimeric benzodiazepine synthesis and testing

biomolecules Article Dimeric Benzodiazepines as Peptide Mimetics to Overcome p53-Dependent Drug Resistance of Tumors Elbieta Speina 1, Marcin Wilczek 2 and Adam Mieczkowski 1, * Citation: Speina, E.; Wilczek, M.; Mieczkowski, A. Dimeric Benzodiazepines as Peptide Mimeticsto Overcome p53-Dependent Drug Resistance of Tumors. Biomolecules 2023, 13, 291. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/biom13020291](10.3390/biom13020291) Academic Editor: Gabriella D'Orazi Received: 15 December 2022 Revised: 26 January 2023 Accepted: 31 January 2023 Published: 3 February 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 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 * Correspondence: [amiecz@ibb.waw.pl](amiecz@ibb.waw.pl) Abstract: Benzodiazepines that consist of one 􀀋-and one 􀀌-amino acid residues linked together in aseven-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 1. Introduction Synthetic benzodiazepines and their analogues have found a wide range of applications as psychoactive [1] and anticancer [2,3] agents, and their biological activities have been further applied to other medical applications [4,5]. On the other hand, the naturally occurring sevenmembered, heterocyclic benzodiazepine derivatives were rarely isolated from natural sources. The naturally occurring benzodiazepine derivatives could be divided into the following two main groups: benzodiazepine alkaloids or benzodiazepine dipeptides. The first group includes the pentacyclic carbazole alkaloid evodiagenine (1), which is isolated from the fruits of Evodia rutaecarpa (Juss.) Benth. [6] and exhibits cytotoxic activity against Sarcoma 180 and Heps (liver cancer) cell lines [7]. Another example is the tetracyclic quinazoline alkaloid auranthine (2), which is isolated from the mangrove endophytic fungus Penicillium 299\# [8](Figure 1). This compound showed no cytotoxic activities in vitro against various human cancer (MDA-MB-435, HepG2, HCT-116, and Calu-3) and normal IKHE cell lines [8,9]. The second group contains a series of bicyclic benzodiazepines 3–6, which are isolated from various Penicillium strains and are composed of anthranilic

FAQs

How were the benzodiazepine dimer compounds synthesized?

Two benzodiazepine dimers were obtained through cyclization of appropriate linear tripeptides, derived from research on analogues of anthramycin.

Which cell lines showed cytotoxic activity and selectivity?

The compounds showed promising cytotoxic activity against lung cancer cell lines A549 and NCI-H1299 and epidermoid carcinoma A-431, and displayed significant selectivity compared with normal controls BJ and MRC-5.

What was the relationship between cytotoxic effect and p53 status?

When tested on HCT116 and HCT116 p53−/− isogenic pairs, the compounds produced a cytotoxic effect independent of p53 protein status, unlike cisplatin as the positive control.

Sep 28, 2026

Uploaded by ahduag